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PubMed2006

Antiangiogenic therapy with interferon alfa for neovascular age-related macular degeneration.

BACKGROUND: Antiangiogenic therapy is a new approach to the treatment of neovascular age-related macular degeneration. Interferon alfa is one antiangiogenic agent thought to function by inhibiting the migration and proliferation of vascular endothelial cells. It has been used in the treatment of hepatitis, solid tumors and hematologic malignancies. OBJECTIVES: The aim of this review was to investigate interferon alfa as a treatment modality for neovascular age-related macular degeneration. SEARCH STRATEGY: We searched and identified trials from the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Group Trials Register, in The Cochrane Library (Issue 2, 2005), MEDLINE (1966 to 2005/06 week 1), EMBASE (1980 to 2005/week 23), LILACS (Latin American and Caribbean Health Science Literature Database) (June 2005) and the reference lists of included studies. SELECTION CRITERIA: This review included randomized controlled trials evaluating interferon alfa therapy in people with neovascular age-related macular degeneration who were followed for at least one year. DATA COLLECTION AND ANALYSIS: Both review authors independently extracted data and assessed trial quality. No data synthesis was conducted as only one trial met the inclusion criteria. MAIN RESULTS: The one included trial enrolled and randomized 481 participants from 45 centers worldwide into four groups. The study allowed for analysis of the number of participants who had lost three or more lines of vision at 52 weeks in three interferon alfa-2a groups versus placebo. The results show an odds ratio of 1.60 (95% Confidence Interval 1.01 to 2.53) indicating that interferon is associated with a 60% increased odds of losing three or more lines at 52 weeks. This finding is marginally statistical with a P value of 0.04 and indicates that the treatment has the potential for harm rather than benefit. AUTHORS' CONCLUSIONS: At present there is not enough evidence to recommend the use of interferon alfa-2a for the treatment of age-related macular degeneration.

Angiogenesis Inhibitors↗
PubMed1998

Computer identification of Escherichia coli rRNA gene restriction patterns.

A total of 191 strains of Escherichia coli comprising 164 serovar reference strains and 28 clinical strains were characterized by rRNA gene restriction patterns (ribotypes) generated after cleavage of total DNA with MluI, ClaI or HindIII restriction endonucleases and hybridization of fragments with acetylaminofluorene-labelled 16 + 23S rRNA. A wide diversity of ribotypes was observed with endonucleases MluI (104 patterns), ClaI (90 patterns) and HindIII (98 patterns). When MluI was used, 85% of patterns (11 to 15 fragments) shared five fragments 17.09, 3.94, 3.06, 2.23 and 1.76 kb in size. When these fragments were used as internal standards, the percent errors in fragment length determination was half of that obtained with an external standard. Two fragment size databases of MluI and ClaI ribotypes were built. Automatic identification was obtained after setting the percent fragment size variation tolerance (error) at 5%. MluI ribotyping is recommended as a primary epidemiological marker. Strains with similar MluI ribotype should then be submitted to ClaI ribotyping. Ribotyping with HindIII can only be the third choice, since the patterns were often uncertain due to the frequent occurrence of faint bands. Most of the studied serovars gave discrete patterns and these data provide the basis for a molecular typing system for E. coli which could possibly substitute for serotyping when the latter is not available.

2-Acetylaminofluorene↗
PubMed2006

Treatment outcomes in a centralized specialty clinic for hepatitis C virus are comparable with those from clinical trials.

BACKGROUND: Outcomes from industry-sponsored registration trials are often considered to be more favourable than those achieved in clinical practice because patients involved in the former are highly selected and supported, but it is not known if this impression is valid. OBJECTIVE: To determine the outcome of hepatitis C virus (HCV)-infected patients who received therapies for chronic HCV in a single urban centre and compare the results with those derived from contemporary, industry-sponsored trials. DESIGN: Retrospective chart review of HCV-infected patients referred to the Viral Hepatitis Investigative Unit in Winnipeg, Manitoba, between 1998 and 2003. METHODS: The Viral Hepatitis Investigative Unit database was used to identify all referred patients with positive anti-HCV antibodies. Charts were reviewed for the following data: patient demographics; viral genotype; indications and contraindications to treatment; treatment type; and outcome of antiviral therapy. RESULTS: For 1800 anti-HCV positive patients identified, 1078 charts were available for review. Of these patients, the mean age was 47 years (range 11 years to 90 years) and 53% were men. Genotype 1 was the most common (65%). A total of 331 patients (31%) had received antiviral therapy. The sustained viral responses were similar to those described in industry-sponsored registration trials. Specifically, the sustained viral responses for interferon-alpha monotherapy (n=81) was 22.2%, interferon-alpha plus ribavirin (n=180) 44.4%, pegylated interferon monotherapy (n=38) 44.7% and pegylated interferon plus ribavirin (n=24) 54.2%. CONCLUSION: HCV treatment outcomes from a single urban centre were similar to those described in industry-sponsored registration trials despite the high selection and support provided to patients enrolled in the latter studies.

Adolescent↗
PubMed2004

Lessons from the national cooperative growth study.

OBJECTIVE: To review the National Cooperative Growth Study (NCGS), a national post-marketing surveillance program for children treated with biosynthetic growth hormone (GH) products from Genentech. METHODS: Representative data are presented to summarize the extensive experience of the NCGS. This study is a multicenter, observational surveillance registry begun in 1985 in coordination with the release of the first recombinant DNA biosynthetic GH. RESULTS: After almost 20 years, data from over 47 000 patients representing 165 000 patient years have been collected. There are over 12 000 active subjects (estimated to be approximately 75% of all current patients treated with a Genentech GH product) at 435 centers, providing extensive efficacy and safety data. The GrowTrak program is a secure, user-friendly database which encourages a high level of participation by the pediatric endocrine community in the USA. Efficacy has been shown in a variety of clinical diagnoses, including isolated (IGHD) and organic growth hormone deficiency (OGHD), idiopathic short stature (ISS), and Turner syndrome. Safety monitoring of this large population has provided reassuring evidence that leukemia (de novo or relapse), extracranial nonleukemic neoplasms and central nervous system (CNS) tumor recurrence are not associated with GH therapy. A small risk of intracranial hypertension and slipped capital femoral epiphyses has been suggested, especially in children with renal disease or Turner syndrome. NCGS substudies have also provided important insights into actual clinical practice. For example, screening for renal, cardiac, or auditory comorbidities in Turner syndrome is often done less than is recommended by national guidelines (NCGS 9). Furthermore, almost 65% of children referred for short stature may be lost to follow-up before an evaluation is completed (NCGS 8). CONCLUSIONS: The NCGS has proven to be a valuable method of monitoring the safety and efficacy of biosynthetic GH. The study has attracted wide physician participation due to the data collection software used and the extensive sharing of the analyses of that data with the providers.

Body Height↗
PubMed2000

A universal molecular method for identifying underground plant parts to species.

As part of a large project to determine rooting depth and resource uptake on the Edwards Plateau of central Texas, we developed a DNA-based technique that allows the below-ground parts of all plants to be identified to the level of genus and usually to species. Identification is achieved by comparing DNA sequences of the internal transcribed spacer (ITS) region of the 18S-26S nuclear ribosomal DNA repeat, derived from below-ground plant material, with a reference ITS region database for plants at a site. The method works throughout plants because the plant ITS region can be PCR amplified using a set of universal primers. Congeneric species can usually be identified because the ITS region evolves relatively rapidly. In our study, all roots were easily identified to the level of genus; most congeneric species were identified solely by ITS sequence differences but some required a combination of ITS sequence data and above-ground surveys of species at a site. In addition to showing the feasibility and efficacy of our technique, we compare it with another DNA-based technique used to identify below-ground plant parts. Finally, we also describe a DNA extraction and purification technique that reliably provides high-quality DNA of sufficient quantity from roots so that PCR can be readily accomplished. Our technique should allow the below-ground parts of plants in any system to be identified and thereby open new possibilities for the study of below-ground plant communities.

Base Sequence↗
PubMed1998

Access to a syllabus of human hemoglobin variants (1996) via the World Wide Web.

Information on mutations in human hemoglobin is important in many efforts, including understanding the pathophysiology of hemoglobin diseases, developing therapies, elucidating the dynamics of sequence alterations inhuman populations, and dissecting the details of protein structure/function relationships. Currently, information is available on a large number of mutations and variants, but is distributed among thousands of papers. In an effort to organize this voluminous data set, two Syllabi have been prepared compiling succinct information on human hemoglobin abnormalities. In both of these, each entry provides amino acid and/or DNA sequence alterations, hematological and clinical data, methodology used for characterization, ethnic distribution, and functional properties and stability of the hemoglobin, together with appropriate literature references. A Syllabus of Human Hemoglobin Variants (1996) describes 693 abnormal hemoglobins resulting from alterations in the alpha-, beta-, gamma-, and delta-globin chains, including special abnormalities such as double mutations, hybrid chains, elongated chains, deletions, and insertions. We have converted this resource to an electronic form that is accessible via the World Wide Web at the Globin Gene Server (http://globin.cse.psu.edu). Hyperlinks are provided from each entry in the tables of variants to the corresponding full description. In addition, a simple query interface allows the user to find all entries containing a designated word or phrase. We are in the process of converting A Syllabus of Thalassemia Mutations (1997) to a similar electronic format.

Computer Communication Networks↗
PubMed2003

The 2.2 A resolution structure of RpiB/AlsB from Escherichia coli illustrates a new approach to the ribose-5-phosphate isomerase reaction.

Ribose-5-phosphate isomerases (EC 5.3.1.6) interconvert ribose 5-phosphate and ribulose 5-phosphate. This reaction permits the synthesis of ribose from other sugars, as well as the recycling of sugars from nucleotide breakdown. Two unrelated types of enzyme can catalyze the reaction. The most common, RpiA, is present in almost all organisms (including Escherichia coli), and is highly conserved. The second type, RpiB, is present in some bacterial and eukaryotic species and is well conserved. In E.coli, RpiB is sometimes referred to as AlsB, because it can take part in the metabolism of the rare sugar, allose, as well as the much more common ribose sugars. We report here the structure of RpiB/AlsB from E.coli, solved by multi-wavelength anomalous diffraction (MAD) phasing, and refined to 2.2A resolution. RpiB is the first structure to be solved from pfam02502 (the RpiB/LacAB family). It exhibits a Rossmann-type alphabetaalpha-sandwich fold that is common to many nucleotide-binding proteins, as well as other proteins with different functions. This structure is quite distinct from that of the previously solved RpiA; although both are, to some extent, based on the Rossmann fold, their tertiary and quaternary structures are very different. The four molecules in the RpiB asymmetric unit represent a dimer of dimers. Active-site residues were identified at the interface between the subunits, such that each active site has contributions from both subunits. Kinetic studies indicate that RpiB is nearly as efficient as RpiA, despite its completely different catalytic machinery. The sequence and structural results further suggest that the two homologous components of LacAB (galactose-6-phosphate isomerase) will compose a bi-functional enzyme; the second activity is unknown.

Aldose-Ketose Isomerases↗
PubMed2006

Transcriptomic response to differentiation induction.

BACKGROUND: Microarrays used for gene expression studies yield large amounts of data. The processing of such data typically leads to lists of differentially-regulated genes. A common terminal data analysis step is to map pathways of potentially interrelated genes. METHODS: We applied a transcriptomics analysis tool to elucidate the underlying pathways of leukocyte maturation at the genomic level in an established cellular model of leukemia by examining time-course data in two subclones of U-937 cells. Leukemias such as Acute Promyelocytic Leukemia (APL) are characterized by a block in the hematopoietic stem cell maturation program at a point when expansion of clones which should be destined to mature into terminally-differentiated effector cells get locked into endless proliferation with few cells reaching maturation. Treatment with retinoic acid, depending on the precise genomic abnormality, often releases the responsible promyelocytes from this blockade but clinically can yield adverse sequellae in terms of potentially lethal side effects, referred to as retinoic acid syndrome. RESULTS: Briefly, the list of genes for temporal patterns of expression was pasted into the ABCC GRID Promoter TFSite Comparison Page website tool and the outputs for each pattern were examined for possible coordinated regulation by shared regelems (regulatory elements). We found it informative to use this novel web tool for identifying, on a genomic scale, genes regulated by drug treatment. CONCLUSION: Improvement is needed in understanding the nature of the mutations responsible for controlling the maturation process and how these genes regulate downstream effects if there is to be better targeting of chemical interventions. Expanded implementation of the techniques and results reported here may better direct future efforts to improve treatment for diseases not restricted to APL.

Cell Differentiation↗
PubMed2003

Hepatitis C virus and liver disease: global transcriptional profiling and identification of potential markers.

Microarray analysis of RNA from hepatitis C virus (HCV)-infected cirrhotic livers was performed to identify a gene expression signature of liver disease. The expression levels of approximately 13600 genes were analyzed using surgical material and core biopsy specimens from HCV-infected cirrhotic liver explants in comparison with reference samples of normal nondiseased liver. In addition, normal liver samples were compared with each other to determine normal physiologic variation in gene expression. A set of genes, including some associated with stress, acute-phase immune response, and hepatic stellate cell activation, had variable expression levels in normal livers. These genes were subtracted from the sets of genes differentially expressed in cirrhotic livers. To exclude cancer-related genes from our marker sets, we subtracted genes that also were expressed differentially in hepatocellular carcinomas. The resultant HCV- and liver disease-associated gene set provided a molecular portrait of several processes occurring in the HCV-infected liver. It included (1). genes expressed in activated lymphocytes infiltrating the cirrhotic liver, and activated liver macrophages; (2). genes involved in remodeling of extracellular matrix-cell and cell-cell interactions associated with cytoskeleton rearrangements; (3). genes related to the anti-apoptotic pathway of Bcl-2 signaling; and (4). genes involved with the interferon response and virus-host interactions. In conclusion, our microarray analysis identified several potential gene markers of HCV-associated liver disease and contributed to our rapidly expanding database of experiments describing HCV pathogenesis.

Apoptosis↗
PubMed2005

The human plasma proteome: analysis of Chinese serum using shotgun strategy.

We have investigated the serum proteome of Han-nationality Chinese by using shotgun strategy. A complete proteomics analysis was performed on two reference specimens from a total of 20 healthy donors, in which each sample was made from ten-pooled male or female serum, respectively. The methodology used encompassed (1) removal of six high-abundant proteins; (2) tryptic digestion of low- and high-abundant proteins of serum; (3) separation of peptide mixture by RP-HPLC followed by ESI-MS/MS identification. A total of 944 nonredundant proteins were identified under a stringent filter condition (X(corr) > or = 1.9, > or = 2.2, and > or = 3.75, < or = C(n) > or = 0.1, and R(sp) > or = 4.0) in both pooled male and female samples, in which 594 and 622 entire proteins were found, respectively. Compared with the total 3020 protein identifications confirmed by more than one laboratory or more than one specimen in HUPO Plasma Proteome Project (PPP) participating laboratories recently, 206 proteins were identified with at least two distinct peptides per protein and 185 proteins were considered as high-confidence identification. Moreover, some lower abundance serum proteins (ng/mL range) were detected, such as complement C5 and CA125, routinely used as an ovarian cancer marker in plasma and serum. The resulting nonredundant list of serum proteins would add significant information to the knowledge base of human plasma proteome and facilitate disease markers discovery.

Biomarkers↗
PubMed2004

Granulocyte-Colony Stimulating Factor (G-CSF) as an adjunct to antibiotics in the treatment of pneumonia in adults.

BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is a naturally-occurring cytokine that has been shown to increase neutrophil function and number. Exogenous administration of recombinant G-CSF (filgrastim, pegfilgrastim or lenograstim) has found extensive use in the treatment of febrile neutropaenia, but its role in the treatment of infection in non-neutropaenic hosts is less well defined. OBJECTIVES: We explored the role of G-CSF as an adjunct to antibiotics in the treatment of pneumonia in non-neutropaenic adults. SEARCH STRATEGY: We searched the following electronic databases in 2003 and updated the search in 2004: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2004); MEDLINE (January 1966 to March Week 1, 2004); EMBASE (1998 to December 2003); online databases of clinical trials; and reference lists of articles. We also contacted study authors, manufacturers and distributors of G-CSF. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) which included hospitalised adult patients with either community acquired pneumonia or hospital-acquired pneumonia. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. The primary outcome measure was 28 day mortality. Secondary outcome measures included other markers of mortality as well as markers of adverse events, including organ dysfunction. An assessment of methodological quality was made for each study. MAIN RESULTS: Six studies with a total of 1984 people were identified. G-CSF use appeared to be safe with no increase in the incidence of total serious adverse events (pooled odds ratio (OR) 0.91; 95% confidence interval (CI): 0.73 to 1.14) or organ dysfunction. However, the use of G-CSF was not associated with improved 28 day mortality (pooled OR 0.86; 95% CI: 0.56 to 1.31). REVIEWERS' CONCLUSIONS: There is no current evidence supporting the routine use of G-CSF in the treatment of pneumonia. Studies in which G-CSF is administered prophylactically or earlier in therapy may be of interest.

Adult↗
PubMed2006

The YEASTRACT database: a tool for the analysis of transcription regulatory associations in Saccharomyces cerevisiae.

We present the YEAst Search for Transcriptional Regulators And Consensus Tracking (YEASTRACT; www.yeastract.com) database, a tool for the analysis of transcription regulatory associations in Saccharomyces cerevisiae. This database is a repository of 12 346 regulatory associations between transcription factors and target genes, based on experimental evidence which was spread throughout 861 bibliographic references. It also includes 257 specific DNA-binding sites for more than a hundred characterized transcription factors. Further information about each yeast gene included in the database was obtained from Saccharomyces Genome Database (SGD), Regulatory Sequences Analysis Tools and Gene Ontology (GO) Consortium. Computational tools are also provided to facilitate the exploitation of the gathered data when solving a number of biological questions as exemplified in the Tutorial also available on the system. YEASTRACT allows the identification of documented or potential transcription regulators of a given gene and of documented or potential regulons for each transcription factor. It also renders possible the comparison between DNA motifs, such as those found to be over-represented in the promoter regions of co-regulated genes, and the transcription factor-binding sites described in the literature. The system also provides an useful mechanism for grouping a list of genes (for instance a set of genes with similar expression profiles as revealed by microarray analysis) based on their regulatory associations with known transcription factors.

Binding Sites↗
PubMed2004

PEDRo: a database for storing, searching and disseminating experimental proteomics data.

BACKGROUND: Proteomics is rapidly evolving into a high-throughput technology, in which substantial and systematic studies are conducted on samples from a wide range of physiological, developmental, or pathological conditions. Reference maps from 2D gels are widely circulated. However, there is, as yet, no formally accepted standard representation to support the sharing of proteomics data, and little systematic dissemination of comprehensive proteomic data sets. RESULTS: This paper describes the design, implementation and use of a Proteome Experimental Data Repository (PEDRo), which makes comprehensive proteomics data sets available for browsing, searching and downloading. It is also serves to extend the debate on the level of detail at which proteomics data should be captured, the sorts of facilities that should be provided by proteome data management systems, and the techniques by which such facilities can be made available. CONCLUSIONS: The PEDRo database provides access to a collection of comprehensive descriptions of experimental data sets in proteomics. Not only are these data sets interesting in and of themselves, they also provide a useful early validation of the PEDRo data model, which has served as a starting point for the ongoing standardisation activity through the Proteome Standards Initiative of the Human Proteome Organisation.

Animals↗
PubMed2006

The gene overexpressed in polycythemia rubra vera, PRV-1, and the gene encoding a neutrophil alloantigen, NB1, are alleles of a single gene, CD177, in chromosome band 19q13.31.

BACKGROUND: PRV-1 mRNA is overexpressed by neutrophils from polycythemia vera patients and is homologous to NB1 a gene overexpressed in reactive neutrophilia. STUDY DESIGN AND METHODS: These investigations were designed to confirm searches of genome databases suggesting that PRV-1 and NB1 are alleles of the same gene, CD177, and confirm a pseudogene adjacent to CD177. Methods included polymerase chain reaction (PCR), cloning, sequencing, and fluorescent hybridization studies. RESULTS: The coding region of PRV-1 was PCR-amplified from human fetal RNA, cloned, and used to screen the RPCI-11 bacterial artificial chromosome (BAC) library. Five BACs were reactive with the PRV-1 probe. PCR analysis of the BACs with primers encompassing PRV-1 exons, containing four known single-nucleotide polymorphisms, followed by sequencing rendered amplicons identical to PRV-1 in all five BACs. Analysis of all five by restriction digestion yielded fragments possible only if both the gene and the pseudogene are present. End sequencing of the BACs localized them to the same chromosome region. G-banding and fluorescence in situ hybridization at the 400- and 850-band levels of resolution mapped one BAC to chromosome band 19q13.2 and sublocalized the BAC to band 19q13.31, respectively. CONCLUSION: PRV-1 and NB1 are alleles of the same gene now referred to as CD177. Changes in CD177 expression may be a marker of increased or decreased myelopoiesis and are therefore an effect of, rather than a cause of, myeloproliferative disorders.

Alleles↗
PubMed2000

Variability and validity of polymorphism association studies in Parkinson's disease.

BACKGROUND: In recent years, interest in gene-environment interactions has spurred a great number of association studies on polymorphism of different genes. OBJECTIVE: To review case-control studies of genetic polymorphisms in PD, and perform meta-analysis of individual gene polymorphism. METHODS: The authors searched the Medline database (PubMed) for publications (English language) from January 1966 to November 1999 for association studies in PD. The key words used were "PD" and "polymorphism." The authors supplemented the search with relevant references quoted in these published articles. Those with four or more independent studies of a specific gene polymorphism were subjected to meta-analysis, with the exception of cytochrome-P450 enzyme polymorphisms, for which meta-analyses results were already available in the literature. RESULTS: The authors identified 84 studies on 14 genes, including dopamine receptors (DRD2 and DRD4), dopamine transporter (DAT), monoamine oxidase (MAOA and MAOB), catechol-O-methyltransferase (COMT), N-acetyltransferase 2 (NAT2), APOE, glutathione transferase (GSTT1, GSTM1, GSTP1, and GSTZ1), and mitochondrial genes (tRNAGlu and ND2). Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT)n polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNAGlu (OR = 3.0). No significant differences were found for the other genes. CONCLUSION: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNAGlu. Although significant association does not imply a causal relationship between the presence of the polymorphisms and PD pathogenesis, their pathophysiologic significance should be studied further.

Apolipoproteins E↗
PubMed2006

The acute phase reactant, fibrinogen, as a guide to plasma exchange therapy for acute Guillain-Barré syndrome.

The Guillian Barré syndrome is an acute inflammatory disorder for which plasma exchange is effective treatment. Up to 10% relapse after plasma exchange suggesting that treatment sometimes finishes before disease activity has resolved. We studied whether plasma fibrinogen, an inflammatory marker, might be used to determine when to discontinue plasma exchange in patients with acute Guillain-Barré syndrome. We conducted a post-hoc analysis of apheresis database and hospital records of patients treated with plasma exchange for acute Guillain-Barré syndrome during 1999-2004. Data were analyzed from 28 patients who underwent a total of 29 courses of plasma exchange for acute Guillain-Barré syndrome. The mean (+/-SD) plasma fibrinogen concentration was 422.5 (+/-96.4) mg/dl at the time of presentation and, in 17 of the 29, it was above 400 mg/dl (reference range 200-400). Twenty of the 21 patients whose fibrinogen fell by more than 30% from baseline by the time of the final plasma exchange treatment had neurological improvement. There was improvement in only 3 of the 8 instances where fibrinogen decreased by less than 30% by the end of plasma exchange therapy. A > or =30% decrease in fibrinogen by the conclusion of plasma exchange was significantly associated with sustained neurological improvement (P = 0.0025). The plasma fibrinogen level appears to reflect disease activity in acute Guillain-Barré syndrome. A <30% fall in fibrinogen level despite plasma exchange may indicate the need to continue plasma exchange to maximize the benefit of treatment or minimize the risk of relapse. Therapeutic plasma exchange need not be extended when plasma fibrinogen remains > or =30% below its level at presentation by the time of the final planned plasma exchange procedure.

Acute Disease↗
PubMed2004

caGEDA: a web application for the integrated analysis of global gene expression patterns in cancer.

The explosion of microarray data from pilot studies, basic research and large-scale clinical trials requires the development of integrative computational tools that can not only analyse gene expression patterns but that can also evaluate the methods of analysis adopted and then provide a boost to post-analysis translational interpretation of those patterns. We have developed a web application called caGEDA (cancer gene expression data analyzer) that can: (1) upload gene expression profiles from cDNA or oligonucleotide microarrays; (2) conduct a diverse range of serial linear normalisations; (3) identify differentially expressed genes using a variety of tests - either threshold or permutation tests; (4) produce tables of literature references to papers reporting that specific genes (identified by accession numbers) are up- or down-regulated in specific cancers; (5) estimate the error of sample class prediction using the significant gene set for features; (6) perform low-bias and accurate validated learning using three computational validation techniques (leave-one out validation, k-fold validation, random re-sampling validation); and (7) validate a classifier with a randomly selected or user-defined validation set. Significant genes are reported in a table of links to entries in the following databases: Locus Link, Genome View, UCSC, Ensembl, UniGene, dbSNP, AmiGO and OMIM. caGEDA is seamlessly integrated via embedded forms with UCSD's (University of California at San Diego) 2HAPI server (for medical subject heading (MeSH) term exploration) and EZ-Retrieve (to identify common transcription factors located upstream of sets of genes that exhibit similar modes of differential expression). caGEDA offers a variety of previously described and novel tests for differentially expressed genes, most notably the permutation percentile separability test, which is most appropriate for identifying genes that are significantly differentially expressed in a subset of patients. caGEDA, which is open source and free to academic users, will soon be greatly enhanced by operating with the components of the National Cancer Institute's new cancer bioinformatics grid (caBIG).

Biomarkers, Tumor↗
PubMed1997

Introduction of a distance cut-off into structural alignment by the double dynamic programming algorithm.

Two approximations were introduced into the double dynamic programming algorithm, in order to reduce the computational time for structural alignment. One of them was the so-called distance cut-off, which approximately describes the structural environment of each residue by its local environment. In the approximation, a sphere with a given radius is placed at the center of the side chain of each residue. The local environment of a residue is constituted only by the residues with side chain centers that are present within the sphere, which is expressed by a set of center-to-center distances from the side chain of the residue to those of all the other constituent residues. The residues outside the sphere are neglected from the local environment. Another approximation is associated with the distance cut-off, which is referred to here as the delta N cut-off. If two local environments are similar to each other, the numbers of residues constituting the environments are expected to be similar. The delta N cut-off was introduced based on the idea. If the difference between the numbers of the constituent residues of two local environments is greater than a given threshold value, delta N, the evaluation of the similarity between the local environments is skipped. The introduction of the two approximations dramatically reduced the computational time for structural alignment by the double dynamic programming algorithm. However, the approximations also decreased the accuracy of the alignment. To improve the accuracy with the approximations, a program with a two-step alignment algorithm was constructed. At first, an alignment was roughly constructed with the approximations. Then, the epsilon-suboptimal region for the alignment was determined. Finally, the double dynamic programming algorithm with full structural environments was applied to the residue pairs within the epsilon-suboptimal region to produce an improved alignment.

Algorithms↗