bluuebunny/crossref_metadata_2025 huggingface dataset:
GLOBAL METAL-ION BINDING PROTEIN FINGERPRINT: A METHOD TO IDENTIFY MOTIF-LESS METAL-ION BINDING PROTEINS
Authors: MOHAN ABHILASH , ANISHETTY SHARMILA , GAUTAM PENNATHUR
Published: May 2010

Metal-ion binding proteins play a vital role in biological processes. Identifying putative metal-ion binding proteins is through knowledge-based methods. These involve the identification of specific motifs that characterize a specific class of metal-ion binding protein. Metal-ion binding motifs have been identified for the common metal ions.

A robust global fingerprint that is useful in identifying a metal-ion binding protein from a non-metal-ion binding protein has not been devised. Such a method will help in identifying novel metal-ion binding proteins and proteins that do not possess a canonical metal-ion binding motif. We have used a set of physico-chemical parameters of metal-ion binding proteins encoded by the genes CzcA, CzcB and CzcD as a training set to supervised classifiers and have been able to identify several other metal ion binding proteins leading us to believe that metal-ion binding proteins have a global fingerprint, which cannot be pinned down to a single feature of the protein sequence.
Realizing metalloporphyrin functionalization of 4-vinylpyridine copolymer via axial coordination reaction
Authors: Gao Baojiao , Wang Ruixin , Du Ruikui
Published: May 2010

Cobalt tetra(para-chlorophenyl)porphyrin ( CoTCPP ) and zinc tetraphenyl porphyrin ( ZnTPP ) were linked on the side chains of the copolymer of 4-vinylpyridine (4VP) and styrene (St), P(4VP-co-St), via axial coordination reactions, respectively, and the metalloporphyrin-functionalized macromolecules, CoTCPP -P(4VP-co-St) and ZnTPP -P(4VP-co-St), were prepared. Their chemical structures were characterized by FTIR and 1H NMR. The spectral properties of the two macromolecular axial coordination complexes were mainly studied, and their photophysical behavior were discussed in depth. The experimental results show that the metalloporphyrin-functionalized macromolecules, CoTCPP -P(4VP-co-St) and ZnTPP -P(4VP-co-St), can be prepared favorably through axial coordination reaction with the side pyridine groups of the copolymer P(4VP-co-St) as ligands. The two complexes have characteristic spectra similar to that of the small molecular metalloporphyrins, CoTCPP and ZnTPP , respectively. At the same time, they also display the characteristic spectroscopic property of axial coordination complexes: the electronic adsorption spectra of CoTCPP -P(4VP-co-St) and ZnTPP -P(4VP-co-St) red-shifted obviously as compared to that of CoTCPP and ZnTPP , and the fluorescence emission of ZnTPP -P(4VP-co-St) blue-shifted apparently with respect to that of ZnTPP . For CoTCPP -P(4VP-co-St) and ZnTPP -P(4VP-co-St), some polymer effects were found: (1) the bonding degree of the small molecular metalloporphyrin, CoTCPP or ZnTPP , on the side chains of the copolymer P(4VP-co-St) has a limit value because of the steric hindrance and there is a bonding degree difference between the actual value and the theoretical value; (2) for ZnTPP -P(4VP-co-St), slight energy transfer between adjacent ZnTPP units on an identical macromolecule occurs, leading to slight static quench of the fluorescence emission as the bonding density of ZnTPP units on the side chains of the copolymer P(4VP-co-St) reaches a certain value.
Applications of polymerized metal tetra-amino phthalocyanines towards hydrogen peroxide detection
Authors: Mashazi Philani , Togo Chamunorwa , Limson Janice , Nyokong Tebello
Published: May 2010

This work reports the use of metallo tetra-amino phthalocyanines ( MTAPc, M = Co and Mn ) polymer thin films on gold and glassy carbon electrode surfaces for the detection and monitoring of hydrogen peroxide ( H2O2 ). The polymer-modified electrodes were characterized using electrochemical and microscopic-based methods. Atomic force microscopy (AFM) was used to study the bare and polymer-modified ITO surfaces. The electrocatalytic reduction of H2O2 with glassy carbon polymer-modified electrodes gave higher current densities compared to their gold counterparts. The electroanalytical properties of H2O2 were obtained using a real-time calibration curve of the amperometric determination in pH 7.4 aqueous solution. The limits of detection (LoD) of the polymer-modified electrodes towards electroreduction of H2O2 were of the order of 10–7 M, with high sensitivity ranging from 6.0–15.4 mA.mM-1.cm-2.
The U.S. Decennial Census: Politics and Political Science
Authors: Prewitt Kenneth
Published: May 2010

Political scientists make heavy use of census statistics but have given scant attention to the politics behind the production of those statistics. Key issues that merit analytic attention by political science include vote dilution, the policy of population growth and composition, distributional accuracy and census undercounts, the establishment of statistical races, the color-blind challenge to the ethnoracial classification, the political independence of federal statistics, the important distinction between the scientific production and the political use of the census and other statistical products, public concern about government intrusiveness, and the shift from survey and census data to administrative and digital data.
Rationalist Approaches to Conflict Prevention and Resolution
Authors: Kydd Andrew H.
Published: May 2010

An emerging literature on civil and international conflict management is developing and testing insights from formal theories of conflict. Third parties may attempt to prevent or resolve conflict by providing material incentives or by providing or filtering information. Material incentives are the province of states, for the most part, while weaker third parties can provide information. There is considerable debate over whether threats of third-party intervention actually deter conflict, provoke conflict, have no effect, or have nonmonotonic effects on the likelihood of conflict. Providing information via mediation is seen as effective in preventing conflict, but questions remain about precisely how it works and about the appropriate characteristics of the mediator, such as whether mediators should be biased or unbiased.
Accountability in Coalition Governments
Authors: Maravall José María
Published: May 2010

Most theoretical studies of coalition politics have focused on selection, rather than accountability: Coalition partners are selected according to the proximity of their positions in a Euclidean policy space. This proximity, together with institutional attributes of the party systems or the coalitions, serves also to explain the duration of the coalition. Empirical studies of retrospective voting, often with little connection to accountability theory, have generally concluded that the political survival of coalitions is considerably independent from elections. Such results, however, refer to governments as a whole. In this work, voters allocate rewards and punishments for past outcomes focusing on the prime ministers and their parties. If differences in clarity of responsibility exist, they do not seem to produce greater economic accountability of single-party governments—it is similarly limited under both coalition and single-party governments. Coalitions, however, increase the risks of losing office due to political crises, rather than elections. Prime ministers can respond to challenges by reshuffling the government or the coalition. Because such crises are launched under economic conditions that improve the welfare of citizens, coalitions may undermine democratic accountability.
Reflections on Ethnographic Work in Political Science
Authors: Wedeen Lisa
Published: May 2010

The objectivist truth claims traditionally pressed by most political scientists have made the use of ethnographic methods particularly fraught in the discipline. This article explores what ethnography as a method entails. It makes distinctions between positivist and interpretivist ethnographies and highlights some of the substantive contributions ethnography has made to the study of politics. Lamenting the discipline's abandonment of a conversation with anthropology after Geertz, this review also insists on moving beyond the anthropological controversies so powerfully expressed in the edited volume Writing Culture (1986) and other texts of the 1980s and 1990s. I contend that interpretive social science does not have to forswear generalizations or causal explanations and that ethnographic methods can be used in the service of establishing them. Rather than fleeing from abstractions, ethnographies can and should help ground them.
Public Opinion on Gender Issues: The Politics of Equity and Roles
Authors: Burns Nancy , Gallagher Katherine
Published: May 2010

How do individuals form their opinions about gender issues? In this article, we draw upon work on public policy and the social organization of gender to provide a framework for thinking about the existing literature. We strive to illuminate the ways in which the literature's disagreements—about the conceptual scope of the field, about predispositions and policy views, and about theory and explanation—lay the groundwork for a conversation that will bring to light new aspects of the field and provide directions for future research.
Regionalism
Authors: Mansfield Edward D. , Solingen Etel
Published: May 2010

We review and analyze some recent research on regionalism. We begin by discussing how various studies have defined regions and regionalism. Because much of the work has been conducted by economists, we then turn to a summary of the economics of regionalism. However, it is widely held that economic factors alone are insufficient to explain regionalism's causes and consequences and that political factors are centrally important. We analyze how domestic and international political factors have guided both economic regionalism and security regionalism. We conclude by outlining some avenues for future research, placing particular emphasis on the need to better integrate insights from political economy and international security in the study of regionalism.
An AP-3-dependent mechanism drives synaptic-like microvesicle biogenesis in pancreatic islet β-cells
Authors: Suckow Arthur T. , Craige Branch , Faundez Victor , Cain William J. , Chessler Steven D.
Published: May 2010

Pancreatic islet β-cells contain synaptic-like microvesicles (SLMVs). The origin, trafficking, and role of these SLMVs are poorly understood. In neurons, synaptic vesicle (SV) biogenesis is mediated by two different cytosolic adaptor protein complexes, a ubiquitous AP-2 complex and the neuron-specific AP-3B complex. Mice lacking AP-3B subunits exhibit impaired GABAergic (inhibitory) neurotransmission and reduced neuronal vesicular GABA transporter (VGAT) content. Since β-cell maturation and exocytotic function seem to parallel that of the inhibitory synapse, we predicted that AP-3B-associated vesicles would be present in β-cells. Here, we test the hypothesis that AP-3B is expressed in islets and mediates β-cell SLMV biogenesis. A secondary aim was to test whether the sedimentation properties of INS-1 β-cell microvesicles are identical to those of bona fide SLMVs isolated from PC12 cells. Our results show that the two neuron-specific AP-3 subunits β3B and μ3B are expressed in β-cells, the first time these proteins have been found to be expressed outside the nervous system. We found that β-cell SLMVs share the same sedimentation properties as PC12 SLMVs and contain SV proteins that sort specifically to AP-3B-associated vesicles in the brain. Brefeldin A, a drug that interferes with AP-3-mediated SV biogenesis, inhibits the delivery of AP-3 cargoes to β-cell SLMVs. Consistent with a role for AP-3 in the biogenesis of GABAergic SLMV in β-cells, INS-1 cell VGAT content decreases upon inhibition of AP-3 δ-subunit expression. Our findings suggest that β-cells and neurons share molecules and mechanisms important for mediating the neuron-specific membrane trafficking pathways that underlie synaptic vesicle formation.
Regional differences in osmotic behavior in brain during acute hyponatremia: an in vivo MRI-study of brain and skeletal muscle in pigs
Authors: Overgaard-Steensen Christian , Stødkilde-Jørgensen Hans , Larsson Anders , Broch-Lips Martin , Tønnesen Else , Frøkiær Jørgen , Ring Troels
Published: May 2010

Brain edema is suggested to be the principal mechanism underlying the symptoms in acute hyponatremia. Identification of the mechanisms responsible for global and regional cerebral water homeostasis during hyponatremia is, therefore, of utmost importance. To examine the osmotic behavior of different brain regions and muscles, in vivo-determined water content (WC) was related to plasma sodium concentration ([Na+]) and brain/muscle electrolyte content. Acute hyponatremia was induced with desmopressin acetate and infusion of a 2.5% glucose solution in anesthetized pigs. WC in different brain regions and skeletal muscle was estimated in vivo from T1 maps determined by magnetic resonance imaging (MRI). WC, expressed in gram water per 100 g dry weight, increased significantly in slices of the whole brain [342(SD = 14) to 363(SD = 21)] (6%), thalamus [277(SD = 13) to 311(SD = 24)] (12%) and white matter [219(SD = 7) to 225(SD = 5)] (3%). However, the WC increase in the whole brain and white mater WC was less than expected from perfect osmotic behavior, whereas in the thalamus, the water increase was as expected. Brain sodium content was significantly reduced. Muscle WC changed passively with plasma [Na+]. WC determined with deuterium dilution and tissue lyophilzation correlated well with MRI-determined WC. In conclusion, acute hyponatremia induces brain and muscle edema. In the brain as a whole and in the thalamus, regulatory volume decrease (RVD) is unlikely to occur. However, RVD may, in part, explain the observed lower WC in white matter. This may play a potential role in osmotic demyelination.
Synthesis and Characterization of Well-Defined SolubleAlq3- andZnq2-Functionalized Polymers via RAFT Copolymerization
Authors: Wang Chengchao , Zhang Wei , Zhou Nianchen , Qiu Yansheng , Cheng Zhengping , Zhu Xiulin
Published: May 2010

The reversible addition-fragmentation chain transfer (RAFT) copolymerizations of 2-((8-hydroxyquinolin-5-yl)methoxy)ethyl methacrylate (HQHEMA) with styrene (St) or methyl methacrylate (MMA) were successfully carried out in the presence of 2-cyanoprop-2-yl dithionaphthalenoate (CPDN). The polymerization behaviors showed the typical living natures by the first-order polymerization kinetics, the linear dependence of molecular weights of the polymers on the monomer conversions with the relatively narrow molecular weight distributions(Mw/Mn), and the successful chain extension experiments. The soluble polymers having tris(8-hydroxyquinoline)aluminum (Alq3) and bis(8-hydroxyquinoline) znic(II) (Znq2) side chains were obtained via complexation of the polymers with aluminium isopropoxide or zinc acetate in the presence of monomeric 8-hydroxyquinoline, which had strong fluorescent emission at 520 nm. The obtained polymers were characterized by GPC, NMR, UV-vis, and fluorescent spectra.
Flaxseed Ingestion Alters Ratio of Enterolactone Enantiomers in Human Serum
Authors: Saarinen Niina M. , Smeds Annika I. , Peñalvo José L. , Nurmi Tarja , Adlercreutz Herman , Mäkelä Sari
Published: May 2010

Enterolactone (EL) is an enterolignan found in human subjects. In this pilot study, the enantiomeric ratios of serum EL were determined in serum from healthy adults during consumption of habitual diet, and after an 8-day supplementation with flaxseed (25 g/day). (−)EL dominated in all serum samples collected during habitual diet consumption. However, the ratio of (−)EL and (+)EL enantiomers differed markedly between individuals. Flaxseed ingestion increased significantly the proportion of (+)EL in all subjects. Moreover, a small but significant increase in serum (−)EL concentration was measured. After flaxseed ingestion, (−)EL concentrations correlated with those of (+)EL suggesting that the stereochemistry of the parent plant lignan in flaxseed is not a major determinant of EL formation in human subjects. Comparison of EL concentrations obtained with the validated chromatographic methods (HPLC-MS/MS, HPLC-CEAD, and GC-MS) and the time-resolved fluoroimmunoassay (TR-FIA) revealed that the immunoassay method underestimates human serum EL concentrations after the flaxseed ingestion.
Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy
Authors: Wu Han-Chung , Chang De-Kuan
Published: May 2010

Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.
Diamond Blackfan Anemia at the Crossroad between Ribosome Biogenesis and Heme Metabolism
Authors: Chiabrando Deborah , Tolosano Emanuela
Published: May 2010

Diamond-Blackfan anemia (DBA) is a rare, pure red-cell aplasia that presents during infancy. Approximately 40% of cases are associated with other congenital defects, particularly malformations of the upper limb or craniofacial region. Mutations in the gene coding for the ribosomal protein RPS19 have been identified in 25% of patients with DBA, with resulting impairment of 18S rRNA processing and 40S ribosomal subunit formation. Moreover, mutations in other ribosomal protein coding genes account for about 25% of other DBA cases. Recently, the analysis of mice from which the gene coding for the heme exporter Feline Leukemia Virus subgroup C Receptor (FLVCR1) is deleted suggested that this gene may be involved in the pathogenesis of DBA. FLVCR1-null mice show a phenotype resembling that of DBA patients, including erythroid failure and malformations. Interestingly, some DBA patients have disease linkage to chromosome 1q31, where FLVCR1 is mapped. Moreover, it has been reported that cells from DBA patients express alternatively spliced isoforms of FLVCR1 which encode non-functional proteins. Herein, we review the known roles of RPS19 and FLVCR1 in ribosome function and heme metabolism respectively, and discuss how the deficiency of a ribosomal protein or of a heme exporter may result in the same phenotype.
Euler‐Maclaurin Closed Form Finite State Space Model for a String Applied to Broadband Plate Vibrations
Authors: Panza Michael J.
Published: May 2010

The Euler‐Maclaurin sun formula is applied to the infinite series Green′s function solution in the space‐time Laplace transform domain for the one dimensional wave equation for a string fixed at each end. The resulting approximate closed form solution is used to derive a single third order input‐output ordinary differential equation to model the string dynamics. The average modal density of a plate is shown to be comparable to a string. A finite three state‐space model is developed for the string and applied to the vibrations of a plate subjected to broadband random and impulse inputs. The applications include the direct problem of determining the response to a disturbance input and the inverse problem of identifying the disturbance input with a finite state observer based on the finite string model. Numerical simulations using many plate modes are obtained in the time and frequency domains and are used to compare the multimodal plate model to the finite string based model and to demonstrate how the finite string based model can be used to represent the multimodal vibrations of the plate.
Feature Detection Techniques for Preprocessing Proteomic Data
Authors: Sellers Kimberly F. , Miecznikowski Jeffrey C.
Published: May 2010

Numerous gel‐based and nongel‐based technologies are used to detect protein changes potentially associated with disease. The raw data, however, are abundant with technical and structural complexities, making statistical analysis a difficult task. Low‐level analysis issues (including normalization, background correction, gel and/or spectral alignment, feature detection, and image registration) are substantial problems that need to be addressed, because any large‐level data analyses are contingent on appropriate and statistically sound low‐level procedures. Feature detection approaches are particularly interesting due to the increased computational speed associated with subsequent calculations. Such summary data corresponding to image features provide a significant reduction in overall data size and structure while retaining key information. In this paper, we focus on recent advances in feature detection as a tool for preprocessing proteomic data. This work highlights existing and newly developed feature detection algorithms for proteomic datasets, particularly relating to time‐of‐flight mass spectrometry, and two‐dimensional gel electrophoresis. Note, however, that the associated data structures (i.e., spectral data, and images containing spots) used as input for these methods are obtained via all gel‐based and nongel‐based methods discussed in this manuscript, and thus the discussed methods are likewise applicable.
Human Enhancer of Filamentation 1 Is a Mediator of Hypoxia-Inducible Factor-1α–Mediated Migration in Colorectal Carcinoma Cells
Authors: Kim Sun-Hee , Xia Dianren , Kim Sang-Wook , Holla Vijaykumar , Menter David G. , DuBois Raymond N.
Published: May 2010

Human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is a scaffolding protein that is implicated in regulating diverse cellular processes, such as cellular attachment, motility, cell cycle progression, apoptosis, and inflammation. Here, we identify HEF1 as a novel hypoxia-inducible factor-1α (HIF-1α)–regulated gene and reveal that HEF1 mediates hypoxia-induced migration of colorectal carcinoma cells. HEF1 is highly expressed in cultured colorectal carcinoma cells exposed to hypoxia and in the hypoxic areas of human colorectal cancer (CRC) specimens. Moreover, our data show that HIF-1α mediates the effects of hypoxia on induction of HEF1 expression via binding to a hypoxia-responsive element of the HEF1 promoter. Importantly, the induction of HEF1 expression significantly enhances hypoxia-stimulated HIF-1α transcriptional activity by modulating the interaction between HIF-1α and its transcriptional cofactor p300. Inhibition of HEF1 expression also reduced the levels of hypoxia-inducible genes, including those that regulate cell motility. Cell migration was reduced dramatically following knockdown of HEF1 expression under hypoxic conditions. Thus, this positive feedback loop may contribute to adaptive responses of carcinoma cells encountering hypoxia during cancer progression. Cancer Res; 70(10); 4054–63. ©2010 AACR.
Signatures of MicroRNAs and Selected MicroRNA Target Genes in Human Melanoma
Authors: Philippidou Demetra , Schmitt Martina , Moser Dirk , Margue Christiane , Nazarov Petr V. , Muller Arnaud , Vallar Laurent , Nashan Dorothee , Behrmann Iris , Kreis Stephanie
Published: May 2010

Small noncoding microRNAs (miRNA) regulate the expression of target mRNAs by repressing their translation or orchestrating their sequence-specific degradation. In this study, we investigated miRNA and miRNA target gene expression patterns in melanoma to identify candidate biomarkers for early and progressive disease. Because data presently available on miRNA expression in melanoma are inconsistent thus far, we applied several different miRNA detection and profiling techniques on a panel of 10 cell lines and 20 patient samples representing nevi and primary or metastatic melanoma. Expression of selected miRNAs was inconsistent when comparing cell line–derived and patient-derived data. Moreover, as expected, some discrepancies were also detected when miRNA microarray data were correlated with qPCR-measured expression levels. Nevertheless, we identified miRNA-200c to be consistently downregulated in melanocytes, melanoma cell lines, and patient samples, whereas miRNA-205 and miRNA-23b were markedly reduced only in patient samples. In contrast, miR-146a and miR-155 were upregulated in all analyzed patients but none of the cell lines. Whole-genome microarrays were performed for analysis of selected melanoma cell lines to identify potential transcriptionally regulated miRNA target genes. Using Ingenuity pathway analysis, we identified a deregulated gene network centered around microphthalmia-associated transcription factor, a transcription factor known to play a key role in melanoma development. Our findings define miRNAs and miRNA target genes that offer candidate biomarkers in human melanoma. Cancer Res; 70(10); 4163–73. ©2010 AACR.
Schweinfurthin A Selectively Inhibits Proliferation and Rho Signaling in Glioma and Neurofibromatosis Type 1 Tumor Cells in a NF1-GRD–Dependent Manner
Authors: Turbyville Thomas J. , Gürsel Demirkan B. , Tuskan Robert G. , Walrath Jessica C. , Lipschultz Claudia A. , Lockett Stephen J. , Wiemer David F. , Beutler John A. , Reilly Karlyne M.
Published: May 2010

Neurofibromatosis type 1 (NF1) is the most common genetic disease affecting the nervous system. Patients typically develop many tumors over their lifetime, leading to increased morbidity and mortality. The NF1 gene, mutated in NF1, is also commonly mutated in sporadic glioblastoma multiforme (GBM). Because both NF1 and GBM are currently incurable, new therapeutic approaches are clearly needed. Natural products represent an opportunity to develop new therapies, as they have been evolutionarily selected to play targeted roles in organisms. Schweinfurthin A is a prenylated stilbene natural product that has previously shown specific inhibitory activity against brain and hematopoietic tumor lines. We show that patient-derived GBM and NF1 malignant peripheral nerve sheath tumor (MPNST) lines, as well as tumor lines derived from the Nf1−/+;Trp53−/+ (NPcis) mouse model of astrocytoma and MPNST are highly sensitive to inhibition by schweinfurthin A and its synthetic analogs. In contrast, primary mouse astrocytes are resistant to the growth inhibitory effects of schweinfurthin A, suggesting that schweinfurthin A may act specifically on tumor cells. Stable transfection of the GTPase-activating protein related domain of Nf1 into Nf1−/−;Trp53−/− astrocytoma cells confers resistance to schweinfurthin A. In addition, the profound effect of schweinfurthin A on dynamic reorganization of the actin cytoskeleton led us to discover that schweinfurthin A inhibits growth factor–stimulated Rho signaling. In summary, we have identified a class of small molecules that specifically inhibit growth of cells from both central and peripheral nervous system tumors and seem to act on NF1-deficient cells through cytoskeletal reorganization correlating to changes in Rho signaling. Mol Cancer Ther; 9(5); 1234–43. ©2010 AACR.
ENMD-1198, a New Analogue of 2-Methoxyestradiol, Displays Both Antiangiogenic and Vascular-Disrupting Properties
Authors: Pasquier Eddy , Sinnappan Snega , Munoz Marcia A. , Kavallaris Maria
Published: May 2010

The formation of a new vascular network by angiogenesis is a key driver in tumor growth and metastasis, making this an attractive therapeutic target. Different strategies are being developed to either prevent tumor angiogenesis or disrupt the tumor vasculature already in place. In this in vitro study, we investigated the antivascular properties of ENMD-1198, a new anticancer drug currently in clinical trials. ENMD-1198 is a new analogue of 2-methoxyestradiol, a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma and hormone-refractory prostate cancer. Using both bone marrow–derived and dermal microvascular endothelial cell lines, we analyzed the effect of ENMD-1198 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-methoxyestradiol at inhibiting endothelial cell proliferation, motility, migration, and morphogenesis. In addition, ENMD-1198 induced a significant decrease in vascular endothelial growth factor receptor-2 protein expression in endothelial cells. Furthermore, videomicroscopy experiments showed that ENMD-1198 was able to completely disrupt preformed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerization of the microtubule network and accumulation of actin stress fibers and large focal adhesions in vascular endothelial cells. Collectively, our results show that this new compound displays potent antivascular properties, and this study provides important insights into the mechanism of action of this promising new anticancer drug. Mol Cancer Ther; 9(5); 1408–18. ©2010 AACR.
mRNA and microRNA Expression Profiles of the NCI-60 Integrated with Drug Activities
Authors: Liu Hongfang , D'Andrade Petula , Fulmer-Smentek Stephanie , Lorenzi Philip , Kohn Kurt W. , Weinstein John N. , Pommier Yves , Reinhold William C.
Published: May 2010

As part of the Spotlight on Molecular Profiling series, we present here new profiling studies of mRNA and microRNA expression for the 60 cell lines of the National Cancer Institute (NCI) Developmental Therapeutics program (DTP) drug screen (NCI-60) using the 41,000-probe Agilent Whole Human Genome Oligo Microarray and the 15,000-feature Agilent Human microRNA Microarray V2. The expression levels of ∼21,000 genes and 723 human microRNAs were measured. These profiling studies include quadruplicate technical replicates for six and eight cell lines for mRNA and microRNA, respectively, and duplicates for the remaining cell lines. The resulting data sets are freely available and searchable online in our CellMiner database. The result indicates high reproducibility for both platforms and an essential biological similarity across the various cell types. The mRNA and microRNA expression levels were integrated with our previously published 1,429-compound database of anticancer activity obtained from the NCI DTP drug screen. Large blocks of both mRNAs and microRNAs were identified with predominately unidirectional correlations to ∼1,300 drugs, including 121 drugs with known mechanisms of action. The data sets presented here will facilitate the identification of groups of mRNAs, microRNAs, and drugs that potentially affect and interact with one another. Mol Cancer Ther; 9(5); 1080–91. ©2010 AACR.
Preclinical Evaluation of Nilotinib Efficacy in an Imatinib-Resistant KIT-Driven Tumor Model
Authors: Cullinane Carleen , Natoli Anthony , Hui Yorlon , Conus Nelly , Jackson Susan , Brüggen Joseph , Manley Paul W. , McArthur Grant A.
Published: May 2010

The novel KIT inhibitor nilotinib is currently being evaluated for its clinical utility in the treatment of gastrointestinal stromal tumor. However, the effects of nilotinib in cells expressing commonly occurring KIT mutations remain to be fully defined. The aim of this study was therefore to investigate the efficacy of nilotinib against cells expressing imatinib-sensitive or imatinib-resistant KIT mutations and to evaluate [18F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging as a biomarker of nilotinib response in vivo. Nilotinib inhibited the proliferation of imatinib-responsive V560G-KIT FDC-P1 and imatinib-resistant D816V-KIT FDC-P1 cells with a GI50 of 4.9 and 630 nmol/L, respectively, whereas apoptosis studies revealed that nilotinib and imatinib were equipotent against the V560G cell line. In contrast, although 10 μmol/L nilotinib induced >50% apoptosis in the D816V cells at 16 hours, 10 μmol/L imatinib had no effect on cell survival at 24 hours. Syngeneic DBA2/J mice bearing FDC-P1-KIT tumors were evaluated for response to nilotinib by FDG-PET. V560G-KIT FDC-P1 tumor FDG uptake was significantly reduced compared with baseline levels following 2 days of nilotinib treatment. In contrast, no effect of nilotinib was observed on tumor growth or FDG-PET uptake into D816V tumors despite intratumoral drug levels reaching in excess of 10 μmol/L at 4 hours after dosing. Biomarker analysis revealed the inhibition of KIT phosphorylation in V560G but not D816V tumors. These findings show the in vivo activity of nilotinib in the treatment of tumors bearing V560G-KIT but not D816V-KIT and the utility of FDG-PET imaging to assess tumor response to this agent. Mol Cancer Ther; 9(5); 1461–8. ©2010 AACR.
Analysis of Food and Drug Administration–Approved Anticancer Agents in the NCI60 Panel of Human Tumor Cell Lines
Authors: Holbeck Susan L. , Collins Jerry M. , Doroshow James H.
Published: May 2010

Since the early 1990s the Developmental Therapeutics Program of the National Cancer Institute (NCI) has utilized a panel of 60 human tumor cell lines (NCI60) representing 9 tissue types to screen for potential new anticancer agents. To date, about 100,000 compounds and 50,000 natural product extracts have been screened. Early in this program it was discovered that the pattern of growth inhibition in these cell lines was similar for compounds of similar mechanism. The development of the COMPARE algorithm provided a means by which investigators, starting with a compound of interest, could identify other compounds whose pattern of growth inhibition was similar. With extensive molecular characterization of these cell lines, COMPARE and other user-defined algorithms have been used to link patterns of molecular expression and drug sensitivity. We describe here the results of screening current Food and Drug Administration (FDA)-approved anticancer agents in the NCI60 screen, with an emphasis on those agents that target signal transduction. We analyzed results from agents with mechanisms of action presumed to be similar; we also carried out a hierarchical clustering of all of these agents. The addition of data from recently approved anticancer agents will increase the utility of the NCI60 databases to the cancer research community. These data are freely accessible to the public on the DTP website (http://dtp.cancer.gov/). The FDA-approved anticancer agents are themselves available from the NCI as a plated set of compounds for research use. Mol Cancer Ther; 9(5); 1451–60. ©2010 AACR.
Autophagy Dysfunction in Alzheimer’s Disease
Authors: Li Liang , Zhang Xiaojie , Le Weidong
Published: May 2010

Autophagy is a lysosome degradation pathway that turns over cytoplasmic materials and helps the cell to maintain homeostasis. Usually, it is activated under conditions of nutrient deprivation in order to enhance cell survival. Dysfunction in autophagy has been reported to contribute to several neurodegenerative diseases. Recent studies have shown that both amyloid β precursor protein and tau protein are associated with the autophagic pathway. Abnormal processing or modification of these proteins may cause an impairment in the autophagy-lysosome pathway, which constitutively promotes the generation of amyloid β peptides in Alzheimer’s disease (AD). In addition, the impairment in the autophagy-lysosome system disturbs the turnover of other molecules associated with AD, which may also contribute to the neuronal dysfunction in AD. In this article, we have reviewed recent reports related to this topic and analyzed the dynamic changes in the autophagic pathway in AD. The findings from the studies reviewed suggest that autophagy is altered in the early stage of the disease, and dysfunction in autophagy may play an important role in the pathological process of AD.
Expression of Glucocorticoid Receptor and Early Growth Response Gene 1 during Postnatal Development of Two Inbred Strains of Mice Exposed to Early Life Stress
Authors: Navailles Sylvia , Zimnisky Ross , Schmauss Claudia
Published: May 2010

Early life stress can elicit profound changes in adult gene expression and behavior. One consequence of early life stress is a decreased expression of glucocorticoid receptors (GRs) in the frontal cortex and hippocampus. However, neither the time of onset nor the mechanism(s) leading to decreased GR expression during postnatal development are known. The present study used two inbred strains of mice that differ in their behavioral responsiveness to stress (Balb/c and C57Bl/6), exposed them to an established paradigm of early life stress (infant maternal separation), and measured their expression of frontal cortical and hippocampal GRs and the putative transcriptional activator of the GR gene, early growth response gene (egr)-1, at defined stages of postnatal development. In both strains, real-time RT-PCR experiments revealed that decreased expression of GR in adolescence and adulthood is, in fact, preceded by increased GR expression during early life stress exposure. Thus, the early life stress-induced disruption of the normal stress-hyporesponsive period during infancy is accompanied by increased GR expression. Moreover, chronic treatment with the antidepressant drug fluoxetine during adolescence or adulthood reversed the effect of early life stress on adult GR mRNA expression. In contrast to the strain-independent effect of early life stress on GR expression, however, changes in egr-1 expression occurred only in Balb/c mice, and unlike the biphasic developmental changes in GR mRNA expression, egr-1 mRNA was decreased throughout postnatal development. Moreover, there was no consistent overlap of anatomic regions affected by decreased GR and egr-1 protein expression. Thus, in Balb/c mice, changes in GR and egr-1 expression can independently contribute to the phenotypes resulting from early life stress exposure. These findings illustrate that the impact of early life stress on gene expression changes is modulated by the genetic background and that the persistent changes in GR and egr-1 expression that arise early during postnatal developmental are reversible by chronic fluoxetine treatment during adolescence and adulthood.
Head Injury Caused by Tear Gas Cartridge in Teenage Population
Authors: Abrar A. Wani , Zargar Javeed , Ramzan Altaf U. , Malik Nayil K. , Qayoom A. , Kirmani A.R. , Nizami Furqan A. , Wani M.A.
Published: May 2010

Objectives: The aim of this study was to assess the head injury in children caused by an unusual projectile, a tear gas cartridge. The study is the only one on this subject which has been done in a teenage population. Method: This was a prospective study conducted over a period of 4 years in which all the patients aged less than or equal to 18 years and who had a head injury due to a tear gas cartridge were included. Results: We had 5 patients in our study group. All the patients were males. Commonest CT scan finding was brain contusion with skull fracture. One of our patients died. One patient continues to be in vegetative state whereas 3 had a good outcome. Conclusion: Tear gas cartridge, though considered as one of the benign modalities of controlling agitated crowds, is not really benign. It can cause serious injuries and mortality. The personnel using them might be trained in a better way so that the people do not receive direct hits. In addition some changes in the design of tear gas cartridge can be done to decrease the impact to the skull.
Left Ventricular Hypertrophy Influences Cardiac Prognosis in Patients Undergoing Dobutamine Cardiac Stress Testing
Authors: Charoenpanichkit Charaslak , Morgan Timothy M. , Hamilton Craig A. , Wallace Eric L. , Robinson Killian , Ntim William O. , Hundley W. Gregory
Published: May 2010

Background—

This study was performed to determine the utility of dobutamine stress test results for predicting myocardial infarction (MI) and cardiac death in patients with chest pain and left ventricular hypertrophy (LVH).

Methods and Results—

Three hundred fifty-three participants with a mean±SD age of 64±12 years (54%men) underwent dobutamine cardiovascular magnetic resonance stress testing and then were followed up for 6±2 years (mean±SD; range, 0.5–11.5) to assess the post–dobutamine cardiovascular magnetic resonance stress test occurrence of MI or cardiac death. LV mass and the presence or absence of ischemia were determined; LVH was defined as an LV mass index >96 g/m
2
in men and >77 g/m
2
in women. LVH was present in 62 participants (18% of the men and 17% of the women,
P
=0.90). Seventy-one (20%) participants experienced an MI or cardiac death during follow-up. The MI and cardiac death rate was more frequent in those with versus without LVH (32% vs 17%,
P
=0.009). In multivariable analysis that accounted for the presence of preexisting coronary artery disease, hypertension, diabetes, stress-induced ischemia, and reduced LV ejection fraction, LVH was an independent predictor of MI and cardiac death (hazard ratio=1.99; 95% CI, 1.13–3.50;
P
=0.02).

Conclusions—

LVH is predictive of future MI and cardiac death in patients with or without inducible ischemia during dobutamine cardiac stress testing. As a result, LVH should be reported in those referred for dobutamine cardiac stress tests, particularly in those without inducible ischemia, in whom one would otherwise assume a favorable cardiac prognosis.
Increased Risk of Bleeding in Patients on Clopidogrel Therapy After Drug-Eluting Stents Implantation
Authors: Tsai Thomas T. , Ho P. Michael , Xu Stanley , Powers J. David , Carroll Nikki M. , Shetterly Susan M. , Maddox Thomas M. , Rumsfeld John S. , Margolis Karen , Go Alan S. , Magid David J.
Published: May 2010

Background—

Studies suggest that extended clopidogrel use after drug-eluting stent (DES) implantation may decrease the risk of myocardial infarction (MI) and death. Little is known about the competing risk of bleeding from clopidogrel in “real world” clinical practice.

Methods and Results—

We studied 7689 patients undergoing drug-eluting stent implantation enrolled in the HMO Research Network-Stent Registry between 2004 and 2007. Patients were analyzed in 6-month intervals for the occurrence of major bleeding, MI, and death. Clopidogrel use was determined by pharmacy dispensing data. Regression models assessed the association between clopidogrel use and outcomes. Overall, 3603 patients (49.1%) received clopidogrel for >6 months. During a mean follow-up of 418 days (SD, ±168 days), 217 (2.9%) patients died, 279 (3.7%) had a MI, and 271 (3.6%) had major bleeding. After adjustment, patients on clopidogrel therapy were associated with increased major bleeding in all time intervals (0 to 6 months: relative risk (RR)=2.70, 95% CI=1.41 to 5.19; 7 to 12 months: RR=1.71, 95% CI=1.05 to 2.79; 13 to 18 months: RR=2.34, 95% CI=1.26 to 4.34), compared with patients off clopidogrel. Clopidogrel use was also associated with decreased risk of MI for all time intervals (0 to 6 months: RR=0.52, 95% CI=0.36 to 0.77; 7 to 12 months: RR=0.46, 95% CI=0.30 to 0.70; 13 to 18 months: RR=0.53, 95% CI=0.29 to 0.99) and decreased death in the 7 to 12 month interval (RR=0.50, 95% CI=0.30 to 0.83).

Conclusions—

Clopidogrel use was associated with increased major bleeding and decreased MI persisting to 18 months. Bleeding risks on clopidogrel therapy deserve consideration in the ongoing debate regarding optimal clopidogrel duration after PCI.
Previous Coronary Stent Implantation and Cardiac Events in Patients Undergoing Noncardiac Surgery
Authors: Cruden Nicholas L.M. , Harding Scott A. , Flapan Andrew D. , Graham Cat , Wild Sarah H. , Slack Rachel , Pell Jill P. , Newby David E. ,   on behalf of the Scottish Coronary Revascularisation Register Steering Committee
Published: May 2010

Background—

Noncardiac surgery performed after coronary stent implantation is associated with an increased risk of stent thrombosis, myocardial infarction, and death. The influence of stent type and period of risk still have to be defined.

Methods and Results—

We linked the Scottish Coronary Revascularisation Register with hospital admission data to undertake a Scotland-wide retrospective cohort study examining cardiac outcomes in all patients who received drug-eluting or bare-metal stents between April 2003 and March 2007 and subsequently underwent noncardiac surgery. Of 1953 patients, 570 (29%) were treated with at least 1 drug-eluting stent and 1383 (71%) with bare-metal stents only. There were no differences between drug-eluting and bare-metal stents in the primary end point of in-hospital mortality or ischemic cardiac events (14.6% versus 13.3%;
P
=0.3) or the secondary end points of in-hospital mortality (0.7% versus 0.6%;
P
=0.8) and acute myocardial infarction (1.2% versus 0.7%;
P
=0.3). Perioperative death and ischemic cardiac events occurred more frequently when surgery was performed within 42 days of stent implantation (42.4% versus 12.8% beyond 42 days;
P
<0.001), especially in patients revascularized after an acute coronary syndrome (65% versus 32%;
P
=0.037). There were no temporal differences in outcomes between the drug-eluting and bare-metal stent groups.

Conclusions—

Patients undergoing noncardiac surgery after recent coronary stent implantation are at increased risk of perioperative myocardial ischemia, myocardial infarction, and death, particularly after an acute coronary syndrome. For at least 2 years after percutaneous coronary intervention, cardiac outcomes after noncardiac surgery are similar for both drug-eluting and bare-metal stents.
Future Cardiovascular Disease in China
Authors: Moran Andrew , Gu Dongfeng , Zhao Dong , Coxson Pamela , Wang Y. Claire , Chen Chung-Shiuan , Liu Jing , Cheng Jun , Bibbins-Domingo Kirsten , Shen Yu-Ming , He Jiang , Goldman Lee
Published: May 2010

Background—

The relative effects of individual and combined risk factor trends on future cardiovascular disease in China have not been quantified in detail.

Methods and Results—

Future risk factor trends in China were projected based on prior trends. Cardiovascular disease (coronary heart disease and stroke) in adults ages 35 to 84 years was projected from 2010 to 2030 using the Coronary Heart Disease Policy Model–China, a Markov computer simulation model. With risk factor levels held constant, projected annual cardiovascular events increased by >50% between 2010 and 2030 based on population aging and growth alone. Projected trends in blood pressure, total cholesterol, diabetes (increases), and active smoking (decline) would increase annual cardiovascular disease events by an additional 23%, an increase of approximately 21.3 million cardiovascular events and 7.7 million cardiovascular deaths over 2010 to 2030. Aggressively reducing active smoking in Chinese men to 20% prevalence in 2020 and 10% prevalence in 2030 or reducing mean systolic blood pressure by 3.8 mm Hg in men and women would counteract adverse trends in other risk factors by preventing cardiovascular events and 2.9 to 5.7 million total deaths over 2 decades.

Conclusions—

Aging and population growth will increase cardiovascular disease by more than a half over the coming 20 years, and projected unfavorable trends in blood pressure, total cholesterol, diabetes, and body mass index may accelerate the epidemic. National policy aimed at controlling blood pressure, smoking, and other risk factors would counteract the expected future cardiovascular disease epidemic in China.