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SRP073318
Homo sapiens
87 Downloadable Samples
Illumina HiSeq 2500
Description
mRNA expression profiles for 3 breast cancer cell lines seeded at different density and grown for different duration Overall design: This experiment is part of a study fo the effect of cell density on drug sensitivity [1]. Cells plated at different densities in 384-well plates were harvested at the indicated times and RNA was extracted using the RNeasy mini kit (Qiagen). To ensure sufficient RNA amounts wells with low cell numbers were pooled. Some conditions have been tested in biollogical replicates grown at the same time. Libraries were prepared by the Broad Technology Labs (BTL) following the protocol for SCRB-Seq described in [2]. Transcripts were quantified by the BTL computational pipeline using Cuffquant version 2.2.1 [3]. [1] Hafner, M., Niepel, M., Chung, M., Sorger, P.K., Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. DOI:10.1038/NMETH.3853 [2] Soumillon, M., Cacchiarelli, D., Semrau, S., van Oudenaarden, A. & Mikkelsen, T.S. Characterization of directed differentiation by high-throughput single-cell RNA-Seq http://biorxiv.org/content/early/2014/03/05/003236 [3] Trapnell, C., Roberts, A., Goff, L., Pertea, G., Kim, D., Kelley, D.R., Pimentel, H., Salzberg, S.L., Rinn, J.L. & Pachter, L. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks, Nat. Protoc. 7, 562-578 (2012).
Publication Title
Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 25 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Crosstalk and complexity within signaling pathways has limited our ability to devise rational strategies for using network biology to treat human disease. This is particularly problematic in cancer where oncogenes that drive or maintain the tumorigenic state alter the normal flow of molecular information within signaling networks that control growth, survival and death. Understanding the architecture of oncogenic signaling pathways, and how these networks are re-wired by ligands or drugs, could provide opportunities for the specific targeting of oncogene-driven tumors. Here we use a systems biology-based approach to explore synergistic therapeutic strategies to optimize the killing of triple negative breast cancer cells, an incompletely understood tumor type with a poor treatment outcome. Using targeted inhibition of oncogenic signaling pathways combined with DNA damaging chemotherapy, we report the surprising finding that time-staggered EGFR inhibition, but not simultaneous co-administration, can dramatically sensitize the apoptotic response of a subset of triple-negative cells to conventional DNA damaging agents. A systematic analysis of the order and timing of inhibitor/genotoxin presentationusing a combination of high-density time-dependent activity measurements of signaling networks, gene expression profiles, cell phenotypic responses, and mathematical modelingrevealed an approach for altering the intrinsic oncogenic state of the cell through dynamic re-wiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death, through re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.
Publication Title
Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Microarray expression profilling of mouse primary mixed cortical/hippocampal neurons, primary fibroblasts and L929 cells to compare ISGs signature in disctinct cell types
Publication Title
Inefficient type I interferon-mediated antiviral protection of primary mouse neurons is associated with the lack of apolipoprotein l9 expression.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Background: The vast majority of human genes (.70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. Methodology/Principal Findings: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. Conclusions/Significance: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatability gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF2 and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MGthymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse TranscriptionPolymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches
Publication Title
Identifying alternative hyper-splicing signatures in MG-thymoma by exon arrays.
Sample Metadata Fields
Sex
View Samples- Drosophila melanogaster
- 16 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Gene expression in larval, early third instar eye-antenna discs was assessed to reveal an ATF4 contribution to target gene induction following COX7a knockdown. As hypothesised, these COX7a-RNAi induced target genes require the transcription factor ATF4 for induction, irrespective of concomitant Notch pathway activation through Delta over-expression.
Publication Title
ATF4-Induced Warburg Metabolism Drives Over-Proliferation in Drosophila.
Sample Metadata Fields
No sample metadata fields
View Samples- Drosophila melanogaster
- 10 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Gene expression in larval, early third instar eye-antenna discs was assesed in genotypes with Notch Gain-of-Function (UAS-Delta or UAS-Notch[intra2]) over-expression or mitochondrial COX7a Loss-of-function (UAS-COX7a-RNAi) or a combination of both (UAS-Delta, UAS-COX7a-RNAi). The analysis revealed that, despite a strong genetic interaction between Notch pathway activation and knockdown of COX7a, no transcriptional cooperation or synergy was detectable in early L3 eye-antenna discs. Rather, COX7a knockdown induced a unique transcriptional signature, which further experiments revealed to be mediated by the transcription factor ATF4.
Publication Title
ATF4-Induced Warburg Metabolism Drives Over-Proliferation in Drosophila.
Sample Metadata Fields
No sample metadata fields
View Samples- Pseudomonas aeruginosa
- 4 Downloadable Samples
- Affymetrix Pseudomonas aeruginosa Array (paeg1a)
Description
Quorum sensing, a cell-to-cell communication system based on small signal molecules, is employed by the human pathogen Pseudomonas aeruginosa to regulate virulence and biofilm development. Moreover, regulation by small trans-encoded RNAs has become a focal issue in virulence gene expression of bacterial pathogens. In this study, we have identified the small RNA PhrS as an activator of PqsR synthesis, one of the key quorum sensing regulators in P. aeruginosa. Genetic studies revealed a novel mode of regulation by a sRNA, whereby PhrS uses a base-pairing mechanism to activate a short upstream open reading frame to which the pqsR gene is translationally coupled. Expression of phrS is induced by the oxygen-responsive regulator ANR when the oxygen supply decreases. Thus, PhrS is the first bacterial sRNA that provides a regulatory link between oxygen availability and quorum sensing, which may impact on oxygen-limited growth in P. aeruginosa biofilms.
Publication Title
The small RNA PhrS stimulates synthesis of the Pseudomonas aeruginosa quinolone signal.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 671 Downloadable Samples
- Illumina HiSeq 2500
Description
To define molecular markers of tyrosine kinase inhibitor-induced cardiotoxicity, we measured transcriptome changes in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with one of four tyrosine kinase inhibitors (Erlotinib, Lapatinib, Sorafenib, or Sunitinib) displaying a range of mild to severe cardiotoxicity or a vehicle-only control (DMSO). Gene expression changes were assessed at the cell population level using total RNA-seq, which measured levels of both mRNAs and non-coding RNAs. hiPSC-CMs used in this study were the Cor.4U cells purchased from Ncardia. Overall design: hiPSC-CMs were treated with each TKI (Erlotinib, Lapatinib, Sorafenib or Sunitinib) at three doses (1, 3 and 10 µM) for 24 hours and the intermediate dose (3 µM) for an additional three time points (6h, 72h and 168h). hiPSC-CMs were also treated with the DMSO vehicle-only control at four time points (6h, 24h, 72h and 168h). Each treatment condition had three biological replicates, collected from three independent experiments using three different lots of hiPSC-CMs. Total RNA was collected from all these samples.
Publication Title
Adaptation of Human iPSC-Derived Cardiomyocytes to Tyrosine Kinase Inhibitors Reduces Acute Cardiotoxicity via Metabolic Reprogramming.
Sample Metadata Fields
Sex, Specimen part, Subject, Compound, Time
View Samples- Mus musculus
- 29 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
PD is the second most common neurodegenerative disease worldwide with growing prevalence. MPTP is a neurotoxin which causes the appearance of Parkinson's disease (PD) pathology. The involvement of the cholinergic system in PD has been identified decades ago and anti-cholinergic drugs were upon the first drugs used for symptomatic treatment of PD. Of note, MPTP intoxication is a model of choice for symptomatic neuroprotective therapies since it have been quite predictive. Mice were exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. Transgenic AChE-S (the synaptic variant), AChE-R (the shorter, protective variant) and FVB/N control mice were included in this study. Two brain regions were examined: the pre-frontal cortex (PFC) and the striatal caudate-putamen (CPu). Each condition (i.e brain region and transgenic variant) was examined on both naive and MPTP-exposed mice.
Publication Title
Meta-analysis of genetic and environmental Parkinson's disease models reveals a common role of mitochondrial protection pathways.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 26 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Sub-thalamic deep brain stimulation (DBS) reversibly modulates Parkinsons disease (PD) motor symptoms, providing an unusual opportunity to compare leukocyte transcripts in the same subjects before and after neurosurgery and after disconnecting the stimulus (ON-and OFF-stimulus). Here, we report rapid stimulus-induced and largely reversible changes in PD leukocyte transcripts, which were larger in scope than the disease-induced changes. These transcript changes classified advanced pre- from post-surgery PD patients and discriminated patients from controls. Moreover, the extent of changes correlated with the neurological efficacy of the DBS neurosurgery, and covered both regulatory pathways and individual transcript changes, e.g. SNCA, PARK7 and the splicing factor SFRS1. Following 1 hour OFF-stimulus, these changes were largely reversed. We extracted from these differences a modified transcripts signature which discriminated controls from advanced PD patients, pre- from post-surgery and ON-from OFF-stimulus conditions. A further gene-list independent analysis detected reversed pathways. Our findings suggest future uses of this approach and the discovered molecular signature for early diagnostics of PD and for identifying novel targets for therapeutic intervention in this and other DBS-treatable neurological diseases.
Publication Title
Deep brain stimulation induces rapidly reversible transcript changes in Parkinson's leucocytes.
Sample Metadata Fields
Sex, Specimen part, Disease stage
View Samples