Integrated Drug Expression Analysis for leukemia: an integrated in silico and in vivo approach to drug discovery

Ung, MH; Sun, Chengyi; Weng, Chia-Wei; Huang, Chieh-Chen; Lin, Chi-Chen; Cc, Liu; Cheng, Chao

doi:10.1038/tpj.2016.18

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…Another drug loxapine, a typical anti-psychotic, was effectiveness as an add-on therapy for irritability in ASD 80 . Ribavirin is another interesting 15 candidate. Recently autism was shown to be associated with eIF4E overexpression which in turn leads to excessive translation of neuroligins 81 .…”

Section: Autistic Spectrum Disordersmentioning

confidence: 99%

When GWAS meets the Connectivity Map: drug repositioning for seven psychiatric disorders

Chau

Chiu

et al. 2016

Preprint

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Our knowledge of disease genetics has advanced rapidly during the past decade, with the advent of high-throughput genotyping technologies such as genome-wide association studies (GWAS). However, few methodologies were developed and systemic studies performed to identify novel drug candidates utilizing GWAS data. In this study we focus on drug repositioning, which is a cost-effective approach to shorten the developmental process of new therapies. We proposed a novel framework of drug repositioning by comparing GWAS-imputed transcriptome with drug expression profiles from the Connectivity Map. The approach was applied to 7 psychiatric disorders. We discovered a number of novel repositioning candidates, many of which are supported by preclinical or clinical evidence. We found that the predicted drugs are significantly enriched for known psychiatric medications, or therapies considered in clinical trials. For example, drugs repurposed for schizophrenia are strongly enriched for antipsychotics (p = 4.69E-06), while those repurposed for bipolar disorder are enriched for antipsychotics (p = 2.26E-07) and antidepressants (p = 1.17E-05).These findings provide support to the usefulness of GWAS signals in guiding drug discoveries and the validity of our approach in drug repositioning. We also present manually curated lists of top repositioning candidates for each disorder, which we believe will serve as a useful resource for researchers.

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Section: Autistic Spectrum Disordersmentioning

confidence: 99%

When GWAS meets the Connectivity Map: drug repositioning for seven psychiatric disorders

Chau

Chiu

et al. 2016

Preprint

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“…Five hundred of the most and least highly expressed genes from the cDNA microarray of ampullary cancer were input to CMap to predict potential drugs. To reveal meaningful biological connections of the gene list, the gene-signature perturbation approach was performed in the present study 33 , 34 . A two-sided t -test was applied to classify the effectiveness of compounds for differential gene expressions.…”

Section: Methodsmentioning

confidence: 99%

Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer

Wang¹,

Chao²,

Chen³

et al. 2021

Int. J. Med. Sci.

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Ampullary cancer is a rare periampullary cancer currently with no targeted therapeutic agent. It is important to develop a deeper understanding of the carcinogenesis of ampullary cancer. We attempted to explore the characteristics of ampullary cancer in our dataset and a public database, followed by a search for potential drugs. We used a bioinformatics pipeline to analyze complementary (c)DNA microarray data of ampullary cancer and surrounding normal duodenal tissues from five patients. A public database from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) was applied for external validation. Bioinformatics tools used included the Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID), MetaCore, Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, BioCarta, Reactome, and Connectivity Map (CMap). In total, 9097 genes were upregulated in the five ampullary cancer samples compared to normal duodenal tissues. From the MetaCore analysis, genes of peroxisome proliferator-activated receptor alpha ( PPARA ) and retinoid X receptor ( RXR )-regulated lipid metabolism were overexpressed in ampullary cancer tissues. Further a GSEA of the KEGG, Hallmark, Reactome, and Gene Ontology databases revealed that PPARA and lipid metabolism-related genes were enriched in our specimens of ampullary cancer and in the NCBI GSE39409 database. Expressions of PPARA messenger (m)RNA and the PPAR-α protein were higher in clinical samples and cell lines of ampullary cancer. US Food and Drug Administration (FDA)-approved drugs, including alvespimycin, trichostatin A (a histone deacetylase inhibitor), and cytochalasin B, may have novel therapeutic effects in ampullary cancer patients as predicted by the CMap analysis. Trichostatin A was the most potent agent for ampullary cancer with a half maximal inhibitory concentration of < 0.3 μM. According to our results, upregulation of PPARA and lipid metabolism-related genes are potential pathways in the carcinogenesis and development of ampullary cancer. Results from the CMap analysis suggested potential drugs for patients with ampullary cancer.

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“…Wet-lab results can conversely be used to improve the accuracy and reliability of the model. This integrated approach has been shown to be successful in a wide range of applications, as in 36 – 38 . Moreover, opposite to most in-vitro assays, SALSA monitors individual virtual cells, allowing to study their distinct behaviours.…”

Section: Introductionmentioning

confidence: 99%

An in-silico study of cancer cell survival and spatial distribution within a 3D microenvironment

Cortesi

Liverani

Mercatali

et al. 2020

Sci Rep

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3D cell cultures are in-vitro models representing a significant improvement with respect to traditional monolayers. Their diffusion and applicability, however, are hampered by the complexity of 3D systems, that add new physical variables for experimental analyses. In order to account for these additional features and improve the study of 3D cultures, we here present SALSA (ScAffoLd SimulAtor), a general purpose computational tool that can simulate the behavior of a population of cells cultured in a 3D scaffold. This software allows for the complete customization of both the polymeric template structure and the cell population behavior and characteristics. In the following the technical description of SALSA will be presented, together with its validation and an example of how it could be used to optimize the experimental analysis of two breast cancer cell lines cultured in collagen scaffolds. This work contributes to the growing field of integrated in-silico/in-vitro analysis of biological systems, which have great potential for the study of complex cell population behaviours and could lead to improve and facilitate the effectiveness and diffusion of 3D cell culture models. Cell culture is currently experiencing a fundamental shift from traditional 2D to 3D systems, that are more realistic representations of a biological tissue. These novel approaches, that integrate important aspects of cellular habitat, such as a non-uniform microenvironment, more complex diffusion processes and cell interactions with local physical features of the synthetic extracellular matrix (ECM), are bound to provide fundamental insights into cell biology, generating a closer approximation of reality as shown in 1-4. However, in order for 3D systems to become the standard in-vitro cell culturing technique, several issues still need to be addressed. In fact, the increased complexity in structural properties is, at the same time, the added value of these experimental systems and the limitation in optimising biological assays and protocols originally standardised for cells grown on 2D plastic surfaces. This complicates experimental design and data collection. While innovative 3D native assays are being developed 5,6 , computational models can complement the wet-lab experimental activity and help to address some of the limitations of 3D culture settings 7-9. The mathematical formalization of complex behaviours, however, is often maintained separate from the experimental analysis. As an example there are multiple models describing cancer-related cellular processes 10-17 and the effect of antineoplastic therapies 18-24 but most of them are presented as theoretical frameworks that do not aim at driving the experimental activity. To integrate this important functionality we developed a general purpose scaffold simulator named SALSA that can be programmed to reproduce the behaviour of a population of arbitrary cells, grown in 3D scaffolds of tunable size and material. It relies on a custom hybrid continuous/discrete framework that is particularly b...

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Integrated Drug Expression Analysis for leukemia: an integrated in silico and in vivo approach to drug discovery

Cited by 4 publications

References 48 publications

When GWAS meets the Connectivity Map: drug repositioning for seven psychiatric disorders

When GWAS meets the Connectivity Map: drug repositioning for seven psychiatric disorders

Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer

An in-silico study of cancer cell survival and spatial distribution within a 3D microenvironment

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