bluuebunny/crossref_metadata_2025 huggingface dataset:
SOME TRAVELING WAVE SOLITONS OF THE GREEN–NAGHDI SYSTEM
Authors: DENG SHENGFU , GUO BOLING , WANG TINGCHUN
Published: March 2011

The traveling wave solutions for an equivalent system of the Green–Naghdi system are considered. The qualitative analysis methods of planar autonomous systems yield their phase portraits. The exact expressions of smooth soliton wave solutions, cusp soliton wave solutions, smooth periodic wave solutions and periodic cusp wave solutions are obtained. Some numerical simulations of these solutions are also given. These reveal some new properties of the Green–Naghdi system.
A Supernodal Approach to Incomplete LU Factorization with Partial Pivoting
Authors: Li Xiaoye S. , Shao Meiyue
Published: March 2011

We present a new supernode-based incomplete LU factorization method to construct a preconditioner for solving sparse linear systems with iterative methods. The new algorithm is primarily based on the ILUTP approach by Saad, and we incorporate a number of techniques to improve the robustness and performance of the traditional ILUTP method. These include new dropping strategies that accommodate the use of supernodal structures in the factored matrix and an area-based fill control heuristic for the secondary dropping strategy. We present numerical experiments to demonstrate that our new method is competitive with the other ILU approaches and is well suited for modern architectures with memory hierarchy.
Emerging Themes and Therapeutic Prospects for Anti-Infective Peptides
Authors: Yount Nannette Y. , Yeaman Michael R.
Published: March 2011

Pathogens resistant to most conventional anti-infectives are a harbinger of the need to discover and develop novel anti-infective agents and strategies. Endogenous host defense peptides (HDPs) have retained evolution-tested efficacy against pathogens that have become refractory to traditional antibiotics. Evidence indicates that HDPs target membrane integrity, bioenergetics, and other essential features of microbes that may be less mutable than conventional antibiotic targets. For these reasons, HDPs have received increasing attention as templates for development of potential anti-infective therapeutics. Unfortunately, advances toward this goal have proven disappointing, in part owing to limited understanding of relevant structure-activity and selective toxicity relationships in vivo, a limited number of reports and overall understanding of HDP pharmacology, and the difficulty of cost-effective production of such peptides on a commodity scale. However, recent molecular insights and technology innovations have led to novel HDP-based and mimetic anti-infective peptide candidates designed to overcome these limitations. Although initial setbacks have presented challenges to therapeutic development, emerging themes continue to highlight the potential of HDP-based anti-infectives as a platform for next-generation therapeutics that will help address the growing threat of multidrug-resistant infections.
Abnormalities in arterial-ventricular coupling in older healthy persons are attenuated by sodium nitroprusside
Authors: Chantler Paul D. , Nussbacher Amit , Gerstenblith Gary , Schulman Steven P. , Becker Lewis C. , Ferrucci Luigi , Fleg Jerome L. , Lakatta Edward G. , Najjar Samer S.
Published: March 2011

The coupling between arterial elastance ( EA; net afterload) and left ventricular elastance ( ELV; pump performance), known as EA/ ELV, is a key determinant of cardiovascular performance and shifts during exercise due to a greater increase in ELV versus EA. This normal exercise-induced reduction in EA/ ELV decreases with advancing age. We hypothesized that sodium nitroprusside (SNP) can acutely ameliorate the age-associated deficits in EA/ ELV. At rest and during graded exercise to exhaustion, EA was characterized as end-systolic pressure/stroke volume and ELV as end-systolic pressure/end-systolic volume. Resting EA/ ELV did not differ between old (70 ± 8 yr, n = 15) and young (30 ± 5 yr, n = 17) subjects because of a tandem increase in EA and ELV in older subjects. During peak exercise, a blunted increase in ELV in old (7.8 ± 3.1 mmHg/ml) versus young (11.4 ± 6.5 mmHg/ml) subjects blunted the normal exercise-induced decline in EA/ ELV in old (0.25 ± 0.11) versus young (0.16 ± 0.05) subjects. SNP administration to older subjects lowered resting EA/ ELV by 31% via a reduction in EA (10%) and an increase in ELV (47%) and lowered peak exercise EA/ ELV (36%) via an increase in ELV (68%) without a change in EA. Importantly, SNP attenuated the age-associated deficits in EA/ ELV and ELV during exercise, and at peak exercise EA/ ELV in older subjects on drug administration did not differ from young subjects without drug administration. In conclusion, some age-associated deficiencies in EA/ ELV, EA, and ELV, in older subjects can be acutely abolished by SNP infusion. This is relevant to common conditions in older subjects associated with a significant impairment of exercise performance such as frailty or heart failure with preserved ejection fraction.
Effect of a patent foramen ovale on pulmonary gas exchange efficiency at rest and during exercise
Authors: Lovering Andrew T. , Stickland Michael K. , Amann Markus , O'Brien Matthew J. , Hokanson John S. , Eldridge Marlowe W.
Published: March 2011

The prevalence of a patent foramen ovale (PFO) is ∼30%, and this source of right-to-left shunt could result in greater pulmonary gas exchange impairment at rest and during exercise. The aim of this work was to determine if individuals with an asymptomatic PFO (PFO+) have greater pulmonary gas exchange inefficiency at rest and during exercise than subjects without a PFO (PFO−). Separated by 1 h of rest, 8 PFO+ and 8 PFO− subjects performed two incremental cycle ergometer exercise tests to voluntary exhaustion while breathing either room air or hypoxic gas [fraction of inspired O2 (FiO2) = 0.12]. Using echocardiography, we detected small, intermittent boluses of saline contrast bubbles entering directly into the left atrium within 3 heart beats at rest and during both exercise conditions in PFO+. These findings suggest a qualitatively small intracardiac shunt at rest and during exercise in PFO+. The alveolar-to-arterial oxygen difference (AaDo2) was significantly ( P < 0.05) different between PFO+ and PFO− in normoxia (5.9 ± 5.1 vs. 0.5 ± 3.5 mmHg) and hypoxia (10.1 ± 5.9 vs. 4.1 ± 3.1 mmHg) at rest, but not during exercise. However, arterial oxygen saturation was significantly different between PFO+ and PFO− at peak exercise in normoxia (94.3 ± 0.9 vs. 95.8 ± 1.0%) as a result of a significant difference in esophageal temperature (38.4 ± 0.3 vs. 38.0 ± 0.3°C). An asymptomatic PFO contributes to pulmonary gas exchange inefficiency at rest but not during exercise in healthy humans and therefore does not explain intersubject variability in the AaDo2 at maximal exercise.
Effects of recruitment/derecruitment dynamics on the efficacy of variable ventilation
Authors: Ma Baoshun , Suki Béla , Bates Jason H. T.
Published: March 2011

Variable (or noisy) ventilation (VV) has been demonstrated in animal models of acute lung injury to be superior to constant (or conventional) ventilation (CV), in terms of improved gas exchange and mitigation of lung injury, for reasons that are not entirely clear. We hypothesized that the efficacy of VV is related to the fact that recruitment and derecruitment of lung units are dynamic processes. To test this hypothesis, we modeled the lung computationally as a symmetrically bifurcating airway tree terminating in elastic units. Each airway was fully open or completely closed, at any point in time, according to its pressure history. The model is able to accurately mimic previous experimental measurements showing that the lungs of mice injured by acid aspiration are better recruited after 60 min of VV than CV. The model also shows that recruitment/derecruitment dynamics contribute to the relative efficacy of VV, provided lung units open more rapidly than they close once a critical opening or closing pressure threshold has been crossed. We conclude that the dynamics of recruitment and derecruitment in the lung may be important factors responsible for the benefits of VV compared with CV.
Synthesis and X-ray diffraction data of 1-[N-(methyl)-(3,5-dimethylphenylamino)]methylnaphthalene
Authors: Camargo H. A. , Habran N. M. , Henao J. A. , Amado D. F. , Kouznetsov V. V.
Published: March 2011

The 1-[N-(methyl)-(3,5-dimethylphenylamino)]methylnaphthalene (chemical formula C20H21N) was prepared by means of a condensation between alpha-naphthylaldehyde and 3,5-dimethylaniline in anhydrous ethanol to obtain the aldimine (1) which was reduced with NaBH4 to afford the 1-[N-(3,5-dimethylphenylamino)]methylnaphtalene (2), and finally, the compound (3) was obtained by N-alkylation reaction of (2) with methyl iodine (CH3I) and potassium carbonate (K2CO3) in acetone. Final compound (3) was purified by chromatographic column. The XRPD pattern for the new compound, 1-[N-(methyl)-(3,5-dimethylphenylamino)]methylnaphthalene, was obtained. This compound crystallizes in monoclinic system with space group P21/a (No. 14) and refined unit-cell parameters a=13.260(4) Å, b=15.495(5) Å, c=7.719(5) Å, β=90.19(6), and V=1586(1) Å3.
Synthesis and XRPD studies of new barium dicarboxylates
Authors: Grzesiak M. , Rafalska-Łasocha A. , Łasocha W.
Published: March 2011

New salts of barium with dicarboxylic acids (glutaric, adipic, pimelic, suberic, sebacic, and dodecanedioic) were synthesized and characterized by powder diffraction techniques. In addition to the basic crystallographic data and chemical analyses of barium glutarate hexahydrate {1}, barium adipate {2}, barium pimelate {3}, barium disuberate {4}, barium sebacate {5}, and barium dodecanedioate {6}, the processes of their thermal decomposition were investigated by XRPD. All the compounds decompose to barium carbonate at temperatures between 400 and 500 °C.
X-ray powder diffraction data for Al-Cu-W phases
Authors: Grushko B. , Mi S. B.
Published: March 2011

Ternary Al-Cu-W alloys were investigated. The previously reported Al3Ti-type phase (space group I4/mmm) with the average composition Al67Cu11.5W21.5 was found to have a=3.7296(4) Å and c=8.3797(10) Å. The ternary phase forming around Al67Cu21W12 has a hexagonal structure with a=8.6594(13) Å and c=15.2677(21) Å.
Powder diffraction analysis of gemstone inclusions
Authors: Leon-Reina Laura , Compana José M. , De la Torre Ángeles G. , Moreno Rosa , Ochando Luis E. , Aranda Miguel A. G.
Published: March 2011

Gemstones are pieces of materials that once cut and polished are used as jewels or adornments. Gemstones may be single crystal (such as diamonds), polycrystalline (such as lapis lazuli), or amorphous (such as amber). In any case, gems may have inclusions that may yield a variety of optic effects. It is also important to unravel the crystal structure of the inclusion(s) in order to determine the origin of the gem and to help to understand their formation mechanism. Here, we expand the use of powder diffraction to identify crystalline inclusions in bulk gemstones highlighting Mo Kα radiation to penetrate within compact gems. Initially, rock crystal quartz with rutile needles was investigated and rutile diffraction peaks were more conspicuous in the Mo pattern than in the Cu pattern. Next, rock crystal quartz with beetle legs was characterized and the red iron oxide inclusion was identified as hematite. The study of a fake gem, glass showing aventurine effect, gave the diffraction peaks of metallic copper. Later, polycrystalline gems, moss agate, and aventurine quartz were also studied. The powder patterns of these compact gemstones could be successfully fitted using the Rietveld method. Finally, we discuss opportunities for further improvements in laboratory powder diffraction to characterize inclusions in compact gems.
XRPD investigations of “Prussian blue” artists’ pigment
Authors: Rafalska-Łasocha Alicja , Podulka Katarzyna , Łasocha Wiesław
Published: March 2011

The compound NH4Fe[Fe(CN)6]·xH2O—a commercially available “Prussian blue” pigment—crystallizes in theFm3m space group,a=10.232(1) Å, based on X-ray powder diffraction (XRPD) data. XRPD investigations of other commercially available “Prussian blue” pigments and oil paints were undertaken. Results for the pigments showed that the XRPD techniques were able to differentiate several different Prussian blue phases that differed only slightly in chemical compositions. Results for the oil paints allowed for the determination of the major crystalline phases used as fillers. However, on the basis of XRPD investigations of oil paints prepared in our laboratory containing a mixture of true Prussian blue Fe4[Fe(CN)6]3·14H2O and BaSO4(a common filler), the pigment was detectable only in concentrations higher than 2%. This result suggests that XRPD may not be a preferred technique for the identification of Prussian blue in paintings and other works of art because the concentration of this pigment in such materials is commonly less than 2%.
Anticancer Drugs from Marine Flora: An Overview
Authors: Sithranga Boopathy N. , Kathiresan K.
Published: February 2011

Marine floras, such as bacteria, actinobacteria, cyanobacteria, fungi, microalgae, seaweeds, mangroves, and other halophytes are extremely important oceanic resources, constituting over 90% of the oceanic biomass. They are taxonomically diverse, largely productive, biologically active, and chemically unique offering a great scope for discovery of new anticancer drugs. The marine floras are rich in medicinally potent chemicals predominantly belonging to polyphenols and sulphated polysaccharides. The chemicals have displayed an array of pharmacological properties especially antioxidant, immunostimulatory, and antitumour activities. The phytochemicals possibly activate macrophages, induce apoptosis, and prevent oxidative damage of DNA, thereby controlling carcinogenesis. In spite of vast resources enriched with chemicals, the marine floras are largely unexplored for anticancer lead compounds. Hence, this paper reviews the works so far conducted on this aspect with a view to provide a baseline information for promoting the marine flora-based anticancer research in the present context of increasing cancer incidence, deprived of the cheaper, safer, and potent medicines to challenge the dreadful human disease.
Recognition of Relevant ORP, pH, and DO Bending Points in Ammonia Removal from Drinking Water through Online BAF System
Authors: Abu Hasan Hassimi , Sheikh Abdullah Siti Rozaimah , Kamarudin Siti Kartom , Tan Kofli Noorhisham
Published: February 2011

This study was undertaken to identify the relevant bending points in ORP, pH, and DO profiles in ammonia removal through online monitoring. A novelty BAF system as newl application for drinking water treatment that equipped with ORP, pH, DONH4 +andNO3 −sensors was used. Two types of polluted drinking water strength (low and high strength) with variousNH4 +concentrations and aeration flow were treated at a fixed-time reaction of 24 h. Experiments were conducted at four track studies (TS) of TS1 (NH4 +=50 mg/L, aeration=0.3 L/min), TS2 (NH4 += 100 mg/L, aeration=2.0 L/min), TS3 (NH4 +=100 mg/L, no aeration) and TS4 (NH4 +=10 mg/L, aeration=0.1 L/min). The results showed that the removal ofNH4 +was more than 95% for TS1, TS2, and TS4. From the online monitoring performances, DO elbow and ammonia valley appeared in ORP and pH profiles, respectively. Similarly, new positive plateaus were observed in DO, indicating that the nitrifiers stopped to consume the DO afterNH4 +was completely removed. Hence, based on the bending points, the aeration system is possible to be automatically stopped just after DO elbow and ammonia valley appears in order to save the energy consumption and to shorten the time demands for the drinking water treatment process.
Vitamin B12 Deficiency due to Chlorofluorocarbon: A Case Report
Authors: Bhaskar Hemlata , Chaudhary Rekha
Published: February 2011

Background. Vitamin B12 is vital for optimal functioning of various organ systems but more importantly the central nervous system and the hematological system. Deficiency of vitamin B12 clinically manifests as excessive daytime fatigue, memory difficulties, encephalopathy, myelopathy, peripheral neuropathy, and optic neuropathy. In occupational medicine, vitamin B12 deficiency has been reported with exposure to nitrous oxide in health care workers. However, not much is known about exposure to Freons in other industries and vitamin B12 deficiency.Aim. We are reporting a case of vitamin B12 deficiency in the setting of exposure to chlorofluorocarbon (CFC) gases.Case Report. A 55-year-old male refrigerator mechanic experienced recurrent visual symptoms, which included diplopia and blurring. A complete workup was done and was significant of vitamin B12 deficiency. However, his B12 levels were refractory to supplementation. Appropriate precautions at workplace improved patient's symptoms and were associated with significant improvement in B12 levels.Conclusion. To the best of our knowledge, this is the first reported case of vitamin B12 deficiency (that remains refractory to supplementation) in the setting of exposure to Freon gases.
Reducing False Alarms of Intensive Care Online‐Monitoring Systems: An Evaluation of Two Signal Extraction Algorithms
Authors: Borowski M. , Siebig S. , Wrede C. , Imhoff M.
Published: February 2011

Online‐monitoring systems in intensive care are affected by a high rate of false threshold alarms. These are caused by irrelevant noise and outliers in the measured time series data. The high false alarm rates can be lowered by separating relevant signals from noise and outliers online, in such a way that signal estimations, instead of raw measurements, are compared to the alarm
limits. This paper presents a clinical validation study for two recently developed online signal filters. The filters are based on robust repeated median regression in moving windows of varying width. Validation is done offline using a large annotated reference database. The performance criteria are sensitivity and the proportion of false alarms suppressed by the signal filters.
AP-1 as a Regulator of MMP-13 in the Stromal Cell of Giant Cell Tumor of Bone
Authors: Mak Isabella W. Y. , Turcotte Robert E. , Popovic Snezana , Singh Gurmit , Ghert Michelle
Published: February 2011

Matrix-metalloproteinase-13 (MMP-13) has been shown to be an important protease in inflammatory and neoplastic conditions of the skeletal system. In particular, the stromal cells of giant cell tumor of bone (GCT) express very high levels of MMP-13 in response to the cytokine-rich environment of the tumor. We have previously shown that MMP-13 expression in these cells is regulated, at least in part, by the RUNX2 transcription factor. In the current study, we identify the expression of the c-Fos and c-Jun elements of the AP-1 transcription factor in these cells by protein screening assays and real-time PCR. We then used siRNA gene knockdown to determine that these elements, in particular c-Jun, are upstream regulators of MMP-13 expression and activity in GCT stromal cells. We conclude that there was no synergy found between RUNX2 and AP-1 in the regulation of the MMP13 expression and that these transcription factors may be independently regulated in these cells.
Cisplatin Tumor Biodistribution and Efficacy after Intratumoral Injection of a Biodegradable Extended Release Implant
Authors: Shikanov Ariella , Shikanov Sergey , Vaisman Boris , Golenser Jacob , Domb Abraham J.
Published: February 2011

Local delivery of chemotherapeutic drugs has long been recognized as a potential method for reaching high drug doses at the target site while minimizing systemic exposure. Cisplatin is one of the most effective chemotherapeutic agents for the treatment of various tumors; however, its systemic toxicity remains the primary dose-limiting factor. Here we report that incorporation of cisplatin into a fatty acid-based polymer carrier followed by a local injection into the solid tumor resulted in a successful tumor growth inhibition in heterotopic mouse bladder tumor model in mice. Platinum concentration in the tumor tissue surrounding the injected implant remained above the therapeutic level up to 14 days after the injection, while the plasma levels were several orders of magnitude lower comparing to systemic delivery. The reported delivery system increased the maximum tolerated dose of cisplatin 5 times compared to systemic delivery, thus potentially improving antitumor efficacy of cisplatin in solid tumor model.
My Brother's Teacher? Siblings and Literacy Development in the Home
Authors: Sokal Laura , Piotrowski Caroline
Published: February 2011

Frequency of sibling literacy interactions were examined in 134 families with at least two children, where at least one of the children attended school in grade one to grade four. Parents in the majority of families reported that their children read together on a regular basis without a parent present. This held across various demographic constellations including gender of the older child. However, children from families with three or more children were less likely to read with their siblings. Implications for parents and teachers are discussed.
One-Year Safety Analysis of the COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133+ Bone Marrow Stem Cells to Placebo in Patients after Acute Myocardial Infarction and Left Ventricular Dysfunction
Authors: Mansour Samer , Roy Denis-Claude , Bouchard Vincent , Stevens Louis Mathieu , Gobeil Francois , Rivard Alain , Leclerc Guy , Reeves François , Noiseux Nicolas
Published: February 2011

Bone marrow stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium. Despite initial excitement, recent clinical trials using non-homogenous stem cells preparations showed variable and mixed results. Selected CD133+ hematopoietic stem cells are candidate cells with high potential. Herein, we report the one-year safety analysis on the initial 20 patients enrolled in the COMPARE-AMI trial, the first double-blind randomized controlled trial comparing the safety, efficacy, and functional effect of intracoronary injection of selected CD133+ cells to placebo following acute myocardial infarction with persistent left ventricular dysfunction. At one year, there is no protocol-related complication to report such as death, myocardial infarction, stroke, or sustained ventricular arrhythmia. In addition, the left ventricular ejection fraction significantly improved at four months as compared to baseline and remained significantly higher at one year. These data indicate that in the setting of the COMPARE-AMI trial, the intracoronary injection of selected CD133+ stem cells is secure and feasible in patients with left ventricle dysfunction following acute myocardial infarction.
Immunogenicity and Protective Efficacy against Murine Tuberculosis of a Prime-Boost Regimen with BCG and a DNA Vaccine Expressing ESAT-6 and Ag85A Fusion Protein
Authors: Lu Jia , Wang Chun , Zhou Zhiguang , Zhang Ying , Cao Tingting , Shi Chunwei , Chen Zhenhua , Chen Lingxia , Cai Changxue , Fan Xionglin
Published: February 2011

Heterologous prime-boost regimens utilizing BCG as a prime vaccine probably represent the best hope for the development of novel tuberculosis (TB) vaccines. In this study, we examined the immunogenicity and protective efficacy of DNA vaccine (pcD685A) expressing the fusion protein of Ag85A and ESAT-6 (r685A) and its booster effects in BCG-immunized mice. The recombinant r685A fusion protein stimulated higher level of antigen-specific IFN-γ release in tuberculin skin test- (TST-) positive healthy household contacts of active pulmonary TB patients than that in TST-negative population. Vaccination of C57BL/6 mice with pcD685A resulted in significant protection against challenge with virulentMycobacterium tuberculosisH37Rv when compared with the control group. Most importantly, pcD685A could act as a BCG booster and amplify Th1-type cell-mediated immunity in the lung of BCG-vaccinated mice as shown the increased expression of IFN-γ. The most significant reduction in bacterial load of both spleen and lung was obtained in mice vaccinated with BCG prime and pcD685A DNA booster when compared with BCG or pcD685A alone. Thus, our study indicates that pcD685A may be an efficient booster vaccine against TB with a strong ability to enhance prior BCG immunity.
Reconfiguration Techniques for Self-X Power and Performance Management on Xilinx Virtex-II/Virtex-II-Pro FPGAs
Authors: Schuck Christian , Haetzer Bastian , Becker Jürgen
Published: February 2011

Xilinx Virtex-II family FPGAs support an advanced low-skew clock distribution network with numerous global clock nets to support high-speed mixed frequency designs. Digital Clock Managers in combination with Global Clock Buffers are already in place to generate the desired frequency and to drive the clock networks with different sources, respectively. Currently, almost all designs run at a fixed clock frequency determined statically during design time. Such systems cannot take the full advantage of partial and dynamic self-reconfiguration. Therefore, we introduce a new methodology that allows the implemented hardware to dynamically self-adopt the clock frequency during runtime by reconfiguring the Digital Clock Managers. We also present a method for online speed monitoring which is based on a two-dimensional online routing. The created speed maps of the FPGA area can be used as an input for the dynamic frequency scaling. Figures for reconfiguration performance and power savings are given. Further, the tradeoffs for reconfiguration effort using this method are evaluated. Results show the high potential and importance of the distributed dynamic frequency scaling method with little additional overhead.
Estimation of Failure Probability and Its Applications in Lifetime Data Analysis
Authors: Han Ming
Published: February 2011

Since Lindley and Smith introduced the idea of hierarchical prior distribution, some
results have been obtained on hierarchical Bayesian method to deal with lifetime data.
But all those results obtained by means of hierarchical Bayesian methods involve
complicated integration compute. Though some computing methods such as Markov
Chain Monte Carlo (MCMC) are available, doing integration is still very inconvenient
for practical problems. This paper introduces a new method, named E-Bayesian
estimation method, to estimate failure probability. In the case of one hyperparameter,
the definition of E‐Bayesian estimation of the failure probability is provided; moreover,
the formulas of E‐Bayesian estimation and hierarchical Bayesian estimation and the
property of E‐Bayesian estimation of the failure probability are also provided. Finally,
calculation on practical problems shows that the provided method is feasible and easy
to perform.
Parasite Mitogen-Activated Protein Kinases as Drug Discovery Targets to Treat Human Protozoan Pathogens
Authors: Brumlik Michael J. , Pandeswara Srilakshmi , Ludwig Sara M. , Murthy Kruthi , Curiel Tyler J.
Published: February 2011

Protozoan pathogens are a highly diverse group of unicellular organisms, several of which are significant human pathogens. One group of protozoan pathogens includes obligate intracellular parasites such as agents of malaria, leishmaniasis, babesiosis, and toxoplasmosis. The other group includes extracellular pathogens such as agents of giardiasis and amebiasis. An unfortunate unifying theme for most human protozoan pathogens is that highly effective treatments for them are generally lacking. We will review targeting protozoan mitogen-activated protein kinases (MAPKs) as a novel drug discovery approach towards developing better therapies, focusing onPlasmodia,Leishmania, andToxoplasma, about which the most is known.
DLC1 Interaction with S100A10 Mediates Inhibition of In Vitro Cell Invasion and Tumorigenicity of Lung Cancer Cells through a RhoGAP-Independent Mechanism
Authors: Yang Xuyu , Popescu Nicholas C. , Zimonjic Drazen B.
Published: March 2011

The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein–protein interactions involving DLC1 in certain cancers. Cancer Res; 71(8); 2916–25. ©2011 AACR.
Large-scale Exploration of Gene–Gene Interactions in Prostate Cancer Using a Multistage Genome-wide Association Study
Authors: Ciampa Julia , Yeager Meredith , Amundadottir Laufey , Jacobs Kevin , Kraft Peter , Chung Charles , Wacholder Sholom , Yu Kai , Wheeler William , Thun Michael J. , Divers W. Ryan , Gapstur Susan , Albanes Demetrius , Virtamo Jarmo , Weinstein Stephanie , Giovannucci Edward , Willett Walter C. , Cancel-Tassin Geraldine , Cussenot Olivier , Valeri Antoine , Hunter David , Hoover Robert , Thomas Gilles , Chanock Stephen , Chatterjee Nilanjan
Published: March 2011

Recent genome-wide association studies have identified independent susceptibility loci for prostate cancer that could influence risk through interaction with other, possibly undetected, susceptibility loci. We explored evidence of interaction between pairs of 13 known susceptibility loci and single nucleotide polymorphisms (SNP) across the genome to generate hypotheses about the functionality of prostate cancer susceptibility regions. We used data from Cancer Genetic Markers of Susceptibility: Stage I included 523,841 SNPs in 1,175 cases and 1,100 controls; Stage II included 27,383 SNPs in an additional 3,941 cases and 3,964 controls. Power calculations assessed the magnitude of interactions our study is likely to detect. Logistic regression was used with alternative methods that exploit constraints of gene–gene independence between unlinked loci to increase power. Our empirical evaluation demonstrated that an empirical Bayes (EB) technique is powerful and robust to possible violation of the independence assumption. Our EB analysis identified several noteworthy interacting SNP pairs, although none reached genome-wide significance. We highlight a Stage II interaction between the major prostate cancer susceptibility locus in the subregion of 8q24 that contains POU5F1B and an intronic SNP in the transcription factor EPAS1, which has potentially important functional implications for 8q24. Another noteworthy result involves interaction of a known prostate cancer susceptibility marker near the prostate protease genes KLK2 and KLK3 with an intronic SNP in PRXX2. Overall, the interactions we have identified merit follow-up study, particularly the EPAS1 interaction, which has implications not only in prostate cancer but also in other epithelial cancers that are associated with the 8q24 locus. Cancer Res; 71(9); 3287–95. ©2011 AACR.
Heat Shock Protein 90-Sheltered Overexpression of Insulin-Like Growth Factor 1 Receptor Contributes to Malignancy of Thymic Epithelial Tumors
Authors: Breinig Marco , Mayer Philipp , Harjung Andreas , Goeppert Benjamin , Malz Mona , Penzel Roland , Neumann Olaf , Hartmann Arndt , Dienemann Hendrik , Giaccone Giuseppe , Schirmacher Peter , Kern Michael André , Chiosis Gabriela , Rieker Ralf Joachim
Published: March 2011

Purpose: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.

Experimental Design: Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.

Results: Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R–signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.

Conclusions: We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials. Clin Cancer Res; 17(8); 2237–49. ©2011 AACR.
Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors
Authors: Yamada Kazuhiko , Yamamoto Noboru , Yamada Yasuhide , Nokihara Hiroshi , Fujiwara Yutaka , Hirata Taizo , Koizumi Fumiaki , Nishio Kazuto , Koyama Noriyuki , Tamura Tomohide
Published: March 2011

Purpose: E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors.

Experimental Design: In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis.

Results: Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, Cmax and area under the plasma concentration–time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(−) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect.

Conclusion: E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors. Clin Cancer Res; 17(8); 2528–37. ©2011 AACR.
Aberrant Methylation of the X-Linked Ribosomal S6 Kinase RPS6KA6 (RSK4) in Endometrial Cancers
Authors: Dewdney Summer B. , Rimel BJ , Thaker Premal H. , Thompson Dominic M , Schmidt Amy , Huettner Phyllis , Mutch David G. , Gao Feng , Goodfellow Paul J.
Published: March 2011

Purpose: Effective treatments for advanced endometrial cancer are lacking. Novel therapies that target specific pathways hold promise for better treatment outcomes with less toxicity. Mutation activation of the FGFR2/RAS/ERK pathway is important in endometrial tumorigenesis. RPS6KA6 (RSK4) is a putative tumor suppressor gene and is a target of the ERK signaling pathway. We explored the role of RSK4 in endometrial cancer.

Experimental Design: We showed that RSK4 is expressed in normal endometrial tissue and is absent or much reduced in endometrial cancer. On the basis of previous reports on methylation in other cancers, we hypothesized that the absence of RSK4 transcript is associated with epigenetic silencing rather than mutation. We determined the methylation and expression status of RSK4 in primary endometrial cancers and cell lines and the effects of treatment with a demethylating agent. The relationship between RSK4 methylation and clinicopathologic features was assessed.

Results: RSK4 is frequently hypermethylated in endometrial cancer cells lines and in primary endometrial cancer compared with normal endometrial tissue. RSK4 methylation was significantly associated with tumor grade, with higher grade tumors having lower levels of methylation (P = 0.03). RSK4 methylation levels were not associated with other clinical variables. We did find that RSK4 methylation was significantly correlated with expression in primary endometrial tumors and in cell lines. Reactivation of RSK4 by 5-azacytidine was successfully performed showing 8- to more than 1,200-fold increases in transcript levels.

Conclusion: RSK4 appears to be epigenetically silenced in endometrial cancer as evidenced by hypermethylation. Its role as a suppressor in endometrial cancer, however, remains uncertain. Clin Cancer Res; 17(8); 2120–9. ©2011 AACR.
(−)-Gossypol Suppresses the Growth of Human Prostate Cancer Xenografts via Modulating VEGF Signaling–Mediated Angiogenesis
Authors: Pang Xiufeng , Wu Yuanyuan , Wu Yougen , Lu Binbin , Chen Jing , Wang Jieqiong , Yi Zhengfang , Qu Weijing , Liu Mingyao
Published: March 2011

(−)-Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human cancers. However, whether (−)-gossypol plays functional roles in tumor angiogenesis has not been directly elucidated yet. In this study, we showed that (−)-gossypol dose dependently inhibited the expression of VEGF, Bcl-2, and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and primary cultured human umbilical vascular endothelial cells (HUVEC) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (−)-gossypol at a dosage of 15 mg/kg/d. This inhibitory action of (−)-gossypol in vivo was largely dependent on suppression of angiogenesis in the solid tumors, where VEGF expression and microvessel density were remarkably decreased. Furthermore, (−)-gossypol inhibited VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (−)-gossypol blocked the activation of VEGF receptor 2 kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, the phosphorylation of key intracellular proangiogenic kinases induced by VEGF was all suppressed by the treatment, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase, and AKT kinase. Taken together, the present study shows that (−)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice. Mol Cancer Ther; 10(5); 795–805. ©2011 AACR.
Regulatory Approval of Cancer Risk-Reducing (Chemopreventive) Drugs: Moving What We Have Learned into the Clinic
Authors: Meyskens Frank L. , Curt Gregory A. , Brenner Dean E. , Gordon Gary , Herberman Ronald B. , Finn Olivera , Kelloff Gary J. , Khleif Samir N. , Sigman Caroline C. , Szabo Eva
Published: March 2011

This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs. Cancer Prev Res; 4(3); 311–23. ©2011 AACR.
δ-Tocopherol Is More Active than α- or γ-Tocopherol in Inhibiting Lung Tumorigenesis In Vivo
Authors: Li Guang-Xun , Lee Mao-Jung , Liu Anna B. , Yang Zhihong , Lin Yong , Shih Weichung J. , Yang Chung S.
Published: March 2011

In contrast to strong epidemiologic, preclinical, and secondary clinical evidence for vitamin E (tocopherols) in reducing cancer risk, large-scale clinical cancer-prevention trials of α-tocopherol have been negative. This vexing contrast helped spur substantial preclinical efforts to better understand and improve the antineoplastic activity of tocopherol through, for example, the study of different tocopherol forms. We previously showed that the γ-tocopherol–rich mixture (γ-TmT) effectively inhibited colon and lung carcinogenesis and the growth of transplanted lung-cancer cells in mice. We designed this study to determine the relative activities of different forms of tocopherol in a xenograft model, comparing the anticancer activities of δ-tocopherol with those of α- and γ-tocopherols. We subcutaneously injected human lung cancer H1299 cells into NCr nu/nu mice, which then received α-, γ-, or δ-tocopherol or γ-TmT in the diet (each at 0.17% and 0.3%) for 49 days. δ-Tocopherol inhibited tumor growth most strongly. γ-Tocopherol and γ-TmT (at 0.3%) also inhibited growth significantly, but α-tocopherol did not. δ-Tocopherol also effectively decreased oxidative DNA damage and nitrotyrosine formation and enhanced apoptosis in tumor cells; again, γ-tocopherol also was active in these regards but less so, and α-tocopherol was not. Each supplemented diet increased serum levels of its tocopherol – up to 45 μmol/L for α-tocopherol, 9.7 μmol/L for γ-tocopherol, and 1.2 μmol/L for δ-tocopherol; dietary γ- or δ-tocopherol, however, decreased serum α-tocopherol levels, and dietary α-tocopherol decreased serum levels of γ-tocopherol. Each dietary tocopherol also increased its corresponding side-chain–degradation metabolites, with concentrations of δ-tocopherol metabolites greater than γ-tocopherol and far greater than α-tocopherol metabolites in serum and tumors. This study is the first in vivo assessment of δ-tocopherol in tumorigenesis and shows that δ-tocopherol is more active than α- or γ-tocopherol in inhibiting tumor growth, possibly through trapping reactive oxygen and nitrogen species and inducing apoptosis; δ-tocopherol metabolites could contribute significantly to these results. Cancer Prev Res; 4(3); 404–13. ©2011 AACR.
The Next Phase of Chemoprevention Research
Authors: Cohen Ezra E.W. , Schilsky Richard L.
Published: March 2011

Phase 0 clinical trials are meant to explore mechanism of action, pharmacokinetics, pharmacodynamics, or biodistribution of investigational compounds in an efficient manner with relatively few subjects. Phase 0 designs have been applied sparingly in cancer research, but this issue of the journal provides an example of their utility reported by Reid and colleagues (beginning on page 347). Indeed, aspects of the phase 0 design lend themselves well to chemoprevention research, suggesting that this approach will become more common in the near future. Cancer Prev Res; 4(3); 293–5. ©2011 AACR.
Reflections on the Spread of Metastasis to Cancer Prevention
Authors: Taketo Makoto Mark
Published: March 2011

Most patients with a lethal cancer die of metastasis, the control of which deserves to be one of the most urgent missions of cancer treatment. For some subsets of colorectal cancer, metastasis is stimulated by chemokines or Notch signaling at early stages that coincide with the inflammatory phase of postoperative wound healing. This temporary phase may provide a unique opportunity for “metastasis prevention,” because some novel agents have been developed that target such chemokine receptors or Notch signaling. Cancer Prev Res; 4(3); 324–8. ©2011 AACR.
The Sine Qua Non of Discovering Novel Biomarkers for Early Detection of Ovarian Cancer: Carefully Selected Preclinical Samples
Authors: Jacobs Ian , Menon Usha
Published: March 2011

This perspective discusses reports by Cramer and colleagues (beginning on page 365 in this issue of the journal) and Zhu and colleagues (beginning on page 375), which provide the first systematic and reliable comparison of a large number of candidate biomarkers for the early detection of ovarian cancer in a sample set well-suited for this purpose. This research has important implications for the future design of cancer biomarker studies. Cancer Prev Res; 4(3); 299–302. ©2011 AACR.
Challenges Related to Developing Serum-Based Biomarkers for Early Ovarian Cancer Detection
Authors: Mai Phuong L. , Wentzensen Nicolas , Greene Mark H.
Published: March 2011

In this issue of the journal, Cramer and colleagues and Zhu and colleagues report carefully designed phase 3 assessments of candidate ovarian cancer screening biomarkers. The main conclusion is that CA-125 remains the “best of a bad lot”; the new candidates have fallen short of expectations. We review factors impeding the development of an effective ovarian cancer screening strategy, highlight the requirements related to validating proposed screening biomarkers, and emphasize the risks from premature clinical applications of unvalidated tests, all underscoring the need for new research strategies. Cancer Prev Res; 4(3); 303–6. ©2011 AACR.