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Multidimensional Drug Profiling By Automated Microscopy

This study by Perlman et al. (2004) explores the innovative use of automated microscopy for multidimensional drug profiling during pharmaceutical development. With a focus on measuring both target and off-target activities, the research addresses the limitations of existing transcriptional and proteomic profiling methods. By automating processes, the study achieves increased efficiency and cost-effectiveness, allowing for multiplex screening of various pathways and mechanisms of action. Through experimental setups involving HeLa cells and various drug titrations, the authors successfully quantify dose-response profiles, paving the way for rapid and unbiased drug screening methodologies.

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Multidimensional Drug Profiling By Automated Microscopy

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  1. Multidimensional Drug ProfilingBy Automated Microscopy Zachary E. Perlman et al. Published 2004 Joseph Martinez and Ginger Yang

  2. Stages of Pharmaceutical Development Activity on Target Off Target Activity Effective Concentration

  3. Use of Automated Microscopy • Limited throughput with current (2004) transcriptional and proteomic profiling • Automate for efficiency and cost effectiveness • Multiplex markers to screen multiple pathways and mechanisms of action • Enhanced efficiency allows concentration dose dependent analyses

  4. Experimental Setup 100 Drugs 1 Toxin (Didemnin B) 6 Alternate Titrations 3 Unknown 90 Known

  5. Testing Scheme Image and Measure Descriptors HeLa Cells in 384 Wells Treat With Drug Titrations 11 Probes

  6. Sample Image Perlman et al (2004)

  7. Quantification of Population Responses Perlman et al (2004)

  8. Comparison of Compound Profiles • Generate a Kolmogorov-Smirnov (KS) Statistic • Compute a z score by dividing KS statistic by a measure of variability in control populations • Create Heat Plot • Determine Primary Effective Concentration (PEC)

  9. Heat Maps

  10. Conclusion • Cytometric dose-response profiling successful at determining drug response profiles quantitatively • The method is fast, cheap, and unbiased. • Future work: has been commercialized today • Questions?

  11. Titration-Invariant Similarity Score (TISS)

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