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Homo sapiens
23 Downloadable Samples
Illumina HumanHT-12 V3.0 expression beadchip
Description
Recent data demonstrate that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways. This network model suggests why inhibition of a single component of a canonical pathway, even when targeting a mutationally activated driver of cancer, has insufficiently dramatic effects on the treatment of cancer. The biological outcome of signals propagated through a network is inherently more robust and resistant to inhibition of a single network component due to compensatory and redundant signaling events. In this study, we performed a functional chemical genetic screen analogous to synthetic lethal screening in yeast genetics to identify novel interactions between signaling inhibitors that would not be predicted based on our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. Among the most robust and surprising results was synergy between sorafenib, a multi-kinase inhibitor with activity against Raf, and diclofenac, a non-steroidal anti-inflammatory drug (NSAID). This synergy did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. The NSAIDs celecoxib and ibuprofen could qualitatively substitute for diclofenac. Similarly, the MEK inhibitor PD325901 and the Raf inhibitor RAF265 could qualitatively substitute for sorafenib. These drug substitution experiments suggest that inhibition of cyclo-oxygenase and MAP kinase signaling are components of the observed synergistic cytotoxicity. Genome-wide expression profiling demonstrates synergy-specific down-regulation of survival-related genes. This study provides proof of principle that synthetic lethal screening can uncover novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially depending on unexplored components of the cell genotype.
Publication Title
Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 12 Downloadable Samples
Illumina HiSeq 2000
Description
Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin the activation of MaSCs. Here we show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout adult life. Foxp1-deficient glands were highly enriched for quiescent Tspan8hi MaSCs, which failed to become activated, even in competitive transplantation assays, and therefore harbor a cell-intrinsic defect. Luminal cells aberrantly expressed basal genes, suggesting that Foxp1 may also contribute to cell-fate decisions. Notably, Foxp1 was uncovered as a direct repressor of the Tspan8 gene in basal cells and deletion of Tspan8 could rescue the profound defects in ductal morphogenesis elicited by Foxp1 loss. Thus, a single transcriptional regulator, Foxp1, can control the exit of MaSCs from dormancy to orchestrate differentiation and development. Overall design: Basal and luminal epithelial cells were extracted from the mammary glands of floxed Foxp1 control and Foxp1 mammary gland conditional knockout mice. mRNA from three biological replicates of each cell population was profiled by RNA sequencing. All mice were female.
Publication Title
Foxp1 Is Indispensable for Ductal Morphogenesis and Controls the Exit of Mammary Stem Cells from Quiescence.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 32 Downloadable Samples
- NextSeq 500
Description
Breast tumors are characterized by inherent heterogeneity but the evolving cellular organization of breast tumors through progression remains poorly understood. Individual clones were tracked by combining mouse models of breast cancer with Confetti reporter strains. Expression profiling of individual clones sorted from tumors arising in K5- and Elf5-driven Pten/p53-deficient mice revealed distinct molecular signatures. Overall design: K5-rtTA-IRES-GFP and ElF5-rtTA-IRES-GFP transgenic mice were crossed with TetO-cre (JAX) and R26R-Confetti reporter strains to generate triple genetically modified mice. The mice were treated with medroxyprogesterone acetate (MPA) and dimethylbenz(a)anthracene (DMBA) to induce carcinogenesis. Three K5-driven and five Elf5-driven mammary tumors were selected. Individual live cells from each tumor were FACS sorted by the four Confetti fluorescent markers (to select individual clones) and by CD24 expression (high or low). Cell subsets for the eight tumors, four fluorescent markers and positive or negative CD24 status were profiled by RNA-seq (38 samples in all). Expression was quantified by counting RNA-seq reads at the gene level and (separately) at the exon level.
Publication Title
Intraclonal Plasticity in Mammary Tumors Revealed through Large-Scale Single-Cell Resolution 3D Imaging.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples
GSE48937- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
HeLa cells transfected to express KDELR1 and HeLa cells incubated with KDEL-Bodipy peptide
Publication Title
Control systems of membrane transport at the interface between the endoplasmic reticulum and the Golgi.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used an inducible ShRNA system and microarrays to detail the global programme of gene expression underlying neuroblastoma differentiation upon CHAF1A silencing .
Publication Title
Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 20 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Physical exercise training is a known protective factor against cardiovascular morbidity and mortality. Nevertheless, the underlying specific molecular mechanisms still remain uncompletely explored. To identify molecular mechanisms by which exercise training induces this favorable phenotype a genomic approach was used in an animal model of mild exercise previously demonstrated by our group to induce cardioprotection.
Publication Title
Gene expression profile of rat left ventricles reveals persisting changes following chronic mild exercise protocol: implications for cardioprotection.
Sample Metadata Fields
No sample metadata fields
View Samples- Drosophila melanogaster
- 5 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Growth of the drosophila eye imaginal discs is controlled by the activation of Notch in the dorsal-ventral boundary. Overexpression in the eye disc of the Notch ligand Delta together with lola and pipsqueak from the GS(2)88A8 line induces tumoral growth. We used microarray to analyze the expression profile of tumoral discs.
Publication Title
Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 2 Downloadable Samples
- IlluminaHiSeq2000
Description
Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but it is not clear how they arise and propagate in the humans. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Close scrutiny revealed the signature of selection against non-synonymous variants in the protein-coding region, tRNA gene variants, and variants in specific regions of the non-coding D-loop. In isolated single PGCs we saw a profound reduction in the cellular mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules during early germline development. Single cell deep mtDNA sequencing showed rare variants reaching higher heteroplasmy levels in later PGCs, consistent with the observed genetic bottleneck, and predicting >80% levels within isolated organelles. Genome-wide RNA-seq showed a progressive upregulation of genes involving mtDNA replication and transcription, linked to a transition from glycolytic to oxidative metabolism. The metabolic shift exposes deleterious mutations to selection at the organellar level during early germ cell development. In this way, the genetic bottleneck prevents the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will, however, show massive shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders. Overall design: RNA-Seq and NGS analysis to investigate transcriptomes and mtDNA sequences of fetal hPGCs
Publication Title
Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Understanding the underlying mechanisms of the well-established platelet hyporeactivity in neonates, would be of great relevance for both improving the clinical management of neonates, a population with a higher bleeding risk than adults (especially among sick and preterm infants), and getting new insights onto the regulatory mechanisms of platelet biology. Transcriptome analysis is a useful tool to identify mRNA signature affecting platelet function. However, human fetal/neonatal platelet transcriptome analysis has never been reported. Here, we used, for the first time, mRNA expression array to compare the platelet transcriptome changes during development. Microarray analysis was performed in pure platelet RNA obtained from adult and cord blood, using the same platform in two independent laboratories.
Publication Title
Comprehensive comparison of neonate and adult human platelet transcriptomes.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 29 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
This study is part of previous epidemiologic project, including a population-based survey (Sao Paulo Ageing & Health study (SPAH Study). The data from this study was collected between 2015 to 2016 and involved elderly women (ages ≥65 yeas) living in the Butanta district, Sao Paulo. The purpose of the study was identification of association between transcriptome and the osteo metabolism diseases phenotype, like osteoporosis, vertebral fracture and coronary calcification.
Publication Title
Overexpression of SNTG2, TRAF3IP2, and ITGA6 transcripts is associated with osteoporotic vertebral fracture in elderly women from community.
Sample Metadata Fields
Sex, Age
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