Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1071491 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We established a human liver organoid (HLO) based screening model for analyzing DILI pathology at organoid resolution. HLO contains polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNAseq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. By developing a 384 well based high-speed live imaging platform, we successfully developed a Liver organoid-based Toxicity screen (LoT) with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity. We functionally validated LoT with 238 marketed drugs at 4 different concentrations. LoT positively predicts genomic predisposition (CYP2C9*2) for Bosentan-induced cholestasis. Thus, LoT is a high-fidelity model for drug safety with a cost-effective platform, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.
2020-10-18 | GSE141183 | GEO
Project description:“Direct to Drug” screening as a precision medicine tool in multiple myeloma
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Project description:Rare cancers comprise over 200 distinct types accounting for 20–25% of U.S. cancer diagnoses yet receive limited therapeutic investment due to small patient populations and resource constraints. Drug repurposing offers a viable strategy, and large-animal models such as minipigs provide physiologically realistic platforms for preclinical evaluation. However, scalable systems for systematically screening large drug libraries in rare cancer models remain unavailable. We developed an integrated pipeline combining a minipig spinal cord glioma (SCG) model with miniaturized ultra-high-throughput screening (uHTS). Primary SCG cells were cultured in 3D platforms for rapid screening of bioactive compounds. Lead candidates underwent validation through 3D spheroid assays, in vivo xenografting, RNA sequencing, immunohistochemistry, and histological analysis. Human SCG tissue samples and population-level datasets assessed translational relevance. uHTS screening identified Clofoctol as a lead compound with potent glioma growth inhibition in both primary SCG cells and xenograft models. Mechanistic studies revealed pleiotrophin (PTN) as a key target, with confirmatory expression patterns in human SCG samples, establishing translational validity. Integration of large-animal cancer models with drug-repurposing pipelines and uHTS platforms is feasible and effective for rare cancer drug discovery. This approach successfully identified Clofoctol, an FDA-approved compound with therapeutic potential for spinal cord gliomas and establishes a scalable model applicable to other orphan cancers.
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Project description:High-throughput phenotypic screening is a cornerstone of drug development and the main technical approach for stem cell research. However, simultaneous detection of activated core factors responsible for cell fate determination and accurate assessment of directional cell transition are difficult using conventional screening methods that focus on changes in only a few biomarkers. The PHDs-seq (Probe Hybridization based Drug screening by sequencing) platform was developed to evaluate compound function based on their transcriptional effects in a wide range of signature biomarkers. In this proof-of-concept demonstration, several sets of markers related to cell fate determination were profiled in adipocyte reprogramming from dermal fibroblasts. After validating the accuracy, sensitivity and reproducibility of PHDs-seq data in molecular and cellular assays, a panel of 128 signalling-related compounds was screened for the ability to induce reprogramming of keloid fibroblasts (KF) into adipocytes. Notably, the potent ATP-competitive VEGFR/PDGFR inhibitor compound, ABT869, was found to promote the transition from fibroblasts to adipocytes. This study highlights the power and accuracy of the PHDs-seq platform for high-throughput drug screening in stem cell research, and supports its use in basic explorations of the molecular mechanisms underlying disease development.
2023-05-19 | GSE227391 | GEO
Project description:High-throughput phenotypic screening is a cornerstone of drug development and the main technical approach for stem cell research. However, simultaneous detection of activated core factors responsible for cell fate determination and accurate assessment of directional cell transition are difficult using conventional screening methods that focus on changes in only a few biomarkers. The PHDs-seq (Probe Hybridization based Drug screening by sequencing) platform was developed to evaluate compound function based on their transcriptional effects in a wide range of signature biomarkers. In this proof-of-concept demonstration, several sets of markers related to cell fate determination were profiled in adipocyte reprogramming from dermal fibroblasts. After validating the accuracy, sensitivity and reproducibility of PHDs-seq data in molecular and cellular assays, a panel of 128 signalling-related compounds was screened for the ability to induce reprogramming of keloid fibroblasts (KF) into adipocytes. Notably, the potent ATP-competitive VEGFR/PDGFR inhibitor compound, ABT869, was found to promote the transition from fibroblasts to adipocytes. This study highlights the power and accuracy of the PHDs-seq platform for high-throughput drug screening in stem cell research, and supports its use in basic explorations of the molecular mechanisms underlying disease development.
2023-05-19 | GSE227388 | GEO
Project description:High-throughput phenotypic screening is a cornerstone of drug development and the main technical approach for stem cell research. However, simultaneous detection of activated core factors responsible for cell fate determination and accurate assessment of directional cell transition are difficult using conventional screening methods that focus on changes in only a few biomarkers. The PHDs-seq (Probe Hybridization based Drug screening by sequencing) platform was developed to evaluate compound function based on their transcriptional effects in a wide range of signature biomarkers. In this proof-of-concept demonstration, several sets of markers related to cell fate determination were profiled in adipocyte reprogramming from dermal fibroblasts. After validating the accuracy, sensitivity and reproducibility of PHDs-seq data in molecular and cellular assays, a panel of 128 signalling-related compounds was screened for the ability to induce reprogramming of keloid fibroblasts (KF) into adipocytes. Notably, the potent ATP-competitive VEGFR/PDGFR inhibitor compound, ABT869, was found to promote the transition from fibroblasts to adipocytes. This study highlights the power and accuracy of the PHDs-seq platform for high-throughput drug screening in stem cell research, and supports its use in basic explorations of the molecular mechanisms underlying disease development.
2023-05-19 | GSE227387 | GEO