9,706 research outputs found
Integration and mining of malaria molecular, functional and pharmacological data: how far are we from a chemogenomic knowledge space?
The organization and mining of malaria genomic and post-genomic data is
highly motivated by the necessity to predict and characterize new biological
targets and new drugs. Biological targets are sought in a biological space
designed from the genomic data from Plasmodium falciparum, but using also the
millions of genomic data from other species. Drug candidates are sought in a
chemical space containing the millions of small molecules stored in public and
private chemolibraries. Data management should therefore be as reliable and
versatile as possible. In this context, we examined five aspects of the
organization and mining of malaria genomic and post-genomic data: 1) the
comparison of protein sequences including compositionally atypical malaria
sequences, 2) the high throughput reconstruction of molecular phylogenies, 3)
the representation of biological processes particularly metabolic pathways, 4)
the versatile methods to integrate genomic data, biological representations and
functional profiling obtained from X-omic experiments after drug treatments and
5) the determination and prediction of protein structures and their molecular
docking with drug candidate structures. Progresses toward a grid-enabled
chemogenomic knowledge space are discussed.Comment: 43 pages, 4 figures, to appear in Malaria Journa
Experimental and computational applications of microarray technology for malaria eradication in Africa
Various mutation assisted drug resistance evolved in Plasmodium falciparum strains and insecticide
resistance to female Anopheles mosquito account for major biomedical catastrophes standing against
all efforts to eradicate malaria in Sub-Saharan Africa. Malaria is endemic in more than 100 countries and
by far the most costly disease in terms of human health causing major losses among many African
nations including Nigeria. The fight against malaria is failing and DNA microarray analysis need to keep
up the pace in order to unravel the evolving parasite’s gene expression profile which is a pointer to
monitoring the genes involved in malaria’s infective metabolic pathway. Huge data is generated and
biologists have the challenge of extracting useful information from volumes of microarray data.
Expression levels for tens of thousands of genes can be simultaneously measured in a single
hybridization experiment and are collectively called a “gene expression profile”. Gene expression
profiles can also be used in studying various state of malaria development in which expression profiles
of different disease states at different time points are collected and compared to each other to establish
a classifying scheme for purposes such as diagnosis and treatments with adequate drugs. This paper
examines microarray technology and its application as supported by appropriate software tools from
experimental set-up to the level of data analysis. An assessment of the level of microarray technology
in Africa, its availability and techniques required for malaria eradication and effective healthcare in
Nigeria and Africa in general were also underscored
Identification of a selective G1-phase benzimidazolone inhibitor by a senescence-targeted virtual screen using artificial neural networks
Cellular senescence is a barrier to tumorigenesis in normal cells and tumour cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. 147 virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase (SA-β-gal) assays. Among the found hits a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced SA-β-gal activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1 and CDC25C. Additionally, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long term treatments. Preliminary structure-activity and structure clustering analyses are reported and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells
Assessment of SVM Reliability for Microarray Data Analysis
The goal of our research is to provide techniques that can assess and validate the results of SVM-based analysis of microarray data. We present preliminary results of the effect of mislabeled training samples. We conducted several systematic experiments on artificial and real medical data using SVMs. We systematically flipped the labels of a fraction of the training data. We show that a relatively small number of mislabeled examples can dramatically decrease the performance as visualized on the ROC graphs. This phenomenon persists even if the dimensionality of the input space is drastically decreased, by using for example feature selection. Moreover we show that for SVM recursive feature elimination, even a small fraction of mislabeled samples can completely change the resulting set of genes. This work is an extended version of the previous paper [MBN04]
The Power of the Web in Cancer Drug Discovery and Clinical Trial Design: Research without a Laboratory?
The discovery of effective cancer treatments is a key goal for pharmaceutical companies. However, the current costs of bringing a cancer drug to the market in the USA is now estimated at $1 billion per FDA approved drug, with many months of research at the bench and costly clinical trials. A growing number of papers highlight the use of data mining tools to determine associations between drugs, genes or protein targets, and possible mechanism of actions or therapeutic efficacy which could be harnessed to provide information that can refine or direct new clinical cancer studies and lower costs. This report reviews the paper by R.J. Epstein, which illustrates the potential of text mining using Boolean parameters in cancer drug discovery, and other studies which use alternative data mining approaches to aid cancer research
Information visualization for DNA microarray data analysis: A critical review
Graphical representation may provide effective means of making sense of the complexity and sheer volume of data produced by DNA microarray experiments that monitor the expression patterns of thousands of genes simultaneously. The ability to use ldquoabstractrdquo graphical representation to draw attention to areas of interest, and more in-depth visualizations to answer focused questions, would enable biologists to move from a large amount of data to particular records they are interested in, and therefore, gain deeper insights in understanding the microarray experiment results. This paper starts by providing some background knowledge of microarray experiments, and then, explains how graphical representation can be applied in general to this problem domain, followed by exploring the role of visualization in gene expression data analysis. Having set the problem scene, the paper then examines various multivariate data visualization techniques that have been applied to microarray data analysis. These techniques are critically reviewed so that the strengths and weaknesses of each technique can be tabulated. Finally, several key problem areas as well as possible solutions to them are discussed as being a source for future work
Evaluation of linear classifiers on articles containing pharmacokinetic evidence of drug-drug interactions
Background. Drug-drug interaction (DDI) is a major cause of morbidity and
mortality. [...] Biomedical literature mining can aid DDI research by
extracting relevant DDI signals from either the published literature or large
clinical databases. However, though drug interaction is an ideal area for
translational research, the inclusion of literature mining methodologies in DDI
workflows is still very preliminary. One area that can benefit from literature
mining is the automatic identification of a large number of potential DDIs,
whose pharmacological mechanisms and clinical significance can then be studied
via in vitro pharmacology and in populo pharmaco-epidemiology. Experiments. We
implemented a set of classifiers for identifying published articles relevant to
experimental pharmacokinetic DDI evidence. These documents are important for
identifying causal mechanisms behind putative drug-drug interactions, an
important step in the extraction of large numbers of potential DDIs. We
evaluate performance of several linear classifiers on PubMed abstracts, under
different feature transformation and dimensionality reduction methods. In
addition, we investigate the performance benefits of including various
publicly-available named entity recognition features, as well as a set of
internally-developed pharmacokinetic dictionaries. Results. We found that
several classifiers performed well in distinguishing relevant and irrelevant
abstracts. We found that the combination of unigram and bigram textual features
gave better performance than unigram features alone, and also that
normalization transforms that adjusted for feature frequency and document
length improved classification. For some classifiers, such as linear
discriminant analysis (LDA), proper dimensionality reduction had a large impact
on performance. Finally, the inclusion of NER features and dictionaries was
found not to help classification.Comment: Pacific Symposium on Biocomputing, 201
Could the Anti-Chaperone VER155008 Replace Temozolomide for Glioma Treatment
Cancer inducible molecular chaperone HSP90 is of great importance as an anticancer target. Proteomic analysis showed that inhibiting HSP90 by the geldanamycin derivative, 17-AAG elevated the expression of the co-chaperone Hsp70. In this study we used HSP90 selective inhibitor 17-AAG and HSP70/90 dual inhibitor, VER155008 (VER) in U87-MG glioma cells. miRNAs microarray technology was used to evaluate the efficacy of these inhibitory drugs compared with temozolomide (TMZ), used as a standard treatment for glioma. Microarrays data identified 154 differentially expressed miRNAs using stringent or unstringent parameters. 16 miRNAs were overlapped between treatments, 13 upregulated and one downregulated miRNA were overlapped between TMZ and VER. The miRNA target prediction software was used for these overlapped miRNAs and identified 6 of the 13 upregulated miRNAs target methyltransferase genes. The IC50, together with Akt and HSP70 and 90 protein level data favour VER and TMZ to 17-AAG, however due to the selectivity of VER to cancer cells as a potent antichaperon, it may be more favourable to the standard TMZ
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