Prediction of human response to chemical exposures is a major challenge in both pharmaceutical and toxicological research. Transcriptomics has been a powerful tool to explore chemical-biological interactions. However, limited throughput, high-costs and complexity of transcriptomic interpretations have yielded numerous studies lacking sufficient experimental context for predictive application. We utilized a novel high-throughput transcriptomics platform to explore a broad range of exposures to 24 reference compounds in both differentiated and undifferentiated human HepaRG cultures. Our goals were to 1) explore transcriptomic characteristics distinguishing liver injury compounds, 2) assess impacts of differentiation state on baseline and compound-induced responses (e.g., metabolically-activated), and 3) identify and resolve reference biological-response pathways and their quantitative translation to human exposures. Study data revealed the predictive utility of transcriptomic concentration-response modeling to quantitatively identify human liver injury compounds by their respective benchmark concentrations (BMCs), and model hepatic responses to classical reference compounds yielding plausibly-relevant estimations of human potency.
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View SamplesThe goal of this study was to identify transcriptomic differences in A549 lung cancer cell line following knockout of the RPA1 gene. A549 cells, and many lung tumors, carry constitutive NRF2 activation. Understanding how RPA1 modulates transcription, particularly NRF2-mediated transcription, is relevant for future cancer therapeutics.
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Sex, Specimen part, Cell line
View SamplesThe study was undertaken to compare the gene expression profile in mesenchymal stem/stromal cells from bone marrow of healthy donors and patients with newly diagnosed acute acute myeloid leukemia
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View SamplesIn tumor microenvironment, tumor-associated macrophages (TAMs) have been characterized as M1-like or M2-like phenotype. In this study, we investigated the characteristics and functional roles of different TAMs on cancer metastasis. We isolated TAMs from primary tumor and metastatic lung and performed microarrays to identify the gene expression in distinct TAMs populations.
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Specimen part
View SamplesAmplificaition of HOXD9 and HOXD13 genes was found in MWCNTs induced carcinogencity. By overexpression or silence of of HOXD9 and HOXD13 gene may alter tumorigenicity.
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Cell line
View SamplesPulmonary Hypertension (PH) is a frequent complication of Pulmonary Fibrosis (PF). PH can be seen in PF in the abscence of hypoxemia, irrespective of the degree of fibrosis. At the same time, a consistent number of patients with advanced PF never develop PH. The pathogenesis of PH secondary to PF remains unclear. PF patients are often referred to lung transplantation, but they present a higher incidence of pimary graft dysfunction than other diseases. The cause of this is unknown, and the relationship with PH remains unclear.
Gene expression profiling in the lungs of patients with pulmonary hypertension associated with pulmonary fibrosis.
Specimen part, Disease, Disease stage
View SamplesRecent advances in multiple whole genome technologies provide unprecedented opportunities to profile epigenomic signatures in cancer cells. Previously we used a human gene promoter tiling microarray platform to identify genome-wide DNA methylation changes in a cell line model of breast cancer metastasis. Interestingly, the clustered nature of epigenetic targets that we identified, along with our concurrent karyotype analyses, have now led us to hypothesize that complex genomic alterations in cancer cells (deletions, translocations and ploidy) may be superimposed over promoter-specific methylation events that are responsible for gene-specific expression changes.
Multi-platform whole-genome microarray analyses refine the epigenetic signature of breast cancer metastasis with gene expression and copy number.
Cell line
View SamplesPathologic and epidemiologic evidence has led to a histologic model of breast cancer progression that involves advancement through specific morphologic stages including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive mammary carcinoma (IMC), although not necessarily always in a linear fashion. Numerous observational studies have examined genetic, epigenetic and gene expression differences in breast tissues representing these different stages of progression, but model systems which would allow for experimental testing of specific factors influencing transition through these stages are scarce. The 21T series cell lines, all originally derived from the same patient with metastatic breast cancer, have been proposed to represent a mammary tumor progression series. We report here that three of the 21T cell lines indeed mimic specific stages of human breast cancer progression (21PT-derived cells, ADH; 21NT-derived cells, DCIS; 21MT-1 cells, IMC) when grown in the mammary fat pad of nude mice, albeit after up to a year post-injection. In order to develop a more rapid, readily manipulatable in vitro assay for examining the biologic differences between these cell lines, we have made use of a 3D Matrigel system. When grown in 3D Matrigel, we have found characteristic morphologies of the three cell lines in which quantifiable aspects of the stage-specific in vivo behaviors (i.e. differences in acinar structure formation, cell polarization, cell cohesiveness, cell proliferation, cell invasion) are re-capitulated in a reproducible fashion. Gene expression profiling has revealed a characteristic pattern for each of the three cell lines. Interestingly, WNT pathway alterations are particularly predominant in the early transition from 21PTci (ADH) to 21NTci (DCIS), whereas alterations in expression of genes associated with control of cell motility and invasiveness phenomena are more prominent in the later transition of 21NTci (DCIS) to 21MT-1 (IMC). This system thus reveals potential therapeutic targets and will provide a means of testing the influences of identified genes on transitions between these stages of pre-malignant to malignant growth.
Human 21T breast epithelial cell lines mimic breast cancer progression in vivo and in vitro and show stage-specific gene expression patterns.
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View SamplesThis study compares a cell line (MDA-MB-468GFP-LN) that aggressively metastasizes to lymph nodes to its parental line MDA-MB-468GFP. Derivation of the lines is described in Vantyghem et al, Clinical & Experimental Metastasis (2005) 22: 351361. The goal here was to compare the gene expression profile of MDA-MB-468GFP-LN to MDA-MB-468GFP, Compare differential expression to databases of genes known to be involved in either cancer stem cell identification or lymph node specific metastasis in large scale clinical studies, and to confirm genes by RT-PCR
Lymphatic metastasis of breast cancer cells is associated with differential gene expression profiles that predict cancer stem cell-like properties and the ability to survive, establish and grow in a foreign environment.
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View SamplesTo assess a potential role of transcription factor CREM in the long-term detrimental effects of beta1-adrenoceptor overexpression, four mouse lines were generated and studied: wild-type mice (WT), Crem-normal beta1AR-transgenic mice (beta1ARTG), Crem-deficient non-transgenic mice (Crem-/-) and Crem-deficient beta1AR-transgenic mice (beta1ARTG/Crem-/-). We focused on genes up- or down-regulated in transgenic mice due to the lacking of CREM (beta1ARTG/Crem-/- vs. beta1ARTG).
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Sex, Age, Specimen part
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