bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclotriphosphazene-Pt-DACH Conjugates with Dipeptide Spacers for Drug Delivery Systems
Authors: Yong Woo Cho  , Choi Minyoung , Lee Kyunghae , Song Soo-Chang
Published: January 2010

An intelligent drug delivery system that exhibits a thermosensitive phase transition from a soluble to insoluble state was developed to deliver drugs into a tumor. Cyclotriphosphazene-Pt-DACH ( trans(±)-1,2-diaminocyclohexane) conjugates with dipeptide spacers were synthesized by successive reaction steps. The conjugates exhibited a reversible and thermosensitive phase transition with lower critical solution temperature in aqueous media that was varied by the substitution of different hydrophilic/hydrophobic side groups. The conjugate had similar cytotoxicity as cisplatin, but much greater than carboplatin against various human cancer cell lines. The conjugate was much more potent than cisplatin against the cisplatin-resistant cell line, A2780/CP70. The biodistribution and pharmacokinetic studies indicate that the present thermosensitive conjugate exhibits locally controlled drug delivery feature that could circumvent surgery treatment and reduce toxic side effects due to systemic administration.
Bleomycin Loaded Magnetic Chitosan Nanoparticles as Multifunctional Nanocarriers
Authors: Kavaz Doğa , Odabaş Sedat , Güven Eylem , Demirbilek Murat , Denkbaş Emir Baki
Published: January 2010

Iron oxide (Fe3O4) containing magnetic chitosan nanoparticles were prepared with Concanavalin-A and Bleomycin as multifunctional nanocarriers for the targeted cancer therapy by co-precipitation techniques. The chemical structures of nanoparticles were analyzed by FTIR and the magnetic properties of the nanoparticles were evaluated by electron spin resonance technique and vibrational scanning mangnetometer measurements. The in vitro release profiles of Bleomycin were investigated and chitosan nanoparticles characteristics were optimized for subsequent in vivo applications. The magnetic chitosan nanoparticles are biocompatible-based MTT assays. The therapeutic potential of these nanoparticles are being investigated for in vivo applications.
Gross or net? The role of taxation in the history of equity valuation
Authors: Rutterford Janette
Published: January 2010

This article explores the relationship between taxation and investment analysis technique for both the USA and the UK in the nineteenth and twentieth centuries. The article argues that the complexity of the British tax system, its emphasis on dividend payout rather than total return, the overlap between corporate and personal taxation, and the variation in methods of accounting for taxation in corporate accounts, all contributed to a concentration on dividend rather than earnings valuation metrics. In particular, the Price Earnings Ratio was not used in the UK until after 1965 whereas, in the USA, the simpler classical taxation system facilitated the use of the Price Earnings Ratio as a valuation metric as early as the 1920s.
Library resources for studying accounting history: A research note
Authors: Flesher Dale L. , Elam Rick , Flesher Tonya K.
Published: January 2010

The University of Mississippi offers many resources for studying the history of the accounting profession around the world. The accountancy library holdings are the largest of any library in the world, including virtually everything published in English during the past century, and many earlier items. In addition to tens of thousands of books and over 1,000 accounting and finance journal titles, there are tens of thousands of pamphlets, speeches, committee reports, photos, and courtroom documents that exist at no other library in the world. There are also hundreds of archival collections of old business records that serve as primary resources for all kinds of accounting research. The J.D. Williams Library at the University of Mississippi is truly the international center of accounting research, and many of its resources are available on the Internet to anyone within reach of a computer. The purpose of the article is to describe the various accounting library collections with particular emphasis on the research resources available internationally through the Internet.
Use of financial statements to legitimize a new non-profit organization during the US Civil War: The case of the Northwestern Sanitary Commission
Authors: Normand Carol J. , Wootton Charles W.
Published: January 2010

Research has shown that organizations historically have used accounting and financial reporting to gain needed legitimacy for their actions and existence. In the case of non-profit organizations, this legitimacy is critical for they often depend upon external contributions to survive. This article explores how the newly-formed Chicago-based philanthropic Northwestern Sanitary Commission used its financial reports to legitimize its operations as well as to respond to rumors concerning its stewardship of donated funds and supplies from 1861 to 1865 during the US Civil War. This exploration contributes to our understanding of the historical development of non-profit accounting.
Beneficial Electrophysiological Effects of Trimetazidine in Patients With Postischemic Chronic Heart Failure
Authors: Cera Michela , Salerno Anna , Fragasso Gabriele , Montanaro Claudia , Gardini Chiara , Marinosci Giovanni , Arioli Francesco , Spoladore Roberto , Facchini Alberto , Godino Cosmo , Margonato Alberto
Published: January 2010

The aim of the study was to assess whether trimetazidine (TMZ) could affect dispersion of atrial depolarization and ventricular repolarization. Corrected QT interval (QTc), QTc dispersion (QTc-d), Tpeak—Tend, and Tpeak—Tend dispersion (Tpeak—Tend-d) were measured in 30 patients with chronic heart failure (CHF) before and 6 months after randomization to conventional therapy plus TMZ (17 patients) or conventional therapy alone (13 patients). After 6 months, QTc was significantly reduced in both groups, whereas QT-peak was increased only in control group. Tpeak—Tend-d decreased (from 63.53 ± 24.73 to 42.35 ± 21.07 milliseconds, P = .006) only in TMZ group. When subgrouped according to CHF etiology, only ischemic patients on TMZ showed Tpeak—Tend-d reduction (65.00 ± 27.14 vs 36.67 ± 11.55 milliseconds, P = .001 in ischemic patients; 60.00 ± 20.00 vs 56.00 ± 33.86 milliseconds, P = NS, in nonischemic). These electrophysiological properties indicate an undiscovered mechanism of action of TMZ, which could be useful in conditions at risk of major arrhythmias.
Ethics and the Promotion of Inclusiveness Within Qualitative Research: Case Examples From Asia and the Pacific
Authors: Czymoniewicz-Klippel Melina T. , Brijnath Bianca , Crockett Belinda
Published: January 2010

Qualitative researchers are often confronted by ethical challenges when making research decisions because current guidelines and principles guiding research ethics do not wholly cover the concerns that can arise in complex social research situations. In this article, the authors explore this dilemma in relation to our experiences of conducting sensitive qualitative research with vulnerable groups in developing countries of Asia and the Pacific. With a focus on informed consent, the authors offer three case examples to explicate the difficulties faced in matching ethics theory with proforma approval requirements, which may limit the application of more expansive approaches to research design. To conclude, the authors put forth recommendations for modifications to the ethics system as a whole to promote greater collaboration and inclusion of qualitative researchers to the review and practice of research ethics in Australia.
Places of the imagination: an ethnography of the TV detective tour
Authors: Reijnders Stijn
Published: January 2010

This article considers the phenomenon of the TV detective tour, guided tours of the locations and settings of popular TV detective programs. What explains the growing popularity of these tours? The article proposes that the locations in question serve as physical points of reference to an imagined world. By visiting these locations and focusing on them, tourists are able to construct and subsequently cross a symbolic boundary between an ‘imagined’ and a ‘real’ world. To explain this process, a new concept is introduced: lieux d’imagination . This concept is supported and developed on the basis of ethnographic analysis of three popular TV detective tours: the Inspector Morse Tour in Oxford, the Baantjer Tour in Amsterdam, and the Wallander Tour in Ystad, Sweden. In all, 31 interviews were conducted with tourist office employees, tour guides, local inhabitants, and tourists; these interviews were supplemented with participatory observation. Analysis of interview transcripts and observation records shows that lieux d’imagination result from a complex process of negotiation and appropriation.
Endotoxin, zymosan, and cytokines decrease the expression of the transcription factor, carbohydrate response element binding protein, and its target genes
Authors: Feingold Kenneth R. , Shigenaga Judy K. , Patzek Sophie M. , Chui Lisa G. , Moser Arthur , Grunfeld Carl
Published: January 2010

Carbohydrate response element binding protein (ChREBP) is a recently discovered transcription factor whose levels and activity are increased by glucose leading to the activation of target genes, which include acetyl-CoA carboxylase, fatty acid synthase, and liver-type pyruvate kinase. Here, we demonstrate that lipopolysaccharide (LPS) treatment causes a marked decrease in ChREBP mRNA and protein levels in the liver of mice fed a normal chow diet or in mice fasted for 24 h and then re-fed a high carbohydrate diet. This decrease occurs rapidly and is a sensitive response (half-maximal dose 0.1 μg/mouse). The decrease in ChREBP is accompanied by a decrease in the expression of ChREBP target genes. Zymosan and turpentine treatment also decrease hepatic ChREBP levels and the expression of its target genes. Additionally, tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) decrease liver ChREBP expression both in vivo and in Hep3B cells in culture. Finally, LPS decreased ChREBP expression in muscle and adipose tissue. These studies demonstrate that ChREBP is down-regulated during the acute phase response resulting in alterations in the expression of ChREBP regulated target genes. Thus, ChREBP joins a growing list of transcription factors that are regulated during the acute phase response.
Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells
Authors: Merluzzi Sonia , Frossi Barbara , Gri Giorgia , Parusso Serena , Tripodo Claudio , Pucillo Carlo
Published: January 2010

The evidence of a tight spatial interaction between mast cells (MCs) and B lymphocytes in secondary lymphoid organs, along with the data regarding the abundance of MCs in several B-cell lymphoproliferative disorders prompted us to investigate whether MCs could affect the proliferation and differentiation of B cells. To this aim, we performed coculture assays using mouse splenic B cells and bone marrow–derived MCs. Both nonsensitized and activated MCs proved able to induce a significant inhibition of cell death and an increase in proliferation of naive B cells. Such proliferation was further enhanced in activated B cells. This effect relied on cell-cell contact and MC-derived interleukin-6 (IL-6). Activated MCs could regulate CD40 surface expression on unstimulated B cells and the interaction between CD40 with CD40 ligand (CD40L) on MCs, together with MC-derived cytokines, was involved in the differentiation of B cells into CD138+ plasma cells and in selective immunoglobulin A (IgA) secretion. These data were corroborated by in vivo evidence of infiltrating MCs in close contact with IgA-expressing plasma cells within inflamed tissues. In conclusion, we reported here a novel role for MCs in sustaining B-cell expansion and driving the development of IgA-oriented humoral immune responses.
Structural basis for spectrin recognition by ankyrin
Authors: Ipsaro Jonathan J. , Mondragón Alfonso
Published: January 2010

Maintenance of membrane integrity and organization in the metazoan cell is accomplished through intracellular tethering of membrane proteins to an extensive, flexible protein network. Spectrin, the principal component of this network, is anchored to membrane proteins through the adaptor protein ankyrin. To elucidate the atomic basis for this interaction, we determined a crystal structure of human βI-spectrin repeats 13 to 15 in complex with the ZU5-ANK domain of human ankyrin R. The structure reveals the role of repeats 14 to 15 in binding, the electrostatic and hydrophobic contributions along the interface, and the necessity for a particular orientation of the spectrin repeats. Using structural and biochemical data as a guide, we characterized the individual proteins and their interactions by binding and thermal stability analyses. In addition to validating the structural model, these data provide insight into the nature of some mutations associated with cell morphology defects, including those found in human diseases such as hereditary spherocytosis and elliptocytosis. Finally, analysis of the ZU5 domain suggests it is a versatile protein-protein interaction module with distinct interaction surfaces. The structure represents not only the first of a spectrin fragment in complex with its binding partner, but also that of an intermolecular complex involving a ZU5 domain.
Power and sample size estimation in microarray studies
Authors: Lin Wei-Jiun , Hsueh Huey-Miin , Chen James J
Published: January 2010

Background

Before conducting a microarray experiment, one important issue that needs to be determined is the number of arrays required in order to have adequate power to identify differentially expressed genes. This paper discusses some crucial issues in the problem formulation, parameter specifications, and approaches that are commonly proposed for sample size estimation in microarray experiments. Common methods for sample size estimation are formulated as the minimum sample size necessary to achieve a specified sensitivity (proportion of detected truly differentially expressed genes)on averageat a specified false discovery rate (FDR) level and specified expected proportion (π1) of the true differentially expression genes in the array. Unfortunately, the probability of detecting the specified sensitivity in such a formulation can be low. We formulate the sample size problem as the number of arrays needed to achieve a specified sensitivity with95% probabilityat the specified significance level. A permutation method using a small pilot dataset to estimate sample size is proposed. This method accounts for correlation and effect size heterogeneity among genes.

Results

A sample size estimate based on the common formulation, to achieve the desired sensitivity on average, can be calculated using a univariate method without taking the correlation among genes into consideration. This formulation of sample size problem is inadequate because the probability of detecting the specified sensitivity can be lower than 50%. On the other hand, the needed sample size calculated by the proposed permutation method will ensure detecting at least the desired sensitivity with 95% probability. The method is shown to perform well for a real example dataset using a small pilot dataset with 4-6 samples per group.

Conclusions

We recommend that the sample size problem should be formulated to detect a specified proportion of differentially expressed genes with 95% probability. This formulation ensures finding the desired proportion of true positives with high probability. The proposed permutation method takes the correlation structure and effect size heterogeneity into consideration and works well using only a small pilot dataset.
FiGS: a filter-based gene selection workbench for microarray data
Authors: Hwang Taeho , Sun Choong-Hyun , Yun Taegyun , Yi Gwan-Su
Published: January 2010

Background

The selection of genes that discriminate disease classes from microarray data is widely used for the identification of diagnostic biomarkers. Although various gene selection methods are currently available and some of them have shown excellent performance, no single method can retain the best performance for all types of microarray datasets. It is desirable to use a comparative approach to find the best gene selection result after rigorous test of different methodological strategies for a given microarray dataset.

Results

FiGS is a web-based workbench that automatically compares various gene selection procedures and provides the optimal gene selection result for an input microarray dataset. FiGS builds up diverse gene selection procedures by aligning different feature selection techniques and classifiers. In addition to the highly reputed techniques, FiGS diversifies the gene selection procedures by incorporating gene clustering options in the feature selection step and different data pre-processing options in classifier training step. All candidate gene selection procedures are evaluated by the .632+ bootstrap errors and listed with their classification accuracies and selected gene sets. FiGS runs on parallelized computing nodes that capacitate heavy computations. FiGS is freely accessible at http://gexp.kaist.ac.kr/figs.

Conclusion

FiGS is an web-based application that automates an extensive search for the optimized gene selection analysis for a microarray dataset in a parallel computing environment. FiGS will provide both an efficient and comprehensive means of acquiring optimal gene sets that discriminate disease states from microarray datasets.
SAMPLEX: Automatic mapping of perturbed and unperturbed regions of proteins and complexes
Authors: Krzeminski Mickaël , Loth Karine , Boelens Rolf , Bonvin Alexandre MJJ
Published: January 2010

Background

The activity of proteins within the cell is characterized by their motions, flexibility, interactions or even the particularly intriguing case of partially unfolded states. In the last two cases, a part of the protein is affected either by binding or unfolding and the detection of the respective perturbed and unperturbed region(s) is a fundamental part of the structural characterization of these states. This can be achieved by comparing experimental data of the same protein in two different states (bound/unbound, folded/unfolded). For instance, measurements of chemical shift perturbations (CSPs) from NMR 1H-15N HSQC experiments gives an excellent opportunity to discriminate both moieties.

Results

We describe an innovative, automatic and unbiased method to distinguish perturbed and unperturbed regions in a protein existing in two distinct states (folded/partially unfolded, bound/unbound). The SAMPLEX program takes as input a set of data and the corresponding three-dimensional structure and returns the confidence for each residue to be in a perturbed or unperturbed state. Its performance is demonstrated for different applications including the prediction of disordered regions in partially unfolded proteins and of interacting regions in protein complexes.

Conclusions

The proposed approach is suitable for partially unfolded states of proteins, local perturbations due to small ligands and protein-protein interfaces. The method is not restricted to NMR data, but is generic and can be applied to a wide variety of information.
A genetic screen for modifiers of Drosophila caspase Dcp-1 reveals caspase involvement in autophagy and novel caspase-related genes
Authors: Kim Young-Il , Ryu Taewoo , Lee Judong , Heo Young-Shin , Ahnn Joohong , Lee Seung-Jae , Yoo OokJoon
Published: January 2010

Background

Caspases are cysteine proteases with essential functions in the apoptotic pathway; their proteolytic activity toward various substrates is associated with the morphological changes of cells. Recent reports have described non-apoptotic functions of caspases, including autophagy. In this report, we searched for novel modifiers of the phenotype of Dcp-1 gain-of-function (GF) animals by screening promoter element- inserted Drosophila melanogaster lines (EP lines).

Results

We screened ~15,000 EP lines and identified 72 Dcp-1-interacting genes that were classified into 10 groups based on their functions and pathways: 4 apoptosis signaling genes, 10 autophagy genes, 5 insulin/IGF and TOR signaling pathway genes, 6 MAP kinase and JNK signaling pathway genes, 4 ecdysone signaling genes, 6 ubiquitination genes, 11 various developmental signaling genes, 12 transcription factors, 3 translation factors, and 11 other unclassified genes including 5 functionally undefined genes. Among them, insulin/IGF and TOR signaling pathway, MAP kinase and JNK signaling pathway, and ecdysone signaling are known to be involved in autophagy. Together with the identification of autophagy genes, the results of our screen suggest that autophagy counteracts Dcp-1-induced apoptosis. Consistent with this idea, we show that expression of eGFP-Atg5 rescued the eye phenotype caused by Dcp-1 GF. Paradoxically, we found that over-expression of full-length Dcp-1 induced autophagy, as Atg8b-GFP, an indicator of autophagy, was increased in the eye imaginal discs and in the S2 cell line. Taken together, these data suggest that autophagy suppresses Dcp-1-mediated apoptotic cell death, whereas Dcp-1 positively regulates autophagy, possibly through feedback regulation.

Conclusions

We identified a number of Dcp-1 modifiers that genetically interact with Dcp-1-induced cell death. Our results showing that Dcp-1 and autophagy-related genes influence each other will aid future investigations of the complicated relationships between apoptosis and autophagy.
The contribution of recombination to heterozygosity differs among plant evolutionary lineages and life-forms
Authors: Jaramillo-Correa Juan P , Verdú Miguel , González-Martínez Santiago C
Published: January 2010

Background

Despite its role as a generator of haplotypic variation, little is known about how the rates of recombination evolve across taxa. Recombination is a very labile force, susceptible to evolutionary and life trait related processes, which have also been correlated with general levels of genetic diversity. For example, in plants, it has been shown that long-lived outcrossing taxa, such as trees, have higher heterozygosity (H
e) at SSRs and allozymes than selfing or annual species. However, some of these tree taxa have surprisingly low levels of nucleotide diversity at the DNA sequence level, which points to recombination as a potential generator of genetic diversity in these organisms. In this study, we examine how genome-wide and within-gene rates of recombination evolve across plant taxa, determine whether such rates are influenced by the life-form adopted by species, and evaluate if higher genome-wide rates of recombination translate into higher H
e values, especially in trees.

Results

Estimates of genome-wide (cM/Mb) recombination rates from 81 higher plants showed a significant phylogenetic signal. The use of different comparative phylogenetic models demonstrated that there is a positive correlation between recombination rate and H
e (0.83 ± 0.29), and that trees have higher rates of genome-wide recombination than short-lived herbs and shrubs. A significant taxonomic component was further made evident by our models, as conifers exhibited lower recombination rates than angiosperms. This trend was also found at the within-gene level.

Conclusions

Altogether, our results illustrate how both common ancestry and life-history traits have to be taken into account for understanding the evolution of genetic diversity and genomic rates of recombination across plant species, and highlight the relevance of species life forms to explain general levels of diversity and recombination.
Molecular diversity of antimicrobial effectors in the oyster Crassostrea gigas
Authors: Schmitt Paulina , Gueguen Yannick , Desmarais Erick , Bachère Evelyne , de Lorgeril Julien
Published: January 2010

Background

To gain insight into the molecular diversity of antimicrobial peptides and proteins in the oyster Crassostrea gigas, we characterized and compared the sequence polymorphism of the antimicrobial peptides (AMPs), Cg-Defensins (Cg-Defs) and Cg-Proline Rich peptide (Cg-Prp), and of the bactericidal permeability increasing protein, Cg-BPI. For that, we analyzed genomic and transcript sequences obtained by specific PCR amplification and in silico searches.

Results

High diversification among the three antimicrobial effectors was evidenced by this polymorphism survey. On the basis of sequence phylogenies, each AMP aggregates into clearly defined groups of variants and is the product of a multigenic family displaying a variety of gene structures. In contrast, Cg-bpi forms a single group and is encoded by a single gene copy. Moreover, we identified for both AMPs several genetic mechanisms of diversification such as recombination, parallel mutations leading to phylogenetic homoplasy and indel events. In addition, the non synonymous to synonymous substitutions ratio by codon (dN/dS) revealed several negatively and positively selected sites for both AMPs, suggesting that directional selection pressures have shaped their sequence variations.

Conclusions

This study shows for the first time in a mollusc that antimicrobial peptides and proteins have been subject to distinct patterns of diversification and we evidence the existence of different evolutionary routes leading to such sequence variability.
Correlation between ribonucleoside-diphosphate reductase and three replication proteins in Escherichia coli
Authors: Sánchez-Romero M Antonia , Molina Felipe , Jiménez-Sánchez Alfonso
Published: January 2010

Background

There has long been evidence supporting the idea that RNR and the dNTP-synthesizing complex must be closely linked to the replication complex or replisome. We contributed to this body of evidence in proposing the hypothesis of the replication hyperstructure. A recently published work called this postulate into question, reporting that NrdB is evenly distributed throughout the cytoplasm. Consequently we were interested in the localization of RNR protein and its relationship with other replication proteins.

Results

We tagged NrdB protein with 3×FLAG epitope and detected its subcellular location by immunofluorescence microscopy. We found that this protein is located in nucleoid-associated clusters, that the number of foci correlates with the number of replication forks at any cell age, and that after the replication process ends the number of cells containing NrdB foci decreases.

We show that the number of NrdB foci is very similar to the number of SeqA, DnaB, and DnaX foci, both in the whole culture and in different cell cycle periods. In addition, interfoci distances between NrdB and three replication proteins are similar to the distances between two replication protein foci.

Conclusions

NrdB is present in nucleoid-associated clusters during the replication period. These clusters disappear after replication ends. The number of these clusters is closely related to the number of replication forks and the number of three replication protein clusters in any cell cycle period. Therefore we conclude that NrdB protein, and most likely RNR protein, is closely linked to the replication proteins or replisome at the replication fork. These results clearly support the replication hyperstructure model.
Cloning of the Zygosaccharomyces bailii GAS 1 homologue and effect of cell wall engineering on protein secretory phenotype
Authors: Passolunghi Simone , Riboldi Luca , Dato Laura , Porro Danilo , Branduardi Paola
Published: January 2010

Background

Zygosaccharomyces bailii is a diploid budding yeast still poorly characterized, but widely recognised as tolerant to several stresses, most of which related to industrial processes of production. Because of that, it would be very interesting to develop its ability as a cell factory. Gas1p is a β-1,3-glucanosyltransglycosylase which plays an important role in cell wall construction and in determining its permeability. Cell wall defective mutants of Saccharomyces cerevisiae and Pichia pastoris, deleted in the GAS 1 gene, were reported as super-secretive. The aim of this study was the cloning and deletion of the GAS 1 homologue of Z. bailii and the evaluation of its deletion on recombinant protein secretion.

Results

The GAS 1 homologue of Z. bailii was cloned by PCR, and when expressed in a S. cerevisiae GAS 1 null mutant was able to restore the parental phenotype. The respective Z. bailii Δgas 1 deleted strain was obtained by targeted deletion of both alleles of the ZbGAS 1 gene with deletion cassettes having flanking regions of ~400 bp. The morphological and physiological characterization of the Z. bailii null mutant resulted very similar to that of the corresponding S. cerevisiae mutant. As for S. cerevisiae, in the Z. bailii Δgas 1 the total amount of protein released in the medium was significantly higher. Moreover, three different heterologous proteins were expressed and secreted in said mutant. The amount of enzymatic activity found in the medium was almost doubled in the case of the Candida rugosa lipase CRL1 and of the Yarrowia lipolytica protease XPR2, while for human IL-1β secretion disruption had no relevant effect.

Conclusions

The data presented confirm that the engineering of the cell wall is an effective way to improve protein secretion in yeast. They also confirmed that Z. bailii is an interesting candidate, despite the knowledge of its genome and the tools for its manipulation still need to be improved. However, as already widely reported in literature, our data confirmed that an "always working" solution to the problems related to recombinant protein production can be hardly, if never, found; instead, manipulations have to be finely tuned for each specific product and/or combination of host cell and product.
Regulation of the transcription factor NF-κB1 by microRNA-9 in human gastric adenocarcinoma
Authors: Wan Hai-Ying , Guo Li-Min , Liu Tao , Liu Min , Li Xin , Tang Hua
Published: January 2010

Background

MicroRNAs (miRNAs) are a new class of naturally occurring, small, non-coding RNAs that regulate protein-coding mRNAs by causing mRNA degradation or repressing translation. The roles of miRNAs in lineage determination and proliferation, as well as the localization of several miRNA genes at sites of translocation breakpoints or deletions, have led to speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state.

Results

We showed that miR-9 was downregulated in human gastric adenocarcinoma. Overexpression of miR-9 suppressed the growth of human gastric adenocarcinoma cell line MGC803 cell as well as xenograft tumors derived from them in SCID mice. Bioinformatics analysis indicated a putative miR-9 binding site in the 3'-untranslated region (3'UTR) of the tumor-related gene NF-κB1 mRNA. In an EGFP reporter system, overexpression of miR-9 downregulated EGFP intensity, and mutation of the miR-9 binding site abolished the effect of miR-9 on EGFP intensity. Furthermore, both the NF-κB1 mRNA and protein levels were affected by miR-9. Finally, knockdown of NF-κB1 inhibited MGC803 cell growth in a time-dependent manner, while ectopic expression of NF-κB1 could rescue MGC803 cell from growth inhibition caused by miR-9.

Conclusion

These findings indicate that miR-9 targets NF-κB1 and regulates gastric cancer cell growth, suggesting that miR-9 shows tumor suppressive activity in human gastric cancer pathogenesis.
Characterization of a VHS virus genotype III isolated from rainbow trout (Oncorhychus mykiss) at a marine site on the west coast of Norway
Authors: Duesund Henrik , Nylund Stian , Watanabe Kuninori , Ottem Karl F , Nylund Are
Published: January 2010

Background

Norwegian production of rainbow trout (Oncorhynchus mykiss) has been without any outbreaks of VHS for many years until the disease emerged in a farm in western Norway in November 2007. The fish were, in addition to VHS virus, positive for gill chlamydia-like bacteria, Flavobacterium psychrophilum, and a microsporidian. A new VHS virus genotype III was isolated from the fish in RTgill-W1 cells and the complete coding region (11,065 nucleotides) was sequenced. This virus was also used in a challenge experiment to see if it could cause any mortality in rainbow trout in sea water.

Results

This is the first time a nearly complete sequence of a genotype III virus isolate has been presented. The organization of the genes is the same as in the other VHS virus genotypes studied (GI and GIV). Between the ORFs are nontranslated regions that contain highly conserved sequences encompassing the polyadenylation signal for one gene, and the putative transcription initiation site of the next gene. The intergenic regions vary in length from 74 nt to 128 nt. The nucleotide sequence is more similar to genotype I isolates compared to isolates from genotype II and IV. Analyses of the sequences of the N and G protein genes show that this new isolate is distinct from other VHS virus isolates and groups closely together with isolates from genotype III. In a challenge experiment, using intraperitoneal (ip) injection of the isolate, co-habitation with infected fish, and bath challenge, mortalities slightly above 40% were obtained. There was no significant difference in mortality between the bath challenged group and the ip injected group, while the mortality in the co-habitation group was as low as 30%.

Conclusions

All VHS virus isolates in genotype III are from marine fish in the North East Atlantic. Unlike the other known genotype III isolates, which are of low virulence, this new isolate is moderately virulent. It was not possible to detect any changes in the virus genome that could explain the higher virulence. A major problem for the study of virulence factors is the lack of information about other genotype III isolates.
CD16 (FcRγIII) as a potential marker of osteoclast precursors in psoriatic arthritis
Authors: Chiu Yahui Grace , Shao Tianmeng , Feng Changyong , Mensah Kofi A , Thullen Michael , Schwarz Edward M , Ritchlin Christopher T
Published: January 2010

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterized by bone erosion mediated by osteoclasts (OC). Our previous studies showed an elevated frequency of OC precursors (OCP) in PsA patients. Here, we examined if OC arise from CD16-positive monocytes in PsA.

Methods

Peripheral blood mononuclear cells (PBMC) or monocytes were isolated from human peripheral blood and sorted based on CD16 expression. Sorted cells were cultured alone or with bone wafers in the presence of receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Enumeration and bone erosion activity of OC were examined after culture. The effects of tumor necrosis factor-alpha (TNFα), OC-promoting (M-CSF plus RANKL), and dendritic cell (DC)-promoting (GM-CSF plus interleukin (IL)-4) cytokines on CD16 surface expression were examined by flow cytometry.

Results

PsA and psoriasis (Ps) subjects had a higher percentage of circulating inflammatory CD14+CD16+ cells than healthy controls (HC). Exposure of cells to OC-promoting, but not DC-promoting media, was associated with CD16 up-regulation. PBMC of Ps and PsA had a higher frequency of cells expressing intermediate levels of CD16. OC were mainly derived from CD16+ cells in PsA. Increased CD16 expression was associated with a higher bone erosion activity in PsA.

Conclusions

An increased frequency of circulating CD14+CD16+ cells was noted in PsA compared to controls, and intermediate levels of CD16 may suggest a transitional state of OCP during osteoclastogenesis. Intriguingly, TNFα blocked CD16 expression on a subset of CD14+ monocytes. Collectively, our data suggest that CD16 has the potential to serve as an OCP marker in inflammatory arthritis.
ABL-N-induced apoptosis in human breast cancer cells is partially mediated by c-Jun NH2-terminal kinase activation
Authors: Liu Bin , Han Mei , Sun Rong-Hua , Wang Jun-Jie , Zhang Yan-Ping , Zhang Di-Qun , Wen Jin-Kun
Published: January 2010

Introduction

The present study was designed to determine the possibility of acetylbritannilactone (ABL) derivative 5-(5-(ethylperoxy)pentan-2-yl)-6-methyl-3-methylene-2-oxo-2,3,3a,4,7,7a-hexahydrobenzofuran-4-yl 2-(6-methoxynaphthalen-2-yl)propanoate (ABL-N) as a novel therapeutic agent in human breast cancers.

Methods

We investigated the effects of ABL-N on the induction of apoptosis in human breast cancer cells and further examined the underlying mechanisms. Moreover, tumor growth inhibition of ABL-N was done in xenograft models.

Results

ABL-N induced the activation of caspase-3 in estrogen receptor (ER)-negative cell lines MDA-MB-231 and MDA-MB-468, as evidenced by the cleavage of endogenous substrate Poly (ADP-ribose) polymerase (PARP). Pretreatment of cells with pan-caspase inhibitor z-VAD-fmk or caspase-3-specific inhibitor z-DEVD-fmk inhibited ABL-N-induced apoptosis. ABL-N treatment also resulted in an increase in the expression of pro-apoptotic members (Bax and Bad) with a concomitant decrease in Bcl-2. Furthermore, c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase (p38) were activated in the apoptosis induced by ABL-N and JNK-specific inhibitor SP600125 and JNK small interfering RNA (siRNA) antagonized ABL-N-mediated apoptosis. However, the p38-specific inhibitor SB203580 had no effect upon these processes. Moreover, neither of the caspase inhibitors prevented ABL-N-induced JNK activation, indicating that JNK is upstream of caspases in ABL-N-initiated apoptosis. Additionally, in a nude mice xenograft experiment, ABL-N significantly inhibited the tumor growth of MDA-MB-231 cells.

Conclusions

ABL-N induces apoptosis in breast cancer cells through the activation of caspases and JNK signaling pathways. Moreover, ABL-N treatment causes a significant inhibition of tumor growth in vivo. Therefore, it is thought that ABL-N might be a potential drug for use in breast cancer prevention and intervention.
Madm (Mlf1 adapter molecule) cooperates with Bunched A to promote growth in Drosophila
Authors: Gluderer Silvia , Brunner Erich , Germann Markus , Jovaisaite Virginija , Li Changqing , Rentsch Cyrill A , Hafen Ernst , Stocker Hugo
Published: January 2010

Background

The TSC-22 domain family (TSC22DF) consists of putative transcription factors harboring a DNA-binding TSC-box and an adjacent leucine zipper at their carboxyl termini. Both short and long TSC22DF isoforms are conserved from flies to humans. Whereas the short isoforms include the tumor suppressor TSC-22 (Transforming growth factor-β1 stimulated clone-22), the long isoforms are largely uncharacterized. In Drosophila, the long isoform Bunched A (BunA) acts as a growth promoter, but how BunA controls growth has remained obscure.

Results

In order to test for functional conservation among TSC22DF members, we expressed the human TSC22DF proteins in the fly and found that all long isoforms can replace BunA function. Furthermore, we combined a proteomics-based approach with a genetic screen to identify proteins that interact with BunA. Madm (Mlf1 adapter molecule) physically associates with BunA via a conserved motif that is only contained in long TSC22DF proteins. Moreover, Drosophila Madm acts as a growth-promoting gene that displays growth phenotypes strikingly similar to bunA phenotypes. When overexpressed, Madm and BunA synergize to increase organ growth.

Conclusions

The growth-promoting potential of long TSC22DF proteins is evolutionarily conserved. Furthermore, we provide biochemical and genetic evidence for a growth-regulating complex involving the long TSC22DF protein BunA and the adapter molecule Madm.

See minireview at http://jbiol.com/content/9/1/8.
Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the Randomized Multicenter Phase III Trial BMS099
Authors: Lynch Thomas J. , Patel Taral , Dreisbach Luke , McCleod Michael , Heim William J. , Hermann Robert C. , Paschold Eugene , Iannotti Nicholas O. , Dakhil Shaker , Gorton Steven , Pautret Virginie , Weber Martin R. , Woytowitz Donald
Published: January 2010

Purpose

To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m2) or docetaxel (75 mg/m2), at the investigator's discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for ≤ six cycles; cetuximab (400 mg/m2 on day 1, 250 mg/m2 weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated.

Results

Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components.

Conclusion

The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.
Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial
Authors: Sternberg Cora N. , Davis Ian D. , Mardiak Jozef , Szczylik Cezary , Lee Eunsik , Wagstaff John , Barrios Carlos H. , Salman Pamela , Gladkov Oleg A. , Kavina Alexander , Zarbá Juan J. , Chen Mei , McCann Lauren , Pandite Lini , Roychowdhury Debasish F. , Hawkins Robert E.
Published: January 2010

Purpose

Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC).

Patients and Methods

Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed.

Results

Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo.

Conclusion

Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
Impact of Ethnicity on Primary Treatment Choice and Mortality in Men With Prostate Cancer: Data From CaPSURE
Authors: Moses Kelvin A. , Paciorek Alan T. , Penson David F. , Carroll Peter R. , Master Viraj A.
Published: January 2010

Purpose

Men diagnosed with prostate cancer have multiple options available for treatment. Previous reports have indicated a trend of differing modalities of treatment chosen by African American and white men. We investigated the role of ethnicity in primary treatment choice and how this affected overall and cancer-specific mortality.

Methods

By utilizing data abstracted from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), patients were compared by ethnicity, primary treatment, number of comorbidities, risk level according to modified D'Amico criteria, age, highest educational level attained, type of insurance, treatment facility, and perception of general health. Multinomial logistic regression analysis was performed to determine the effect of the tested variables on primary treatment and mortality.

Results

African American men were more likely to receive nonsurgical therapy than white men with equivalent disease characteristics. Whites were 48% less likely than African Americans to receive androgen deprivation therapy (ADT) compared with surgery (P = .02) and were 25% less likely than African Americans to receive radiation therapy compared with surgery (P = .08). Whites with low-risk disease were 71% less likely to receive ADT than African American men with similar disease (P = .01). Adjusted overall and prostate cancer–specific mortality were not significantly different between whites and African Americans (hazard ratios, 0.73 and 0.37, respectively). Risk level, type of treatment, and type of insurance had the strongest effects on risk of mortality.

Conclusion

There is a statistically significant difference in primary treatment for prostate cancer between African American and white men with similar risk profiles. Additional research on the influence of patient/physician education and perception and the role that socioeconomic factors play in mortality from prostate cancer may be areas of focus for public health initiatives.
Parent–child relationship quality and infantile amnesia in adults
Authors: Peterson Carole. , Nguyen Duyen T. K.
Published: January 2010

The first years of life are typically shrouded by infantile amnesia, but there is enormous variability between adults in how early and how much they can remember from this period. This study examined one possible factor affecting this variability: whether the perceived quality of parent–child relationships is associated with the number of early memories young adults can retrieve, and their age at the time of their first memory. We found such associations but they were qualified by parent gender. Mother–child relationships that were more affectively intense (greater social support but also more negative interchanges) were associated with recalling more early memories, although paternal companionship was most associated with how early an individual's first memory was. Affective tone of retrieved memories was also assessed, and a greater proportion of affectively positive memories (as well as fewer affectively neutral memories for males) was associated with high parental involvement in children's lives.