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Vivian Lee

Publications and source records attributed to Vivian Lee.

At least 19 recordsLinked to original sources
PubMed2006

GOAnnotator: linking protein GO annotations to evidence text.

BACKGROUND: Annotation of proteins with gene ontology (GO) terms is ongoing work and a complex task. Manual GO annotation is precise and precious, but it is time-consuming. Therefore, instead of curated annotations most of the proteins come with uncurated annotations, which have been generated automatically. Text-mining systems that use literature for automatic annotation have been proposed but they do not satisfy the high quality expectations of curators. RESULTS: In this paper we describe an approach that links uncurated annotations to text extracted from literature. The selection of the text is based on the similarity of the text to the term from the uncurated annotation. Besides substantiating the uncurated annotations, the extracted texts also lead to novel annotations. In addition, the approach uses the GO hierarchy to achieve high precision. Our approach is integrated into GOAnnotator, a tool that assists the curation process for GO annotation of UniProt proteins. CONCLUSION: The GO curators assessed GOAnnotator with a set of 66 distinct UniProt/SwissProt proteins with uncurated annotations. GOAnnotator provided correct evidence text at 93% precision. This high precision results from using the GO hierarchy to only select GO terms similar to GO terms from uncurated annotations in GOA. Our approach is the first one to achieve high precision, which is crucial for the efficient support of GO curators. GOAnnotator was implemented as a web tool that is freely available at http://xldb.di.fc.ul.pt/rebil/tools/goa/.

Journal Article↗
PubMed2006

Energetics of lizard embryos are not canalized by thermal acclimation.

In some species of ectotherms, temperature has little or no effect on the amount of energy expended during embryonic development. This phenomenon can result from either of two mechanisms: (1) a shorter incubation period at higher temperatures, which offsets the expected increase in metabolic rate, or (2) a compensatory decrease in the rate at which embryos expend energy for maintenance. To distinguish the relative importance of these two mechanisms, we quantified the acute and chronic effects of temperature on embryonic metabolism in the eastern fence lizard (Sceloporus undulatus). First, we measured metabolic rates of individual embryos at 27 degrees, 31 degrees, and 34 degrees C. Second, we examined the capacity for thermal acclimation by measuring the metabolic rates of embryos at 30 degrees C, after a period of incubation at either 28 degrees or 32 degrees C. As with adult reptiles, the metabolic rates of embryos increased with an acute increase in temperature; the Q(10) of metabolic rate from 27 degrees to 34 degrees C was 2.1 (+/-0.2). No evidence of thermal acclimation was observed either early or late in development. In S. undulatus, a shorter incubation period at higher temperatures appears to play the primary role in canalizing the energy budget of an embryo, but a reduction in the cost of growth could play a secondary role.

Acclimatization↗
PubMed2006

Use of fibrin sealants for the localized, controlled release of cefazolin.

BACKGROUND: Fibrin sealants are used increasingly in surgery to reduce bleeding and improve wound healing. They have great potential as biocompatible, biodegradable drug delivery systems, because the sealant may adhere to the target tissue and allow controlled release of the drug over an extended period. We investigated the encapsulation, stability and controlled release of erythromycin and cefazolin from Beriplast fibrin sealants (Aventis Behring Canada). METHODS: Drug-loaded clots were cast in glass vials and allowed to set. We observed the clots for drug precipitation and aggregation, and we assessed the effect of drug encapsulation on clot strength. Drug stability and release from the clots in phosphate buffered saline (PBS) was quantified by ultraviolet and visible violet absorbance spectroscopy and high-performance liquid chromatography. RESULTS: Erythromycin was found to release slowly from the fibrin clots over the first 2 hours but then degrade rapidly. Cefazolin was found to be very stable in clots in PBS (97% stable at 2 d and 93% stable at 5 d). The drug released in a controlled manner over 2 days, with most being released during the first day. The dose of drug released could be varied by changing the amount placed in the thrombin solution. Clot thickness had no effect on the rate of cefazolin release. CONCLUSION: Overall, the 2-day release profile and the excellent stability of the drug suggest that cefazolin-loaded fibrin sealants may offer an effective route of postoperative antibiotic delivery.

Anti-Bacterial Agents↗
PubMed2005

An evaluation of GO annotation retrieval for BioCreAtIvE and GOA.

BACKGROUND: The Gene Ontology Annotation (GOA) database http://www.ebi.ac.uk/GOA aims to provide high-quality supplementary GO annotation to proteins in the UniProt Knowledgebase. Like many other biological databases, GOA gathers much of its content from the careful manual curation of literature. However, as both the volume of literature and of proteins requiring characterization increases, the manual processing capability can become overloaded. Consequently, semi-automated aids are often employed to expedite the curation process. Traditionally, electronic techniques in GOA depend largely on exploiting the knowledge in existing resources such as InterPro. However, in recent years, text mining has been hailed as a potentially useful tool to aid the curation process. To encourage the development of such tools, the GOA team at EBI agreed to take part in the functional annotation task of the BioCreAtIvE (Critical Assessment of Information Extraction systems in Biology) challenge. BioCreAtIvE task 2 was an experiment to test if automatically derived classification using information retrieval and extraction could assist expert biologists in the annotation of the GO vocabulary to the proteins in the UniProt Knowledgebase. GOA provided the training corpus of over 9000 manual GO annotations extracted from the literature. For the test set, we provided a corpus of 200 new Journal of Biological Chemistry articles used to annotate 286 human proteins with GO terms. A team of experts manually evaluated the results of 9 participating groups, each of which provided highlighted sentences to support their GO and protein annotation predictions. Here, we give a biological perspective on the evaluation, explain how we annotate GO using literature and offer some suggestions to improve the precision of future text-retrieval and extraction techniques. Finally, we provide the results of the first inter-annotator agreement study for manual GO curation, as well as an assessment of our current electronic GO annotation strategies. RESULTS: The GOA database currently extracts GO annotation from the literature with 91 to 100% precision, and at least 72% recall. This creates a particularly high threshold for text mining systems which in BioCreAtIvE task 2 (GO annotation extraction and retrieval) initial results precisely predicted GO terms only 10 to 20% of the time. CONCLUSION: Improvements in the performance and accuracy of text mining for GO terms should be expected in the next BioCreAtIvE challenge. In the meantime the manual and electronic GO annotation strategies already employed by GOA will provide high quality annotations.

Animals↗
PubMed2005

Virulizin, a novel immunotherapy agent, activates NK cells through induction of IL-12 expression in macrophages.

Virulizin, a novel biological response modifier, has demonstrated significant antitumor efficacy in a variety of human tumor xenograft models including melanoma, pancreatic cancer, breast cancer, ovarian cancer and prostate cancer. The significant role of macrophages and NK (Natural killer) cells was implicated in the antitumor mechanism of Virulizin where expansion as well as increased activity of macrophages and NK cells were observed in mice treated with Virulizin. Depletion of macrophages compromised Virulizin-induced NK1.1+ cell infiltration into xenografted tumors and was accompanied by reduced antitumor efficacy. In the present study, involvement of macrophages in NK cell activation was investigated further. We found that depletion of NK cells in CD-1 nude mice by anti-ASGM1 antibody significantly compromised the antitumor activity of Virulizin. Cytotoxicity of NK cells isolated from Virulizin-treated mice was enhanced against NK-sensitive YAC-1 cells and C8161 human melanoma cells, but not against NK-insensitive P815 cells. An increased level of IL-12beta was observed in the serum of mice treated with Virulizin. IL-12 mRNA and protein levels were also increased in peritoneal macrophages isolated from Virulizin-treated mice. Moreover, Virulizin-induced cytotoxic activity of NK cells isolated from the spleen was abolished when an IL-12 neutralizing antibody was co-administered. In addition, depletion of macrophages in mice significantly impaired Virulizin-induced NK cell cytotoxicty. Taken together, the results suggest that Virulizin induces macrophage IL-12 production, which in turn stimulates NK cell-mediated antitumor activity.

Adjuvants, Immunologic↗
PubMed2005

The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis.

Versican is a large chondroitin sulfate proteoglycan belonging to the lectican family. Alternative splicing of versican generates at least four isoforms named V0, V1, V2, and V3. We have shown that the versican V1 isoform not only enhanced cell proliferation, but also modulated cell cycle progression and protected the cells from apoptosis. Futhermore, the V1 isoform was able to not only activate proto-oncogene EGFR expression and modulate its downstream signaling pathway, but also induce p27 degradation and enhance CDK2 kinase activity. As well, the V1 isoform down-regulated the expression of the proapoptotic protein Bad. By contrast, the V2 isoform exhibited opposite biological activities by inhibiting cell proliferation and down-regulated the expression of EGFR and cyclin A. Furthermore, V2 did not contribute apoptotic resistance to the cells. In light of these results, we are reporting opposite functions for the two versican isoforms whose expression is differentially regulated. Our studies suggest that the roles of these two isoforms are associated with the subdomains CSbeta and CSalpha, respectively. These results were confirmed by silencing the expression of versican V1 with small interfering RNA (siRNA), which abolished V1-enhanced cell proliferation and V1-induced reduction of apoptosis.

Animals↗
PubMed2005

Mammographic breast density as an intermediate phenotype for breast cancer.

The amount of radiologically dense breast-tissue appearing on a mammogram varies between women because of differences in the composition of breast tissue, and is referred to here as mammographic density. This review presents evidence that mammographic density is a strong risk factor for breast cancer, and that risk of breast cancer is four to five times greater in women with density in more than 75% of the breast than in women with little or no density in the breast. Density in more than 50% of the breast could account for about a third of breast cancers. The epidemiology of mammographic density is consistent with its being a marker of susceptibility to breast cancer. Twin studies have shown that the proportion of the breast occupied by density, at a given age, is highly heritable, and inherited factors explain 63% of the variance. Mammographic breast density has the characteristics of a quantitative trait and might be determined by genes that are easier to identify than those for breast cancer itself. The genes that determine breast density might also be associated with risk of breast cancer, and their identification is also likely to provide insights into the biology of the breast and identify potential targets for preventive strategies.

Age Factors↗
PubMed2005

Identification and characterization of a novel human nephronectin gene in silico.

We describe the identification and characterization of a human epidermal growth factor (EGF)-like gene, nephronectin (NPNT), which encodes predicted proteins most homologous to the mouse nephronectin (Npnt). Human NPNT is located at the chromosomal position 4q25. Two transcript variants, NPNTa and NPNTb, are identified. Sequence comparison indicated that the human NPNT proteins share 88% amino acid identity with their mouse homologs. The in silico expression analysis showed the NPNT expression in a number of embryonic and adult tissues. NPNT was expressed in fetal ear, eye, heart, lung and kidney. In adults, the NPNT expression was widely found in lung, kidney, brain, uterus, placenta, thyroid gland and blood vessels. This gene is therefore implicated in embryonic development as well as maintenance of various adult tissues.

Amino Acid Sequence↗
PubMed2005

Who tangos with GOA?-Use of Gene Ontology Annotation (GOA) for biological interpretation of '-omics' data and for validation of automatic annotation tools.

The number of large-scale experimental datasets generated from high-throughput technologies has grown rapidly. Biological knowledge resources such as the Gene Ontology Annotation (GOA) database, which provides high-quality functional annotation to proteins within the UniProt Knowledgebase, can play an important role in the analysis of such data. The integration of GOA with analytical tools has proved to aid the clustering, annotation and biological interpretation of such large expression datasets. GOA is also useful in the development and validation of automated annotation tools, in particular text-mining systems. The increasing interest in GOA highlights the great potential of this freely available resource to assist both the biological research and bioinformatics communities.

Animals↗
PubMed2004

PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation.

P-selectin glycoprotein ligand-1 (PSGL-1), a glycoprotein expressed on the cell surface of leukocytes, binds to selectins and mediates leukocyte rolling on the vascular endothelium. Here we report that PSGL-1 binds to the C-terminal (G3 domain) of the extracellular proteoglycan PG-M/versican. Cells transfected with PSGL-1 or a shorter form containing the binding site, or cells expressing endogenous PSGL-1 aggregate in the presence of versican or G3 product. The aggregation appears to be induced by G3 multimers that bind to PSGL-1 and form a network. Endogenous versican and/or G3-containing fragments also bind to PSGL-1 in human plasma. Removal of the endogenous G3-containing fragments reduces the effect of plasma on leukocyte aggregation. Finally, the roles of G3-containing fragments in leukocyte aggregation were confirmed in a mouse model. Taken together, our results strongly support a physiologically relevant role for PSGL-1/versican binding and may have implications in the immunoresponse.

Amino Acid Motifs↗
PubMed2004

NK cell activation and tumor infiltration are involved in the antitumor mechanism of Virulizin.

Previous studies have demonstrated antitumor efficacy of Virulizin in several human tumor xenograft models and a critical role for macrophages in the antitumor mechanism of Virulizin. Although there is growing support for an immune stimulatory mechanism of action for Virulizin, the details remain to be elucidated. The aim of this study was to determine whether infiltration of natural killer (NK) cells into xenografted tumors is altered by Virulizin treatment, and whether such alterations contribute to the antitumor activity of Virulizin. Immunohistochemical analysis demonstrated that xenografted tumors from Virulizin-treated mice had an increase in infiltration of F4/80(+) (macrophages) and NK1.1(+) (NK) cells. The increase in NK1.1(+) cell infiltration occurred at an early stage of Virulizin treatment, which correlated with an early sign of apoptosis. In addition, Virulizin resulted in an increase in the number of NK cells in the spleens, and NK cells isolated from the spleen exhibited increased cytotoxicity to tumor cells in vitro. In NK cell-deficient SCID-beige mice, the antitumor activity of Virulizin was compromised, providing additional support to the hypothesis that NK cells are necessary for inhibition of tumor growth by Virulizin. Finally, depletion of macrophages resulted in the loss of Virulizin-induced increase in NK1.1(+) cell infiltration into xenografted tumors, suggesting the involvement of macrophages in NK cell infiltration into tumors. Taken together, these results strongly support a mechanism in which Virulizin stimulates a sustained expansion and infiltration of NK cells and macrophages into tumors with subsequent activation of NK cells that is responsible for the observed antitumor activity.

Adjuvants, Immunologic↗
PubMed2004

Versican V1 isoform induces neuronal differentiation and promotes neurite outgrowth.

The chondroitin sulfate proteoglycan versican is one of the major extracellular components in the developing and adult brain. Here, we show that isoforms of versican play different roles in neuronal differentiation and neurite outgrowth. Expression of versican V1 isoform in PC12 cells induced complete differentiation, whereas expression of V2 induced an aborted differentiation accompanied by apoptosis. V1 promoted neurite outgrowth of hippocampal neurons, but V2 failed to do so. V1 transfection enhanced expression of epidermal growth factor receptor and integrins, and facilitated sustained extracellular signal-regulated kinase/MAPK phosphorylation. Blockade of the epidermal growth factor receptor, beta1 integrin, or Src significantly inhibited neuronal differentiation. Finally, we demonstrated that versican V1 isoform also promoted differentiation of neural stem cells into neurons. Our results have implications for understanding how versican regulates neuronal development, function, and repair.

Animals↗
PubMed2004

The Gene Ontology Annotation (GOA) Database: sharing knowledge in Uniprot with Gene Ontology.

The Gene Ontology Annotation (GOA) database (http://www.ebi.ac.uk/GOA) aims to provide high-quality electronic and manual annotations to the UniProt Knowledgebase (Swiss-Prot, TrEMBL and PIR-PSD) using the standardized vocabulary of the Gene Ontology (GO). As a supplementary archive of GO annotation, GOA promotes a high level of integration of the knowledge represented in UniProt with other databases. This is achieved by converting UniProt annotation into a recognized computational format. GOA provides annotated entries for nearly 60,000 species (GOA-SPTr) and is the largest and most comprehensive open-source contributor of annotations to the GO Consortium annotation effort. By integrating GO annotations from other model organism groups, GOA consolidates specialized knowledge and expertise to ensure the data remain a key reference for up-to-date biological information. Furthermore, the GOA database fully endorses the Human Proteomics Initiative by prioritizing the annotation of proteins likely to benefit human health and disease. In addition to a non-redundant set of annotations to the human proteome (GOA-Human) and monthly releases of its GO annotation for all species (GOA-SPTr), a series of GO mapping files and specific cross-references in other databases are also regularly distributed. GOA can be queried through a simple user-friendly web interface or downloaded in a parsable format via the EBI and GO FTP websites. The GOA data set can be used to enhance the annotation of particular model organism or gene expression data sets, although increasingly it has been used to evaluate GO predictions generated from text mining or protein interaction experiments. In 2004, the GOA team will build on its success and will continue to supplement the functional annotation of UniProt and work towards enhancing the ability of scientists to access all available biological information. Researchers wishing to query or contribute to the GOA project are encouraged to email: goa@ebi.ac.uk.

Animals↗
PubMed2004

Identification and characterization of a novel human FOXK1 gene in silico.

We describe here the identification and characterization of a human forkhead box gene, FOXK1, that encodes predicted proteins most homologous to the mouse myocyte nuclear factor (MNF)/forkhead box K1 (FoxK1). Human FOXK1 is located at the chromosomal position 7p22. Two transcript variants, FOXK1a and FOXK1b, containing the divergent 5'-ends are identified. Sequence comparison indicated that the human FOXK1 proteins share 66-74% amino acid identity (99% identity in the forkhead domain) with their mouse ortholog. The in silico expression analysis showed FOXK1 expression in immature tissues of brain, eye, heart, lung and thymus. In adults, FOXK1 was predominantly expressed in many malignant tissues, in particular in the tumors of brain, colon and lymph node. This gene is therefore implicated in the process of both normal and neoplastic development.

Amino Acid Sequence↗
PubMed2003

Identification of the motifs and amino acids in aggrecan G1 and G2 domains involved in product secretion.

Members of the large aggregating chondroitin sulfate proteoglycans are characterized by an N-terminal fragment known as G1 domain, which is composed of an immunoglobulin (IgG)-like motif and two tandem repeats (TR). Previous studies have indicated that the expressed product of aggrecan G1 domain was not secreted. Here we demonstrated that the inability of G1 secretion was associated with the tandem repeats but not the IgG-like motif, and specifically with TR1 of aggrecan. We also demonstrated that the G2 domain, a domain unique to aggrecan, had a similar effect on product secretion. The sequence of TR1 of G1 is highly conserved across species, which suggested similar functions played by these motifs. In a yeast two-hybrid assay, TR1 interacted with the calcium homeostasis endoplasmic reticulum protein. Deletion/mutation experiments indicated that the N-terminal fragment of TR1, in particular, the amino acids H(2)R(4) of this motif were key to its effect on product secretion. However, the N-terminal 55 amino acids were required to exert this function. Taken together, our study suggests a possible molecular mechanism for the function of the tandem repeats in product processing.

Aggrecans↗
PubMed2003

Developing novel oncolytic adenoviruses through bioselection.

Mutants of human adenovirus 5 (Ad5) with enhanced oncolytic activity were isolated by using a procedure termed bioselection. Two mutants, ONYX-201 and ONYX-203, were plaque purified from a pool of randomly mutagenized Ad5 that was repeatedly passaged in the human colorectal cancer cell line HT29, and they were subsequently characterized. ONYX-201 and ONYX-203 replicated more rapidly in HT29 cells than wild-type Ad5, and they lysed HT29 cells up to 1,000-fold more efficiently. The difference was most profound when cells were infected at a relatively low multiplicity of infection, presumably due to the compounding effects of multiple rounds of infection. This enhanced cytolytic activity was observed not only in HT29 cells but also in many other human cancer cell lines tested. In contrast, the cytotoxicity of the bioselected mutants in a number of normal primary human cells was similar to that of wild-type Ad5, thus enhancing the therapeutic index (cytotoxicity in tumor cells versus that in normal cells) of these oncolytic agents. Both ONYX-201 and -203 contain seven single-base-pair mutations when compared with Ad5, four of which were common between ONYX-201 and -203. The mutation at nucleotide 8350, shared by both mutant viruses, was shown to be essential for the observed phenotypes. This mutation was mapped to the i-leader region of the major late transcription unit, resulting in the truncation of 21 amino acids from the C terminus of the i-leader protein. This work demonstrates that bioselection is a powerful tool for developing novel tumor-selective oncolytic viruses. Other potential applications of this technology are discussed.

Adenoviruses, Human↗
PubMed2003

Macrophages play a critical role in the anti-tumor activity of Virulizin.

Virulizin, a novel biological response modifier (BRM), has been demonstrated to have a high level of anti-tumor activity against pancreatic cancer and melanoma in many clinical trials and preclinical studies. However, its anti-tumor mechanism has not been fully elucidated. The purpose of this study was to define the mechanism of Virulizin anti-tumor activity in cultures and in a murine xenograft model. The presence of Virulizin stimulated in a dose-dependent manner the cytolytic activity against tumor cells by splenocytes and macrophages, but not by non-adherent splenocytes. The cytotoxic activity of macrophages was significantly increased (approximately 5-fold) in cultures containing 2.5% of Virulizin compared to that of cultures without Virulizin (p<0.001). An increase of 21% in the protease secretion was observed in Virulizin (2.5%)-stimulated macrophages compared to PBS-treated cells (p<0.0001). Moreover, the anti-tumor efficacy of Virulizin observed in CD-1 nude mice was abrogated in mice that were depleted of macrophages, thus stimulation of macrophages may be one mechanism through which Virulizin acts. These results suggest that macrophages may play a critical role in the anti-tumor activity of Virulizin.

Adjuvants, Immunologic↗