bluuebunny/crossref_metadata_2025 huggingface dataset:
Numerical Investigation on Pressure Fluctuations for Different Configurations of Vaned Diffuser Pumps
Authors: Feng Jianjun , Benra Friedrich-Karl , Dohmen Hans Josef
Published: April 2007

Numerical simulations on impeller-diffuser interactions in radial diffuser pumps are conducted to investigate the unsteady flow, and more attention is paid to pressure fluctuations on the blade and vane surfaces. Calculations are performed at different operating points, different blade number configurations, and different radial gaps between the impeller and diffuser to examine their effects on the unsteady flow. Computational results show that a jet-wake flow structure is observed at the impeller outlet. The biggest pressure fluctuation on the blade is found to occur at the impeller trailing edge, on the pressure side near the impeller trailing edge, and at the diffuser vane leading edge, independent of the flow rate, radial gap, and blade number configuration. All of the flow rate, blade number configuration, and radial gap influence significantly the pressure fluctuation and associated unsteady effects in the diffuser pumps.
Photostability of Uranine via Crossed‐Beam Thermal Lens Technique
Authors: Zein El-Din M. , Elsayed K. , Al-Sherbini S. M. , Harith M. A.
Published: April 2007

Uranine is a diagnostic aid in ophthalmology and is used as an immunohistological stain. A photostability study on this important compound using a crossed‐beam thermal lens (TL) technique was carried out. The study is based on the photodegradation (PD) behavior and rate regarding some experimental parameters such as the incident laser power, wavelength, modulation frequency, and sample concentration. The effects of such parameters on the TL signal and PD rate are discussed in details. It has been found that the PD rate is proportional to the power of the pumping laser and the concentration of the sample within the investigated range. However, the modulation frequency is found not to influence the PD rate. The photochemical quantum yield has been measured using potassium ferrioxalate actinometry and it was found to be very low.
Insulin-Like Growth Factor (IGF)-I and Insulin in Normal and Growth-Restricted Mother/Infant Pairs
Authors: Malamitsi-Puchner Ariadne , Briana Despina D. , Gourgiotis Dimitrios , Boutsikou Maria , Puchner Karl-Philipp , Baka Stavroula , Marmarinos Antonios , Hassiakos Dimitrios
Published: April 2007

Insulin-like growth factor (IGF)-I and insulin are essential for fetal growth. We investigated perinatal changes of both factors in 40 mothers and their 20 appropriate-for-gestational-age (AGA) and 20 intrauterine-growth-restricted (IUGR) fetuses and neonates on day 1 (N1) and day 4 (N4) postpartum. Fetal and N1, but not N4, IGF-I levels were increased in AGA (P<.001andP=.037, resp.). N1 insulin levels were lower in IUGR (P=.048). Maternal, fetal, and N1 IGF-I, and fetal insulin levels positively correlated with customized centiles (r=.374,P=.035,r=.608,P<.001,r=.485,P=.006, andr=.654,P=.021, resp.). Female infants presented elevated fetal and N4 IGF-I levels (P=.023andP=.016, resp.). Positive correlations of maternal, fetal, and neonatal IGF-I levels, and fetal insulin levels with customized centiles underline implication of both hormones in fetal growth. IUGR infants present gradually increasing IGF-I levels. Higher IGF-I levels are documented in females.
Iterative Approximation to Convex Feasibility Problems in Banach Space
Authors: Chang Shih-Sen , Yao Jen-Chih , Kim Jong Kyu , Yang Li
Published: April 2007

The convex feasibility problem (CFP) of finding a point in the nonempty intersection "Equation missing" is considered, where "Equation missing" is an integer and each "Equation missing" is assumed to be the fixed point set of a nonexpansive mapping "Equation missing", where "Equation missing" is a reflexive Banach space with a weakly sequentially continuous duality mapping. By using viscosity approximation methods for a finite family of nonexpansive mappings, it is shown that for any given contractive mapping "Equation missing", where "Equation missing" is a nonempty closed convex subset of "Equation missing" and for any given "Equation missing" the iterative scheme "Equation missing" is strongly convergent to a solution of (CFP), if and only if "Equation missing" and "Equation missing" satisfy certain conditions, where "Equation missing" and "Equation missing" is a sunny nonexpansive retraction of "Equation missing" onto "Equation missing". The results presented in the paper extend and improve some recent results in Xu (2004), O'Hara et al. (2003), Song and Chen (2006), Bauschke (1996), Browder (1967), Halpern (1967), Jung (2005), Lions (1977), Moudafi (2000), Reich (1980), Wittmann (1992), Reich (1994).
Protective Effect of VaginalLactobacillus paracaseiCRL 1289 against Urogenital Infection Produced byStaphylococcus aureusin a Mouse Animal Model
Authors: Zárate Gabriela , Santos Viviana , Nader-Macias María Elena
Published: April 2007

Urogenital infections of bacterial origin have a high incidence among the world female population at reproductive age. Lactobacilli, the predominant microorganisms of the healthy vaginal microbiota, have shown a protective effect against the colonization and overgrowth of urogenital pathogens that increased the interest for including them into probiotics products assigned to restore the urogenital balance. In the present work, we determined in a mouse animal model the capability ofLactobacillus paracaseiCRL 1289, a human vaginal strain with probiotic properties, to prevent the vaginal colonization of a uropathogenic strain ofStaphylococcus aureus. Six-week-old female BALB/c mice, synchronized in their estral cycle, were intravaginally inoculated with two doses of109lactobacilli before challenging them with a single dose of105or107CFU ofS. aureus. The vaginal colonization of both microorganisms and the effect on the vaginal structure were determined at 2, 5, and 7 days after pathogen inoculation. Control mice and those challenged only with the pathogen showed an insignificant lactobacilli population, whereas105lactobacilli/mL of vaginal homogenate were recovered at 2 days after challenge from theL. paracaseiCRL 1289 and the probiotic + pathogen groups, decreasing this number on the following days. The treatment withL. paracaseiCRL 1289 decreased significantly the number of staphylococci recovered at 2 and 5 days when mice were challenged only with105CFU of pathogen. The inoculation ofS. aureusproduced a remarkable inflammatory response and structural alterations in the vaginal mucosa that decreases in a significant manner when the mice were protected withL. paracaseiCRL 1289. The results obtained suggest that this particularLactobacillusstrain could prevent the onset of urogenital infections by interfering with the epithelial colonization by uropathogenicS. aureus.
Generalizations of Morphic Group Rings
Authors: Zan Libo , Chen Jianlong , Huang Qinghe
Published: April 2007

An elementain a ringRis called left morphic if there existsb∈Rsuch that1R(a)=Rband1R(b)=Ra.Ris called left morphic if every element ofRis left morphic. An elementain a ringRis called leftπ-morphic (resp., leftG-morphic) if there exists a positive integernsuch thatan(resp.,anwithan≠0) is left morphic.Ris called leftπ-morphic (resp., leftG-morphic) if every element ofRis leftπ-morphic (resp., leftG-morphic). In this paper, theG-morphic problem andπ-morphic problem of group rings are studied.
Lightlike Submanifolds of Indefinite Sasakian Manifolds
Authors: Duggal K. L. , Sahin B.
Published: April 2007

We first prove some results on invariant lightlike submanifolds of indefinite Sasakian manifolds. Then, we introduce a general notion of contact Cauchy-Riemann (CR) lightlike submanifolds and study the geometry of leaves of their distributions. We also study a class, namely, contact screen Cauchy-Riemann (SCR) lightlike submanifolds which include invariant and screen real subcases. Finally, we prove characterization theorems on the existence of contact SCR, screen real, invariant, and contact CR minimal lightlike submanifolds.
Fuzzy Entire Sequence Spaces
Authors: Kavikumar J. , Khamis Azme Bin , Kandasamy R.
Published: April 2007

We first investigate the notion of fuzzy entire sequence space with a suitable example. Also we deal with the properties of the space of fuzzy entire sequences. The concepts of subset and superset of the fuzzy entire sequence spaces are introduced and their properties are discussed.
CD40-CD40L Interaction in Immunity Against Protozoan Infections
Authors: Chamekh Mustapha
Published: April 2007

Activation of the immune system against protozoan infections relies particularly on two specific signals provided by cognate interaction of T cells with antigen presenting cells (APCs). The first signal is attributed to binding of the T-cell receptor (TCR) to peptide/MHC complexes on the surface of APCs, whereas the second signal is triggered through binding of several costimulatory molecules on the surface of APCs with their corresponding receptors on T cells. Among these costimulatory signallings, CD40/CD40L interactions have been particularly investigated in protozoan infection models with regard to their potential to amplify cell-mediated immunity against intracellular parasites. This article reviews current studies of the potential role of CD40/CD40L interaction in the modulation of immune responses against some protozoan parasites and highlights recent developments regarding manipulation of this interaction for promoting control of parasite infections.
Evaluation of Global RNA Amplification and Its Use for High-Throughput Transcript Analysis of Laser-Microdissected Endosperm
Authors: Day Robert C. , McNoe Les , Macknight Richard C.
Published: April 2007

Laser microdissection (LM) provides a useful method for isolating specific cells or tissues from biological samples. Here, we adapted microdissection protocols to allow high-resolution transcript analysis of different tissues from developing Arabidopsis seed. Sufficient RNA (∼50 ng) was extracted from endosperm tissue for RT-PCR. However, to obtain enough RNA for microarray analyses, it was necessary to amplify the RNA. PCR- and IVT-based amplification methods were investigated and several important technical aspects of amplification were identified (such as target truncation and alterations in signal intensity). We found that when starting from only 50 ng of RNA, amplification methods based on PCR and IVT produced sufficient product for reliable microarray hybridizations, with two-round IVT giving the best results. Microarray analyses, using endosperm-derived RNA amplified by two-round IVT, reproducibly identified endosperm enriched marker genes. Thus, when combined with RNA-amplification protocols, LM is a robust and reliable technique for high-throughput tissue-specific gene expression analysis.
Towards a Noninvasive Intracranial Tumor Irradiation Using 3D Optical Imaging and Multimodal Data Registration
Authors: Posada R. , Daul Ch. , Wolf D. , Aletti P.
Published: April 2007

Conformal radiotherapy (CRT) results in high‐precision tumor volume irradiation. In fractioned radiotherapy (FRT), lesions are irradiated in several sessions so that healthy neighbouring tissues are better preserved than when treatment is carried out in one fraction. In the case of intracranial tumors, classical methods of patient positioning in the irradiation machine coordinate system are invasive and only allow for CRT in one irradiation session. This contribution presents a noninvasive positioning method representing a first step towards the combination of CRT and FRT. The 3D data used for the positioning is point clouds spread over the patient′s head (CT‐data usually acquired during treatment) and points distributed over the patient′s face which are acquired with a structured light sensor fixed in the therapy room. The geometrical transformation linking the coordinate systems of the diagnosis device (CT‐modality) and the 3D sensor of the therapy room (visible light modality) is obtained by registering the surfaces represented by the two 3D point sets. The geometrical relationship between the coordinate systems of the 3D sensor and the irradiation machine is given by a calibration of the sensor position in the therapy room. The global transformation, computed with the two previous transformations, is sufficient to predict the tumor position in the irradiation machine coordinate system with only the corresponding position in the CT‐coordinate system. Results obtained for a phantom show that the mean positioning error of tumors on the treatment machine isocentre is 0.4 mm. Tests performed with human data proved that the registration algorithm is accurate (0.1 mm mean distance between homologous points) and robust even for facial expression changes.
Pneumococcal Meningitis during Pregnancy: A Case Report and Review of Literature
Authors: Landrum Lisa M. , Hawkins Angela , Goodman Jean Ricci
Published: April 2007

Background. Bacterial meningitis is a medical emergency for which prompt diagnosis and treatment are imperative to reducing the rate of death and long-term neurologic compromise. Few cases of meningitis have been reported during pregnancy, many of which had devastating outcomes for mother, neonate, or both.Case. A 38-year-old multigravida at 35 weeks of gestation presented with mental status changes, fever, and preterm contractions. Lumbar puncture revealed gram positive cocci consistent withS. pneumoniae. Patient was intubated and admitted to ICU where she was given antibiotics and adjunctive therapy with dexamethasone. Continuous fetal monitoring was utilized throughout her course of her hospitalization. Patient was discharged home after ten days in the hospital and had an uncomplicated vaginal birth after caesarean section (VBAC) at 38 weeks. Both she and the infant are doing well with no permanent neurologic sequelae.Conclusion. A review of literature indicates only isolated cases of pneumococcal meningitis being described during pregnancy. An extended period of time between onset of maternal illness and delivery appears to reduce the risk of neonatal transmission and improve both maternal and fetal outcomes.
Lower-Rim Substituted Calixarenes and Their Applications
Authors: Jose Princy , Menon Shobana
Published: April 2007

This review discusses in detail “calixarenes” since their discovery as by-products of the phenol formaldehyde bakelites till the present scenario wherein calixarene has assumed a new dimension in the field of supramolecular chemistry. Extensive literature exists for calixarenes; but herein we have tried to concentrate on the different lower-rim modified calixarenes with their potential applications. An attempt has also been made to critically evaluate the synthesis procedures for different lower-rim substituted calixarenes.
Construction of Planar Harmonic Functions
Authors: Jahangiri Jay M. , Silverman Herb , Silvia Evelyn M.
Published: April 2007

Complex-valued harmonic functions that are univalent and sense-preserving in the open unit disk can be written in the formf=h+g¯, wherehandgare analytic in the open unit disk. The functionshandgare called the analytic and coanalytic parts off, respectively. In this paper, we construct certain planar harmonic maps either by varying the coanalytic parts of harmonic functions that are known to be harmonic starlike or by adjoining analytic univalent functions with coanalytic parts that are related or derived from the analytic parts.
Experimental and Numerical Investigations of a Dual-Shaft Test Rig with Intershaft Bearing
Authors: Guskov M. , Sinou J.-J. , Thouverez F. , Naraikin O. S.
Published: April 2007

This paper deals with an experimental study of a dual rotor test rig. This machine, which was developed and built at the Laboratoire de Tribologie et Dynamique des Systèmes, Ecole Centrale de Lyon, will be first presented. It is composed of two coaxial shafts that are connected by an intershaft bearing and rotate independently, each one driven by its own motor. Their lateral vibrations and whirling motion are coupled by the intershaft bearing. The experimental tests consisting in run-ups and the associated measured unbalance response of the dual rotor will be investigated. The influence of the rotation of each rotor on the critical speeds and the associated amplitudes will be discussed. Moreover, this paper presents a numerical model of the dual rotor. Correlations between the experimental and numerical tests will be investigated. The objective is to be able to predict phenomena observed in experiments, starting from a rather fine numerical model.
Lp Solutions of BSDEs with Stochastic Lipschitz Condition
Authors: Wang Jiajie , Ran Qikang , Chen Qihong
Published: April 2007

We are concerned with the solutions of a special class of backward stochastic differential equations which are driven by a Brownian motion, where the uniform Lipschitz continuity is replaced by a stochastic one. We prove the existence and uniqueness of the solution in Lp with p>1.
NearS*-Compactness inL-Topological Spaces
Authors: Li Hong-Yan , Shi Fu-Gui
Published: April 2007

The notion of nearS*-compactness is introduced inL-topological spaces based onS*-compactness. Its properties are researched and the relations between it and other near compactness are obtained. Moreover many characterizations of nearS*-compactness are presented.
High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck
Authors: Veness Michael J.
Published: April 2007

Nonmelanoma skin cancers (squamous cell and basal cell carcinomas) occur at an epidemic rate in many countries with the worldwide incidence increasing. The sun-exposed head and neck are the most frequent sites for these cancers to arise and in most patients diagnosed with a cutaneous squamous cell carcinoma, local treatment is usually curative. However, a subset is diagnosed with a high-risk cutaneous squamous cell carcinoma. High-risk factors include size (> 2 cm), thickness/depth of invasion (> 4 mm), recurrent lesions, the presence of perineural invasion, location near the parotid gland, and immunosuppression. These patients have a higher risk (> 10–20%) of developing metastases to regional lymph nodes (often parotid nodes), and in some cases also of experiencing local morbidity (perineural invasion), based on unfavourable primary lesion and patient factors. Despite treatment, many patients developing metastatic cutaneous squamous cell carcinoma experience mortality and morbidity usually as a consequence of uncontrolled metastatic nodal disease. It is therefore important that clinicians treating nonmelanoma skin cancers have an understanding and awareness of these high-risk patients. The aim of this article is to discuss the factors that define a high-risk patient and to present some of the issues pertinent to their management.
Thermolabile Methylenetetrahydrofolate Reductase C677T Polymorphism and Homocysteine Are Risk Factors for Coronary Artery Disease in Moroccan Population
Authors: Bennouar Nawal , Allami Abdellatif , Azeddoug Houssine , Bendris Abdenbi , Laraqui Abdelilah , El Jaffali Amal , El Kadiri Nizar , Benzidia Rachid , Benomar Anwar , Fellat Seddik , Benomar Mohamed
Published: April 2007

Increased plasma total homocysteine (tHcy) levels have been shown to be a risk factor for coronary artery disease (CAD). The common methylenetetrahydrofolate reductase C677T (MTHFR C677T) polymorphism has been reported to be a strong predictor of mild hyperhomocysteinaemia (HHcy). We assessed whether this mutation was associated with increased risk of CAD and plasma levels of tHcy. We also evaluated interactions between this polymorphism, mild elevated tHcy levels and conventional risk factors of CAD.Method. Using PCR-RFLP analysis, we studied the frequency of the C677T genotypes and its effect on CAD and on tHcy concentrations in 400 subjects without and with CAD angiographically confirmed. There were 210 subjects with CAD and 190 subjects without CAD.Results. The frequencies of the C677T genotypes were 53%(59.5%in controls versus 48.1%in cases), 34.8%(32.1 in controls versus 37.1 in cases), and 11.8%(8.4%in controls versus 14.8%in cases), respectively, for 677CC, 677CT, and 677TT. The genotype frequencies were significantly different between case and control groups (P<.05). The 677T allele enhances the risk of CAD associated to HHcy (P<.01). In multivariate analysis models, MTHFR C677T polymorphism effect on CAD was masked by other risk factors. HHcy was only and independently influenced by MTHFR polymorphism and smoking habits, and it is a strong predictor of CAD independently of conventional risk factors.Conclusion. Our data suggest that HHcy is strongly and independently associated to CAD risk increase; and MTHFR C677T polymorphism and smoking habits were the main predictors of tHcy levels. The CAD risk increase is mainly associated with mild HHcy in 677TT, whereas in 677CT and 677CC it is mainly associated with the conventional risk factors.
PAI-1 is a Critical Upstream Regulator of the TGF-β1/EGF-Induced Invasive Phenotype in Mutant p53 Human Cutaneous Squamous Cell Carcinoma
Authors: Wilkins-Port Cynthia E. , Higgins Craig E. , Freytag Jennifer , Higgins Stephen P. , Carlson J. Andrew , Higgins Paul J.
Published: April 2007

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-βsynthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in acquisition of an invasive phenotype. TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs) in human SCC. Among the most prominent is MMP-10 which is known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also up-regulated under these conditions and is an early event in progression of incipient epidermal SCC. A model is proposed in which TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling mechanisms that maintain this elegant balance is critical to developing potential therapeutics for the treatment of human cutaneous malignancies.
Chaos Synchronization Criteria and Costs of Sinusoidally Coupled Horizontal Platform Systems
Authors: Cai Jianping , Wu Xiaofeng , Chen Shuhui
Published: April 2007

Some algebraic sufficient criteria for synchronizing two horizontal platform systems coupled by sinusoidal state error feedback control are derived by the Lyapunov stability theorem for linear time-varying system and Sylvester's criterion. The state variables are restricted in a subregion in order to obtain easily verified criteria. The validity of these algebraic criteria is illustrated with some numerical examples. A new concept, synchronization cost, is introduced based on a measure of the magnitude of the feedback control. The minimal synchronization cost as well as optimal coupling strength is calculated numerically. The results are meaningful in engineering application.
Best Possible Sufficient Conditions for Strong Law of Large Numbers for Multi-Indexed Orthogonal Random Elements
Authors: Su Kuo-Liang
Published: April 2007

It will be shown and induced that thed-dimensional indices in the Banach spaces version conditions∑n(E‖Xn‖p/|nα|p)<∞are sufficient to yieldlimmin1≤j≤d(nj)→∞(1/|nα|)∑k≤n∏j=1d(1−(kj−1)/nj)Xk=0a.s. for arrays of James-type orthogonal random elements. Particularly, it will be shown also that there are the best possible sufficient conditions for multi-indexed independent real-valued random variables.
Well-Posedness of the Boundary Value Problem for Parabolic Equations in Difference Analogues of Spaces of Smooth Functions
Authors: Ashyralyev A.
Published: April 2007

The first and second orders of accuracy difference schemes for the approximate solutions of the nonlocal boundary value problemv′(t)+Av(t)=f(t)(0≤t≤1),v(0)=v(λ)+μ,0<λ≤1, for differential equation in an arbitrary Banach spaceEwith the strongly positive operatorAare considered. The well-posedness of these difference schemes in difference analogues of spaces of smooth functions is established. In applications, the coercive stability estimates for the solutions of difference schemes for the approximate solutions of the nonlocal boundary value problem for parabolic equation are obtained.
Suppression of Base Excitation of Rotors on Magnetic Bearings
Authors: Marx Steven , Nataraj C.
Published: April 2007

This paper deals with rotor systems that suffer harmonic base excitation when supported on magnetic bearings. Magnetic bearings using conventional control techniques perform poorly in such situations mainly due to their highly nonlinear characteristics. The compensation method presented here is a novel optimal control procedure with a combination of conventional, proportional, and differential feedback control. A four-degree-of-freedom model is used for the rotor system, and the bearings are modeled by nonlinear expressions. Each disturbance frequency is expected to produce a multiharmonic system response, a characteristic of nonlinear systems. We apply optimal control choosing to minimize a performance index, which leads to the optimization of the trigonometric coefficients in the correction current function. Results show that the control technique suppresses rotor vibration to amplitudes that were significantly smaller than the disturbance amplitudes for the entire range of disturbance frequencies applied. The control technique explored in this paper is a promising step towards the successful application of magnetic bearings to systems mounted on moving platforms.
Increased Endothelin-1 Levels of BAL Fluid in Patients with Behçet's Disease
Authors: Hamzaoui Kamel , Chelbi Hanene , Kamoun Mariam , Ben Dhifallah Imen , Hamzaoui Agnes
Published: April 2007

Objective and background. Pulmonary aneurysms and thrombosis constitute a significant cause of morbidity and mortality in Behçet's disease (BD). Various factors have been studied to explore the pathogenesis of vascular involvement in BD. As endothelin (ET) is known for its potent vasoconstrictor and proinflammatory properties, we supposed that it is involved during the inflammatory process of BD pulmonary vasculitis.Methods. To investigate the role of ET in BD, ET-1 concentrations were measured in bronchoalveolar lavage fluid (BALF) of 18 nonsmoking BD patients with pulmonary manifestations and 12 control subjects. Immunoreactivity of ET-1 was also evaluated in alveolar macrophages (AMs) cytoplasm.Results. ET-1 levels in BD-BALF were significantly higher than those of controls. ET-1 levels were correlated with the number of alveolar macrophages, but not with BAL-CD4/CD8 ratio. ET-1-immunoreactivity was found mainly in AM of BD-BAL.Conclusions. Increased ET-1 production from AM is associated with pulmonary BD manifestations.
Therapeutic Potential of Retinoid X Receptor Modulators for the Treatment of the Metabolic Syndrome
Authors: Pinaire Jane A. , Reifel-Miller Anne
Published: April 2007

The increasing prevalence of obesity is a fundamental contributor to the growing prevalence of the metabolic syndrome. Rexinoids, a class of compounds that selectively bind and activate RXR, are being studied as a potential option for the treatment of metabolic syndrome. These compounds have glucose-lowering, insulin-sensitizing, and antiobesity effects in animal models of insulin resistance and type 2 diabetes. However, undesirable side effects such as hypertriglyceridemia and suppression of the thyroid hormone axis also occur. This review examines and compares the effects of four RXR-selective ligands: LGD1069, LG100268, AGN194204, and LG101506, a selective RXR modulator. Similar to selective modulators of other nuclear receptors such as the estrogen receptor (SERMs), LG101506 binding to RXR selectively maintains the desirable characteristic effects of rexinoids while minimizing the undesirable effects. These recent findings suggest that, with continued research efforts, RXR-specific ligands with improved pharmacological profiles may eventually be available as additional treatment options for the current epidemic of obesity, insulin resistance, type 2 diabetes, and all of the associated metabolic sequelae.
The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes
Authors: Carey Lisa A. , Dees E. Claire , Sawyer Lynda , Gatti Lisa , Moore Dominic T. , Collichio Frances , Ollila David W. , Sartor Carolyn I. , Graham Mark L. , Perou Charles M.
Published: April 2007

Purpose: Gene expression analysis identifies several breast cancer subtypes. We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes.

Experimental Design: We used immunohistochemical profiles [human epidermal growth factor receptor 2–positive (HER2+)/hormone receptor–negative for HER2+/estrogen receptor–negative (ER−), hormone receptor and HER2− for basal-like, hormone receptor–positive for luminal] to subtype a prospectively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based (doxorubicin plus cyclophosphamide, AC) chemotherapy. We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease–free survival and overall survival.

Results: Of the 107 patients tested, 34 (32%) were basal-like, 11 (10%) were HER2+/ER−, and 62 (58%) were luminal. After neoadjuvant AC, 75% received subsequent chemotherapy and all received endocrine therapy if hormone receptor–positive. The chemotherapy regimen and pretreatment stage did not differ by subtype. Clinical response to AC was higher among the HER2+/ER− (70%) and basal-like (85%) than the luminal subtypes (47%; P < 0.0001). Pathologic complete response occurred in 36% of HER2+/ER−, 27% of basal-like, and 7% of luminal subtypes (P = 0.01). Despite initial chemosensitivity, patients with the basal-like and HER2+/ER− subtypes had worse distant disease–free survival (P = 0.04) and overall survival (P = 0.02) than those with the luminal subtypes. Regardless of subtype, only 2 of 17 patients with pathologic complete response relapsed. The worse outcome among basal-like and HER+/ER− subtypes was due to higher relapse among those with residual disease (P = 0.003).

Conclusions: Basal-like and HER2+/ER− subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers. Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype. The poorer prognosis of basal-like and HER2+/ER− breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved.
Phase II Trials Published in 2002: A Cross-Specialty Comparison Showing Significant Design Differences between Oncology Trials and Other Medical Specialties
Authors: Michaelis Laura C. , Ratain Mark J.
Published: April 2007

Purpose: Phase II trials play an essential role in drug development pathway, and their conclusions often impact the decision to embark on large, pivotal trials. However, the determination of agent activity is highly dependent on trial design. Formal comparisons of phase II trial designs across medical specialties are uncommon. We hypothesized that there are significant differences in the design of trials conducted by oncologists and those conducted by other medical and surgical specialties.

Experimental Design: We screened MEDLINE for the abstracts of phase II trials published in 2002. All abstracts were analyzed and classified by a priori defined variables, including study type, intervention, subspecialty, journal impact factor, method of control, and study conclusions.

Results: Our search yielded 703 abstracts of phase II trials published in 2002. A total of 586/703 (83%) were trials on antineoplastic agents. Twenty percent (143/703) of the trials included explicit control subjects. Oncology trials, as compared with all trials done by other specialties, were significantly less likely to use control subjects (13% versus 56%, P < 0.001) and were less likely to conclude that the investigational intervention was safe and efficacious and/or worthy of additional investigation (76% versus 89%, P < 0.01).

Conclusions: There are significant differences in the phase II trials published in oncology compared with those conducted by other medical and surgical specialties. The impact that such differences have on the efficiency of drug development should be investigated.
The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2
Authors: Liu Weiguo , Baer Maria R. , Bowman Mary Jo , Pera Paula , Zheng Xiang , Morgan Janet , Pandey Ravindra A. , Oseroff Allan R.
Published: April 2007

Purpose: The ATP-binding cassette protein ABCG2 (breast cancer resistance protein) effluxes some of the photosensitizers used in photodynamic therapy (PDT) and, thus, may confer resistance to this treatment modality. Tyrosine kinase inhibitors (TKI) can block the function of ABCG2. Therefore, we tested the effects of the TKI imatinib mesylate (Gleevec) on photosensitizer accumulation and in vitro and in vivo PDT efficacy.

Experimental Design: Energy-dependent photosensitizer efflux and imatinib mesylate's effects on intracellular accumulation of clinically used second- and first-generation photosensitizers were studied by flow cytometry in murine and human cells with and without ABCG2 expression. Effects of ABCG2 inhibition on PDT were examined in vitro using cell viability assays and in vivo measuring photosensitizer accumulation and time to regrowth in a RIF-1 tumor model.

Results: Energy-dependent efflux of 2-(1-hexyloxethyl)-2-devinyl pyropheophorbide-a (HPPH, Photochlor), endogenous protoporphyrin IX (PpIX) synthesized from 5-aminolevulenic acid, and the benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin) was shown in ABCG2+ cell lines, but the first-generation multimeric photosensitizer porfimer sodium (Photofrin) and a novel derivative of HPPH conjugated to galactose were minimally transported. Imatinib mesylate increased accumulation of HPPH, PpIX, and BPD-MA from 1.3- to 6-fold in ABCG2+ cells, but not in ABCG2− cells, and enhanced PDT efficacy both in vitro and in vivo.

Conclusions: Second-generation clinical photosensitizers are transported out of cells by ABCG2, and this effect can be abrogated by coadministration of imatinib mesylate. By increasing intracellular photosensitizer levels in ABCG2+ tumors, imatinib mesylate or other ABCG2 transport inhibitors may enhance efficacy and selectivity of clinical PDT.
c-Kit/PDGFRA Gene Status Alterations Possibly Related to Primary Imatinib Resistance in Gastrointestinal Stromal Tumors
Authors: Miselli Francesca="C"> , Casieri Paola , Negri Tiziana , Orsenigo Marta , Lagonigro M. Stefania , Gronchi Alessandro , Fiore Marco , Casali Paolo G. , Bertulli Rossella , Carbone Antonino , Pierotti Marco A. , Tamborini Elena , Pilotti Silvana
Published: April 2007

Purpose: To correlate morphologic changes with molecular, biochemical, and cytogenetic profiles in gastrointestinal stromal tumor (GIST) patients before and after imatinib treatment.

Experimental Design: We investigated 132 tumor samples obtained from 35 patients with advanced disease who underwent resective surgery after imatinib treatment according to the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group protocol. On the basis of imaging findings, 27 patients were responders and 8 progressors, and retaining this radiological subdivision, we analyzed posttreatment morphologic changes correlating them with molecular, biochemical, and cytogenetic analyses.

Results: On the basis of morphology (residual viable cellularity/proliferation markers), three subgroups were identified showing high, moderate, or low response. All of the progressing cases clustered in the low-response subgroup, whereas the responding cases were distributed in all three subgroups. The correlation between morphology and the molecular findings showed that secondary mutations segregated with the low-response subgroup, whereas c-Kit primary resistance mutations were randomly distributed in the three subgroups. Fluorescence in situ hybridization analysis of c-Kit/PDGFRA genes showed that all of the progressing cases were disomic. Referring to morphology, among the responding cases, a disomic pattern was mainly restricted to the high responders, whereas the moderate and low responders were aneusomic. Comparison of post-imatinib genomic profiles with the 23 available primary tumors showed that 17 cases carried the same cytogenetic pattern. Overall, 12 of the 27 primary tumors presented a gain/loss of c-Kit/PDGFRA gene copy number.

Conclusions: Our findings show that c-Kit/PDGFRA genomic alterations were present at disease onset in 1/3 of the examined cases. They therefore represent an early event possibly related to primary imatinib resistance in GISTs.
Cholecystokinin Down-Regulation by RNA Interference Impairs Ewing Tumor Growth
Authors: Carrillo Jaime , García-Aragoncillo Eva , Azorín Daniel , Agra Noelia , Sastre Ana , González-Mediero Imelda , García-Miguel Purificación , Pestaña Ángel , Gallego Soledad , Segura Dolores , Alonso Javier
Published: April 2007

Purpose: Tumors of the Ewing family are characterized by chromosomal translocations that yield chimeric transcription factors, such as EWS/FLI1, which regulate the expression of specific genes that contribute to the malignant phenotype. In the present study, we show that cholecystokinin (CCK) is a new target of the EWS/FLI1 oncoprotein and assess its functional role in Ewing tumor pathogenesis.

Experimental Design: Relevant EWS/FLI1 targets were identified using a combination of cell systems with inducible EWS/FLI1 expression, Ewing tumors and cell lines, microarrays, and RNA interference with doxycycline-inducible small hairpin RNA (shRNA) vectors. A doxycycline-inducible CCK-shRNA vector was stably transfected in A673 and SK-PN-DW Ewing cell lines to assess the role of CCK in cell proliferation and tumor growth.

Results: Microarray analysis revealed that CCK was up-regulated by EWS/FLI1 in HeLa cells. CCK was overexpressed in Ewing tumors as compared with other pediatric malignancies such as rhabdomyosarcoma and neuroblastoma, with levels close to those detected in normal tissues expressing the highest levels of CCK. Furthermore, EWS/FLI1 knockdown in A673 and SK-PN-DW Ewing cells using two different doxycycline-inducible EWS/FLI1-specific shRNA vectors down-regulated CCK mRNA expression and diminished the levels of secreted CCK, showing that CCK is a EWS/FLI1 specific target gene in Ewing cells. A doxycycline-inducible CCK-specific shRNA vector successfully down-regulated CCK expression, reduced the levels of secreted CCK in Ewing cell lines, and inhibited cell growth and proliferation in vitro and in vivo. Finally, we show that Ewing cell lines and tumors express CCK receptors and that the growth inhibition produced by CCK silencing can be rescued by culturing the cells with medium containing CCK.

Conclusions: Our data support the hypothesis that CCK acts as an autocrine growth factor stimulating the proliferation of Ewing cells and suggest that therapies targeting CCK could be promising in the treatment of Ewing tumors.
ADAM-17 Expression in Breast Cancer Correlates with Variables of Tumor Progression
Authors: McGowan Patricia M. , Ryan Bríd M. , Hill Arnold D.K. , McDermott Enda , O'Higgins Niall , Duffy Michael J.
Published: April 2007

The ADAMs are a family of membrane proteins possessing a disintegrin and metalloprotease domain. One of their main functions is shedding of membrane proteins. The aim of this study was to test the hypothesis that ADAM-17 (also known as tumor necrosis factor-α converting enzyme) is involved in breast cancer progression. Overexpression of ADAM-17 in MCF-7 breast cancer cells increased in vitro invasion and proliferation, whereas down-regulation of ADAM-17 expression in MDA-MB-435 cells decreased invasion and proliferation. At both mRNA and protein levels, ADAM-17 expression was significantly up-regulated in breast cancer compared with normal breast tissue. Using Western blotting, ADAM-17 protein in breast cancer was shown to exist in two forms migrating with approximate molecular masses of 100 and 120 kDa. Based on their known molecular mass, these bands were taken to represent the active and precursor forms of ADAM-17, respectively. The proportion of active to total ADAM-17 increased progressively from normal breast tissue to primary breast cancer to lymph node metastases (P = 0.017, Kruskal-Wallis test). In primary cancers, the active form was expressed more frequently in node-positive compared with node-negative tumors (P = 0.034, χ2 test). Furthermore, in primary carcinomas, both forms of ADAM-17 correlated significantly (Spearman correlation analysis) with levels of urokinase plasminogen activator (precursor form: r = 0.246, P = 0.032, n = 83 and active form: r = 0.428, P = 0.0001, n = 83) and proliferating cell nuclear antigen (precursor form: r = 0.524, P < 0.0001, n = 73 and active form: r = 0.365, P = 0.002, n = 73). Our results support the hypothesis that ADAM-17 is involved in breast cancer progression.
Reciprocal Regulation of SOCS 1 and SOCS3 Enhances Resistance to Ionizing Radiation in Glioblastoma Multiforme
Authors: Zhou Hong , Miki Rika , Eeva Mervi , Fike Francesca M. , Seligson David , Yang Lu , Yoshimura Akihiko , Teitell Michael A. , Jamieson Christina A.M. , Cacalano Nicholas A.
Published: April 2007

Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance.

Experimental Design: SOCS1 and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry. The methylation status of the SOCS1 and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1 or SOCS3 knockout mice were studied in a clonogenic survival assay.

Results: All GBM cell lines tested lacked SOCS1 expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1 genetic locus in GBM cells. Reintroduction of SOCS1 or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells.

Conclusions: SOCS1 and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.
A Novel Chromogranin-A Promoter-Driven Oncolytic Adenovirus for Midgut Carcinoid Therapy
Authors: Leja Justyna , Dzojic Helena , Gustafson Elisabet , Öberg Kjell , Giandomenico Valeria , Essand Magnus
Published: April 2007

Purpose: The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids. We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene.

Experimental Design: The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad[CgA-E1A] for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases.

Results: We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types. Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes.

Conclusion: Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.
Silencing of Hypoxia Inducible Factor-1α by RNA Interference Attenuates Human Glioma Cell GrowthIn vivo
Authors: Gillespie David L. , Whang Kum , Ragel Brian T. , Flynn Jeannette R. , Kelly David A. , Jensen Randy L.
Published: April 2007

Purpose: Higher-grade gliomas are distinguished by increased vascular endothelial cell proliferation and peritumoral edema. These are thought to be instigated by vascular endothelial growth factor, which, in turn, is regulated by cellular oxygen tension. Hypoxia inducible factor-1α (HIF-1α) is a main responder to intracellular hypoxia and is overexpressed in many human cancers, including gliomas.

Experimental Design: We investigated the role of HIF-1α in glioma growth in vivo using RNA interference (RNAi) in U251, U87, and U373 glioma cells.

Results: We found that RNAi can be used to significantly attenuate glioma growth by reducing HIF-1α levels constitutively using short hairpin RNAs and transiently using small interfering RNAs (siRNA). HIF-1α levels on average were reduced 55% in normoxia and 71% in hypoxia. Vascular endothelial growth factor and GLUT-1 levels were reduced 81% and 71%, respectively, in the stable HIF-1α–reduced clones. These clones showed significant growth attenuation (up to 73%) compared with negative controls when grown in vivo in mouse flanks. Cellular proliferation was also reduced significantly, as determined by MIB-1 staining. Treating gliomas grown in mouse flank transiently with siRNA against HIF-1α by intratumoral injection resulted in a significant reduction of HIF-1α activity. This activity was followed using a hypoxia-responsive luciferase construct that enabled hypoxia imaging in vivo. Tumor volume in these siRNA injection experiments was reduced by 50% over the negative controls.

Conclusions: These results indicate that transient RNAi directed against HIF-1α can effectively curb glioma growth in vivo.