Flow cytometry: Impact on early drug discovery

Journal of Biomolecular Screening

Volumn 20, Issue 6, 2015, Pages 689-707

  Edwards, Bruce S ^a   Sklar, Larry A ^a  

^a UNIVERSITY OF NEW MEXICO   (United States)

Author keywords

flow cytometry; high content screening; multiplex assays and technology; phenotypic drug discovery; protein protein interactions; review

Indexed keywords

ANALYTIC METHOD; CELL SUSPENSION; COMBINATORIAL LIBRARY; DRUG DEVELOPMENT; DRUG SCREENING; FLOW CYTOMETRY; HIGH THROUGHPUT SCREENING; PHENOTYPE; PRIORITY JOURNAL; REVIEW; TECHNOLOGY; HUMAN; MOLECULAR LIBRARY; PROCEDURES;

MOLECULAR LIBRARY;

DRUG DISCOVERY; FLOW CYTOMETRY; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; PHENOTYPE; SMALL MOLECULE LIBRARIES;

EID: 84931448067     PISSN: 10870571     EISSN: 1552454X     Source Type: Journal    
DOI: 10.1177/1087057115578273     Document Type: Review

References (155)

1. Chattopadhyay P. K., Hogerkorp C. M., Roederer M.. A Chromatic Explosion: The Development and Future of Multi-parameter Flow Cytometry. Immunology. 2008 ; 125: 441-449
2. Macey M. Flow Cytometry: Principles and Applications. Totowa, NJ: Humana Press ; 2007 :
3. Shapiro H. M. Practical Flow Cytometry. Hoboken, NJ: John Wiley & Sons ; 2003 :
4. Chase E. S., Hoffman R. A.. Resolution of Dimly Fluorescent Particles: A Practical Measure of Fluorescence Sensitivity. Cytometry. 1998 ; 33: 267-279
5. Picot J., Guerin C. L., Le Van Kim C., et al. Flow Cytometry: Retrospective, Fundamentals and Recent Instrumentation. Cytotechnology. 2012 ; 64: 109-130
6. Sklar L. A., Finney D. A.. Analysis of Ligand-Receptor Interactions with the Fluorescence Activated Cell Sorter. Cytometry. 1982 ; 3: 161-165
7. Murphy R. F. Flow Cytometry and Sorting. 1990 ; 2nd ed, pp 355-366. Melamed M. R. Lindmo T. Mendelsohn M. L., ed. New York: Wiley-Liss, Inc ; 1990: 355-366.
8. Sklar L. A., Edwards B. S., Graves S. W., et al. Flow Cytometric Analysis of Ligand-Receptor Interactions and Molecular Assemblies. Annu. Rev. Biophys. Biomol. Struct. 2002 ; 31: 97-119
9. Jepras R., Ludbrook S.. Evolution of Flow Cytometry as a Drug Screening Platform. Drug Discovery World Spring. 2013 ;: 43-50
10. Kim K., Wang L., Hwang I.. A Novel Flow Cytometric High Throughput Assay for a Systematic Study on Molecular Mechanisms Underlying T cell Receptor-Mediated Integrin Activation. PLoS One. 2009 ; 4: e6044
11. Durack G., Lawler G., Kelley S., et al. Time Interval Gating for Analysis of Cell Function Using Flow Cytometry. Cytometry. 1991 ; 12: 701-706
12. Robinson J. P., Durack G., Kelley S.. An Innovation in Flow Cytometry Data Collection and Analysis Producing a Correlated Multiple Sample Analysis in a Single File. Cytometry. 1991 ; 12: 82-90
13. Edwards B. S., Kuckuck F., Sklar L. A.. Plug Flow Cytometry: An Automated Coupling Device for Rapid Sequential Flow Cytometric Sample Analysis. Cytometry. 1999 ; 37: 156-159
14. Edwards B. S., Kuckuck F. W., Prossnitz E. R., et al. Plug Flow Cytometry Extends Analytical Capabilities in Cell Adhesion and Receptor Pharmacology. Cytometry. 2001 ; 43: 211-216
15. Edwards B. S., Kuckuck F. W., Prossnitz E. R., et al. HTPS Flow Cytometry: A Novel Platform for Automated High Throughput Drug Discovery and Characterization. J. Biomol. Screen. 2001 ; 6: 83-90
16. Kuckuck F. W., Edwards B. S., Sklar L. A.. High Throughput Flow Cytometry. Cytometry. 2001 ; 44: 83-90
17. Edwards B. S., Oprea T., Prossnitz E. R., et al. Flow Cytometry for High-Throughput, High-Content Screening. Curr. Opin. Chem. Biol. 2004 ; 8: 392-398
18. Ramirez S., Aiken C. T., Andrzejewski B., et al. High-Throughput Flow Cytometry: Validation in Microvolume Bioassays. Cytometry A. 2003 ; 53: 55-65
19. Bartsch J. W., Tran H. D., Waller A., et al. An Investigation of Liquid Carryover and Sample Residual for a High-Throughput Flow Cytometer Sample Delivery System. Anal. Chem. 2004 ; 76: 3810-3817
20. Jackson W. C., Bennett T. A., Edwards B. S., et al. Performance of In-Line Microfluidic Mixers in Laminar Flow for High-Throughput Flow Cytometry. Biotechniques. 2002 ; 33: 220-226
21. Jackson W. C., Kuckuck F., Edwards B. S., et al. Mixing Small Volumes for Continuous High-Throughput Flow Cytometry: Performance of a Mixing Y and Peristaltic Sample Delivery. Cytometry. 2002 ; 47: 183-191
22. Young S. M., Curry M. S., Ransom J. T., et al. High-Throughput Microfluidic Mixing and Multiparametric Cell Sorting for Bioactive Compound Screening. J. Biomol. Screen. 2004 ; 9: 103-111
23. Edwards B. S., Young S. M., Oprea T. I., et al. Biomolecular Screening of Formylpeptide Receptor Ligands with a Sensitive, Quantitative, High-Throughput Flow Cytometry Platform. Nat. Protoc. 2006 ; 1: 59-66
24. Edwards B. S., Gouveia K., Oprea T. I., et al. The University of New Mexico Center for Molecular Discovery. Comb. Chem. High Throughput Screen. 2014 ; 17: 256-265
25. Edwards B. S., Zhu J., Chen J., et al. Cluster Cytometry for High-Capacity Bioanalysis. Cytometry A. 2012 ; 81: 419-429
26. GravesS. W.SklarL. A.High-Throughput Multiplex Microsphere Screening for Inhibitors of Toxin Protease, Specifically Botulinum neurotoxin Light Chain F Protease. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=588470.
27. GravesS. W.SklarL. A.High-Throughput Multiplex Microsphere Screening for Inhibitors of Toxin Protease, Specifically Botulinum neurotoxin Light Chain A Protease. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=588467.
28. GravesS. W.SklarL. A.High-Throughput Multiplex Microsphere Screening for Inhibitors of Toxin Protease, Specifically Lethal Factor Protease. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=588469.
29. Zhao Z., Haynes M. K., Ursu O., et al. A High-Throughput Phenotypic Screen of Cytotoxic T Lymphocyte Lytic Granule Exocytosis Reveals Candidate Immunosuppressants. J. Biomol. Screen. 2014 ; 20: 359-371
30. ZweifachA.SklarL. A.HTS Screening Project for Inhibitors of Lytic Granule Exocytosis. PubChem Bioassay Screening Summary2012. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=651682.
31. Joslin J., Ainscow E., Anderson P., et al San Diego, CA: Society for Laboratory Automation and Screening ; 2014: 70.
32. Braeckmans K., De Smedt S. C., Leblans M., et al. Encoding Microcarriers: Present and Future Technologies. Nat. Rev. Drug Discov. 2002 ; 1: 447-456
33. Wandinger-NessA.SklarL. A.Project Utilizing Multiplex HTS to Identify Specific Small Molecule Inhibitors of Ras and Ras-Related GTPases. PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1772.
34. Hong L., Simons P., Waller A., et al Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information (US) ; 2010 :
35. Surviladze Z., Waller A., Wu Y., et al. Identification of a Small GTPase Inhibitor Using a High-Throughput Flow Cytometry Bead-Based Multiplex Assay. J. Biomol. Screen. 2010 ; 15: 10-20
36. Surviladze Z., Young S. M., Sklar L. A.. High-Throughput Flow Cytometry Bead-Based Multiplex Assay for Identification of Rho GTPase Inhibitors. Methods Mol. Biol. 2012 ; 827: 253-270
37. Surviladze Z., Waller A., Strouse J. J., et al Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information (US) ; 2010 :
38. Hong L., Kenney S. R., Phillips G. K., et al. Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe. J. Biol. Chem. 2013 ; 288: 8531-8543
39. Surviladze Z., Ursu O., Miscioscia F., et al Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information (US) ; 2010 :
40. Roman D. L., Ota S., Neubig R. R.. Polyplexed Flow Cytometry Protein Interaction Assay: A Novel High-Throughput Screening Paradigm for RGS Protein Inhibitors. J. Biomol. Screen. 2009 ; 14: 610-619
41. NeubigR. R.SklarL. A.Multiplexed High-Throughput Screen for Small Molecule Regulators of RGS Family Protein Interactions. PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1504.
42. Blazer L. L., Roman D. L., Muxlow M. R., et al. Use of Flow Cytometric Methods to Quantify Protein-Protein Interactions. Curr. Protoc. Cytom. 2010 ; 11: 1-15
43. SklarL. A.Multiplexed High-Throughput Screen for Small Molecule Regulators of Bcl-2 Family Protein Interactions via Bim (BCL2-like 11). PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1693.
44. ZouJ.ArdeckyR.PinkertonA. B.. Selective Bcl-2 Inhibitor Probes. Probe Reports from the NIH Molecular Libraries Program; Bethesda, MD, National Center for Biotechnology Information (US), 2010. http://www.ncbi.nlm.nih.gov/pubmed/23658956.
45. Curpan R. F., Simons P. C., Zhai D., et al. High-Throughput Screen for the Chemical Inhibitors of Antiapoptotic bcl-2 Family Proteins by Multiplex Flow Cytometry. Assay Drug Dev. Technol. 2011 ; 9: 465-474
46. Simons P. C., Young S. M., Carter M. B., et al. Simultaneous In Vitro Molecular Screening of Protein-Peptide Interactions by Flow Cytometry, Using Six Bcl-2 Family Proteins as Examples. Nat. Protoc. 2011 ; 6: 943-952
47. TessmerJ.RNA Aptamer-Based HTS for Inhibitors of GRK2. PubChem Bioassay Screening Summary2010. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=488855.
48. NakamuraK.SklarL. A.Multiplex HTS Assay for Modulators of MEK Kinase PB1 Domain Interactions via MEK5. PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1683.
49. StanleyJ. R.SklarL. A.AubeJ.HTS to Find Inhibitors of Pathogenic Pemphigus Antibodies. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=588367.
50. SkowyraD.SklarL. A.Disassembly of the 26S Proteasome (ATP Hydrolysis-Dependent). PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1824.
51. Saunders M. J., Edwards B. S., Zhu J., et al. Microsphere-Based Flow Cytometry Protease Assays for Use in Protease Activity Detection and High-Throughput Screening. Curr. Protoc. Cytom Chapter 13. 2010 ; 12: 1-17
52. Saunders M. J., Graves S. W., Sklar L. A., et al. High-Throughput Multiplex Flow Cytometry Screening for Botulinum Neurotoxin Type a Light Chain Protease Inhibitors. Assay Drug Dev. Technol. 2010 ; 8: 37-46
53. Saunders M. J., Kim H., Woods T. A., et al. Microsphere-Based Protease Assays and Screening Application for Lethal Factor and Factor Xa. Cytometry A. 2006 ; 69: 342-352
54. Young S. M., Bologa C., Prossnitz E. R., et al. High-Throughput Screening with HyperCyt Flow Cytometry to Detect Small Molecule Formylpeptide Receptor Ligands. J. Biomol. Screen. 2005 ; 10: 374-382
55. Krutzik P. O., Nolan G. P.. Fluorescent Cell Barcoding in Flow Cytometry Allows High-Throughput Drug Screening and Signaling Profiling. Nat. Methods. 2006 ; 3: 361-368
56. Krutzik P. O., Nolan G. P.. Intracellular Phospho-Protein Staining Techniques for Flow Cytometry: Monitoring Single Cell Signaling Events. Cytometry A. 2003 ; 55: 61-70
57. Bradford J. A., Buller G., Suter M., et al. Fluorescence-Intensity Multiplexing: Simultaneous Seven-Marker, Two-Color Immunophenotyping Using Flow Cytometry. Cytometry A. 2004 ; 61: 142-152
58. Smurthwaite C. A., Hilton B. J., O'Hanlon R., et al. Fluorescent Genetic Barcoding in Mammalian Cells for Enhanced Multiplexing Capabilities in Flow Cytometry. Cytometry A. 2014 ; 85: 105-113
59. Cariuk P., Gardener M. J., Vaughan T. J.. Evolution of Biologics Screening Technologies. Pharmaceuticals (Basel). 2013 ; 6: 681-688
60. Watson S. R., Kuan H. F., Tran C.. A Simple Trick to Get More Data from Initial Flow Cytometric Binding Assays when Screening for Therapeutic Antibodies. Presented at High Capacity Flow Cytometry Workshop, CYTO2012 Conference, Leipzig ; 2012 ; 2012..
61. Feng Y., Mitchison T. J., Bender A., et al. Multi-Parameter Phenotypic Profiling: Using Cellular Effects to Characterize Small-Molecule Compounds. Nat. Rev. Drug Discov. 2009 ; 8: 567-578
62. Paul S. M., Mytelka D. S., Dunwiddie C. T., et al. How to Improve R&D Productivity: The Pharmaceutical Industry's Grand Challenge. Nat. Rev. Drug Discov. 2010 ; 9: 203-214
63. Lee J. A., Berg E. L.. Neoclassic Drug Discovery: The Case for Lead Generation Using Phenotypic and Functional Approaches. J. Biomol. Screen. 2013 ; 18: 1143-1155
64. Begley C. G., Ellis L. M.. Drug Development: Raise Standards for Preclinical Cancer Research. Nature. 2012 ; 483: 531-533
65. Prinz F., Schlange T., Asadullah K.. Believe It or Not: How Much Can We Rely on Published Data on Potential Drug Targets?. Nat. Rev. Drug Discov. 2011 ; 10: 712
66. Swinney D. C.. The Contribution of Mechanistic Understanding to Phenotypic Screening for First-in-Class Medicines. J. Biomol. Screen. 2013 ; 18: 1186-1192
67. Swinney D. C., Anthony J.. How Were New Medicines Discovered?. Nat. Rev. Drug Discov. 2011 ; 10: 507-519
68. Eder J., Sedrani R., Wiesmann C.. The Discovery of First-in-Class Drugs: Origins and Evolution. Nat. Rev. Drug Discov. 2014 ; 13: 577-587
69. Moffat J. G., Rudolph J., Bailey D.. Phenotypic Screening in Cancer Drug Discovery: Past, Present and future. Nat. Rev. Drug Discov. 2014 ; 13: 588-602
70. Krutzik P. O., Crane J. M., Clutter M. R., et al. High-Content Single-Cell Drug Screening with Phosphospecific Flow Cytometry. Nat. Chem. Biol. 2008 ; 4: 132-142
71. Chen J., Young S. M., Allen C., et al. Identification of a Small Molecule Yeast TORC1 Inhibitor with a Multiplex Screen Based on Flow Cytometry. ACS Chem. Biol. 2012 ; 7: 715-722
72. Chen J., Young S. M., Allen C., et al Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information (US) ; 2010 :
73. De Virgilio C., Loewith R.. Cell Growth Control: Little Eukaryotes Make Big Contributions. Oncogene. 2006 ; 25: 6392-6415
74. De Virgilio C., Loewith R.. The TOR Signalling Network from Yeast to man. Int. J. Biochem. Cell Biol. 2006 ; 38: 1476-1481
75. Zoncu R., Efeyan A., Sabatini D. M.. mTOR: From Growth Signal Integration to Cancer, Diabetes and ageing. Nat. Rev. Mol. Cell Biol. 2011 ; 12: 21-35
76. Huh W. K., Falvo J. V., Gerke L. C., et al. Global Analysis of Protein Localization in Budding Yeast. Nature. 2003 ; 425: 686-691
77. GreshamH. D.SklarL. A.Inhibitors of Bacterial Quorum Sensing. PubChem Bioassay Screening Summary2008. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1206.
78. Sully E. K., Malachowa N., Elmore B. O., et al. Selective Chemical Inhibition of agr Quorum Sensing in Staphylococcus aureus Promotes Host Defense with Minimal Impact on Resistance. PLoS Pathog. 2014 ; 10: e1004174
79. ParraK.SklarL. A.LindsleyC. W.Flow Cytometry HTS of Small Molecules That Regulate V-ATPase Proton Transport in Yeast. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=504622.
80. Werner-WashburneM.SklarL. A.Multiplex HTS Screen of TOR Pathway GFP-Fusion Proteins in Saccharomyces cerevisiae. PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1908.
81. SykesD.SklarL. A.SchreiberS.HTS to Identify Compounds That Promote Myeloid Differentiation. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=588701.
82. HwangI.SklarL. A.Screening for Developing T Cell Immune Modulators. PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=2087.
83. Florian A. E., Lepensky C. K., Kwon O., et al. Flow Cytometry Enables a High-Throughput Homogeneous Fluorescent Antibody-Binding Assay for Cytotoxic T Cell Lytic Granule Exocytosis. J. Biomol. Screen. 2013 ; 18: 420-429
84. ChigaevA.SklarL. A.HTS for Identification of VLA-4 Allosteric Modulators. PubChem Bioassay Screening Summary2010. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=2617.
85. CannonR.SklarL. A.LindsleyC.Phenotypic HTS Multiplex for Anti-Fungal Efflux Pump Inhibitors. PubChem Bioassay Screening Summary2010. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=485335.
86. Ivnitski-Steele I., Larson R. S., Lovato D. M., et al. High-Throughput Flow Cytometry to Detect Selective Inhibitors of ABCB1, ABCC1, and ABCG2 Transporters. Assay Drug Dev. Technol. 2008 ; 6: 263-276
87. KrishnamurthyP.SklarL. A.AubeJ.HTS Screen for Inhibitors of the ABC Transporter ACCC6. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=588561.
88. LarsonR. S.SklarL. A.High Throughput Multiplex Screening for ABC Transporters. PubChem Bioassay Screening Summary2009. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1818.
89. Mathews L. A., Keller J. M., McKnight C., et al. Multiplexing High-Content Flow (HCF) and Quantitative High-Throughput Screening (qHTS) to Identify Compounds Capable of Decreasing Cell Viability, Activating Caspase 3/7, Expressing Annexin V, and Changing Mitochondrial Membrane Integrity. Curr. Protoc. Chem. Biol. 2013 ; 5: 195-212
90. Holleran J., Brown D., Fuhrman M. H., et al. Fluorogen-Activating Proteins as Biosensors of Cell-Surface Proteins in Living Cells. Cytometry A. 2010 ; 77: 776-782
91. Szent-Gyorgyi C., Schmidt B. F., Creeger Y., et al. Fluorogen-Activating Single-Chain Antibodies for Imaging Cell Surface Proteins. Nat. Biotechnol. 2008 ; 26: 235-240
92. JarvikJ. W.SklarL. A.LindsleyC.HTS for Non-Canonical Ligands for Beta-2 Adrenergic Receptor Internalization. PubChem Bioassay Screening Summary2011. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=504448.
93. Gebhard D., Hallowell S., Benvenuti E., et al.. Development of FAP Technology: Fluorogen Activated Protein in High Throughput Flow Cytometry. Presented at CYTO2013 Conference ; 2013 San Diego, CA ; 2013..
94. Yang H. C., Xing S., Shan L., et al. Small-Molecule Screening Using a Human Primary Cell Model of HIV Latency Identifies Compounds That Reverse Latency without Cellular Activation. J. Clin. Invest. 2009 ; 119: 3473-3486
95. Shishido T., Wolschendorf F., Duverger A., et al. Selected Drugs with Reported Secondary Cell-Differentiating Capacity Prime Latent HIV-1 Infection for Reactivation. J. Virol. 2012 ; 86: 9055-9069
96. ThompsonT. A.SklarL. A.Prostate Cell Differentiation Assays. PubChem Bioassay Screening Summary2008. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1260.
97. Haynes M. K., Strouse J. J., Waller A., et al. Detection of Intracellular Granularity Induction in Prostate Cancer Cell Lines by Small Molecules Using the HyperCyt High-Throughput Flow Cytometry System. J. Biomol. Screen. 2009 ; 14: 596-609
98. BurhansW. C.SklarL. A.Yeast Senescence Screen. PubChem Bioassay Screening Summary2010. http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=2714.
99. Carlson C., Koonce C., Aoyama N., et al. Phenotypic Screening with Human iPS Cell-Derived Cardiomyocytes: HTS-Compatible Assays for Interrogating Cardiac Hypertrophy. J. Biomol. Screen. 2013 ; 18: 1203-1211
100. Li H., Xie W., Gore E. R., et al. Development of Phenotypic Screening Assays for Gamma-Globin Induction Using Primary Human Bone Marrow Day 7 Erythroid Progenitor Cells. J. Biomol. Screen. 2013 ; 18: 1212-1222
101. Sanker S., Cirio M. C., Vollmer L. L., et al. Development of High-Content Assays for Kidney Progenitor Cell Expansion in Transgenic Zebrafish. J. Biomol. Screen. 2013 ; 18: 1193-1202
102. Azegrouz H., Karemore G., Torres A., et al. Cell-Based Fuzzy Metrics Enhance High-Content Screening (HCS) Assay Robustness. J. Biomol. Screen. 2013 ; 18: 1270-1283
103. Isherwood B. J., Walls R. E., Roberts M. E., et al. High-Content Analysis to Leverage a Robust Phenotypic Profiling Approach to Vascular Modulation. J. Biomol. Screen. 2013 ; 18: 1246-1259
104. Wolfe A., O'Clair B., Groppi V. E., et al. Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds. J. Biomol. Screen. 2013 ; 18: 1234-1245
105. Honarnejad K., Kirsch A. K., Daschner A., et al. FRET-Based Calcium Imaging: A Tool for High-Throughput/Content Phenotypic Drug Screening in Alzheimer Disease. J. Biomol. Screen. 2013 ; 18: 1309-1320
106. Horman S. R., To J., Orth A. P.. An HTS-Compatible 3D Colony Formation Assay to Identify Tumor-Specific Chemotherapeutics. J. Biomol. Screen. 2013 ; 18: 1298-1308
107. Reisen F., Zhang X., Gabriel D., et al. Benchmarking of Multivariate Similarity Measures for High-Content Screening Fingerprints in Phenotypic Drug Discovery. J. Biomol. Screen. 2013 ; 18: 1284-1297
108. Boyd J. D., Lee-Armandt J. P., Feiler M. S., et al. A High-Content Screen Identifies Novel Compounds That Inhibit Stress-Induced TDP-43 Cellular Aggregation and Associated Cytotoxicity. J. Biomol. Screen. 2014 ; 19: 44-56
109. Cautain B., de Pedro N., Murillo Garzon V., et al. High-Content Screening of Natural Products Reveals Novel Nuclear Export Inhibitors. J. Biomol. Screen. 2014 ; 19: 57-65
110. Ljosa V., Caie P. D., Ter Horst R., et al. Comparison of Methods for Image-Based Profiling of Cellular Morphological Responses to Small-Molecule Treatment. J. Biomol. Screen. 2013 ; 18: 1321-1329
111. Shahane S. A., Huang R., Gerhold D., et al. Detection of Phospholipidosis Induction: A Cell-Based Assay in High-Throughput and High-Content Format. J. Biomol. Screen. 2014 ; 19: 66-76
112. Smith E. B., Ogert R. A., Pechter D., et al. HIV Cell Fusion Assay: Phenotypic Screening Tool for the Identification of HIV Entry Inhibitors via CXCR4. J. Biomol. Screen. 2014 ; 19: 108-118
113. Sugarman E., Koo A., Suyama E., et al. Identification of Inhibitors of Triacylglyceride Accumulation in Muscle Cells: Comparing HTS Results from 1536-Well Plate-Based and High-Content Platforms. J. Biomol. Screen. 2014 ; 19: 77-87
114. Adams M., Cookson V. J., Higgins J., et al. A High-Throughput Assay to Identify Modifiers of Premature Chromosome Condensation. J. Biomol. Screen. 2014 ; 19: 176-183
115. Cappella P., Gasparri F.. Highly Multiplexed Phenotypic Imaging for Cell Proliferation Studies. J. Biomol. Screen. 2014 ; 19: 145-157
116. Xu M., Liu K., Swaroop M., et al. A Phenotypic Compound Screening Assay for Lysosomal Storage Diseases. J. Biomol. Screen. 2014 ; 19: 168-175
117. Pinilla C., Edwards B. S., Appel J. R., et al. Selective Agonists and Antagonists of Formylpeptide Receptors: Duplex Flow Cytometry and Mixture-Based Positional Scanning Libraries. Mol. Pharmacol. 2013 ; 84: 314-324
118. Ye R. D., Boulay F., Wang J. M., et al. International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the Formyl Peptide Receptor (FPR) Family. Pharmacol. Rev. 2009 ; 61: 119-161
119. Houghten R. A., Pinilla C., Appel J. R., et al. Mixture-Based Synthetic Combinatorial Libraries. J. Med. Chem. 1999 ; 42: 3743-3778
120. Houghten R. A., Pinilla C., Giulianotti M. A., et al. Strategies for the Use of Mixture-Based Synthetic Combinatorial Libraries: Scaffold Ranking, Direct Testing In Vivo, and Enhanced Deconvolution by Computational Methods. J. Comb. Chem. 2008 ; 10: 3-19
121. Edwards B. S., Bologa C., Young S. M., et al. Integration of Virtual Screening with High-Throughput Flow Cytometry to Identify Novel Small Molecule Formylpeptide Receptor Antagonists. Mol. Pharmacol. 2005 ; 68: 1301-1310
122. Young S. M., Bologa C. M., Fara D., et al. Duplex High-Throughput Flow Cytometry Screen Identifies Two Novel Formylpeptide Receptor Family Probes. Cytometry A. 2009 ; 75: 253-263
123. Cornelissen F., Cik M., Gustin E.. Phaedra, a Protocol-Driven System for Analysis and Validation of High-Content Imaging and Flow Cytometry. J. Biomol. Screen. 2012 ; 17: 496-506
124. Robinson J. P., Patsekin V., Holdman C., et al. High-Throughput Secondary Screening at the Single-Cell Level. J. Lab. Autom. 2013 ; 18: 85-98
125. Khanna I.. Drug Discovery in Pharmaceutical Industry: Productivity Challanges and Trends. Drug Discov. Today. 2012 ; 17: 1088-1102
126. Lee R., Tran M., Nocerini M., et al. A High-Throughput Hybridoma Selection Method Using Fluorometric Microvolume Assay Technology. J. Biomol. Screen. 2008 ; 13: 210-217
127. Eglen R., Reisine T.. Primary Cells and Stem Cells in Drug Discovery: Emerging Tools for High-Throughput Screening. Assay Drug Dev. Technol. 2011 ; 9: 108-124
128. Pemovska T., Kontro M., Yadav B., et al. Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia. Cancer Discov. 2013 ; 3: 1416-1429
129. Grskovic M., Javaherian A., Strulovici B., et al. Induced Pluripotent Stem Cells - Opportunities for Disease Modelling and Drug Discovery. Nat. Rev. Drug Discov. 2011 ; 10: 915-929
130. Zhang R., Zhang L. H., Xie X.. iPSCs and Small Molecules: A Reciprocal Effort towards Better Approaches for Drug Discovery. Acta Pharmacol. Sin. 2013 ; 34: 765-776
131. Beck B., Blanpain C.. Unravelling Cancer Stem Cell Potential. Nat. Rev. Cancer. 2013 ; 13: 727-738
132. Kreso A., Dick J. E.. Evolution of the Cancer Stem Cell Model. Cell Stem Cell. 2014 ; 14: 275-291
133. O'Brien C. A., Kreso A., Dick J. E.. Cancer Stem Cells in Solid Tumors: An Overview. Semin. Radiat. Oncol. 2009 ; 19: 71-77
134. Winquist R. J., Furey B. F., Boucher D. M.. Cancer Stem Cells as the Relevant Biomass for Drug Discovery. Curr. Opin. Pharmacol. 2010 ; 10: 385-390
135. Joosse S. A., Gorges T. M., Pantel K.. Biology, Detection, and Clinical Implications of Circulating Tumor Cells. EMBO Mol. Med. 2014 ; 7: 1-11
136. Nagrath S., Sequist L. V., Maheswaran S., et al. Isolation of Rare Circulating Tumour Cells in Cancer Patients by Microchip Technology. Nature. 2007 ; 450: 1235-1239
137. Adams J. D., Kim U., Soh H. T.. Multitarget Magnetic Activated Cell Sorter. Proc. Natl. Acad. Sci. U.S.A. 2008 ; 105: 18165-18170
138. Piyasena M. E., Austin Suthanthiraraj P. P., Applegate R. W., et al. Multinode Acoustic Focusing for Parallel Flow Cytometry. Anal. Chem. 2012 ; 84: 1831-1839
139. Piyasena M. E., Graves S. W.. The Intersection of Flow Cytometry with Microfluidics and Microfabrication. Lab Chip. 2014 ; 14: 1044-1059
140. Goddard G. R., Sanders C. K., Martin J. C., et al. Analytical Performance of an Ultrasonic Particle Focusing Flow Cytometer. Anal. Chem. 2007 ; 79: 8740-8746
141. Laurell T., Petersson F., Nilsson A.. Chip Integrated Strategies for Acoustic Separation and Manipulation of Cells and Particles. Chem. Soc. Rev. 2007 ; 36: 492-506
142. George T. C., Basiji D. A., Hall B. E., et al. Distinguishing Modes of Cell Death Using the ImageStream Multispectral Imaging Flow Cytometer. Cytometry A. 2004 ; 59: 237-245
143. Ortyn W. E., Hall B. E., George T. C., et al. Sensitivity Measurement and Compensation in Spectral Imaging. Cytometry A. 2006 ; 69: 852-862
144. Goda K., Ayazi A., Gossett D. R., et al. High-Throughput Single-Microparticle Imaging Flow Analyzer. Proc. Natl. Acad. Sci. U.S.A. 2012 ; 109: 11630-11635
145. Goda K., Tsia K. K., Jalali B.. Serial Time-Encoded Amplified Imaging for Real-Time Observation of Fast Dynamic Phenomena. Nature. 2009 ; 458: 1145-1149
146. McKenna B. K., Evans J. G., Cheung M. C., et al. A Parallel Microfluidic Flow Cytometer for High-Content Screening. Nat. Methods. 2011 ; 8: 401-403
147. Nolan J. P., Duggan E., Liu E., et al. Single Cell Analysis Using Surface Enhanced Raman Scattering (SERS) Tags. Methods. 2012 ; 57: 272-279
148. Bendall S. C., Nolan G. P., Roederer M., et al. A Deep Profiler's Guide to Cytometry. Trends Immunol. 2012 ; 33: 323-332
149. Atkuri K. R., Stevens J. C., Neubert H.. Mass Cytometry: A Highly Multiplexed Single Cell Technology for Advancing Drug Development. Drug Metab. Dispos. 2015 ; 43: 227-233
150. Bendall S. C., Simonds E. F., Qiu P., et al. Single-Cell Mass Cytometry of Differential Immune and Drug Responses across a Human Hematopoietic Continuum. Science. 2011 ; 332: 687-696
151. Newell E. W., Sigal N., Bendall S. C., et al. Cytometry by Time-of-Flight Shows Combinatorial Cytokine Expression and Virus-Specific Cell Niches within a Continuum of CD8+ T Cell Phenotypes. Immunity. 2012 ; 36: 142-152
152. Horowitz A., Strauss-Albee D. M., Leipold M., et al. Genetic and Environmental Determinants of Human NK Cell Diversity Revealed by Mass Cytometry. Sci. Transl. Med. 2013 ; 5: 208-145
153. Bandura D. R., Baranov V. I., Ornatsky O. I., et al. Mass Cytometry: Technique for Real Time Single Cell Multitarget Immunoassay Based on Inductively Coupled Plasma Time-of-Flight Mass Spectrometry. Anal. Chem. 2009 ; 81: 6813-6822
154. Burdett E., Kasper F. K., Mikos A. G., et al. Engineering Tumors: A Tissue Engineering Perspective in Cancer Biology. Tissue Eng. Part B Rev. 2010 ; 16: 351-359
155. Kunz-Schughart L. A., Freyer J. P., Hofstaedter F., et al. The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model. J. Biomol. Screen. 2004 ; 9: 273-285