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PUBLICATIONS

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103 Total Publications
HOME | RESOURCES | Publications

PUBLICATIONS

103 Total Publications

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TITLES and AUTHORS Year Link PDF + Abstract
  • Achieving Accurate Compound Concentration in Cell-Based Screening: Validation of Acoustic Droplet Ejection Technology Grant RJ, Roberts K, Pointon C, Hodgson C, Womersley L, Jones DC, Tang E

    Institution: AstraZeneca

    Publication: Journal of Biomolecular Screening 2009:452-459

    2009 abstract

    Compound handling is a fundamental and critical step in compound screening throughout the drug discovery process. Although most compound-handling processes within compound management facilities use 100% DMSO solvent, conventional methods of manual or robotic liquid-handling systems in screening workflows often perform dilutions in aqueous solutions to maintain solvent tolerance of the biological assay. However, the use of aqueous media in these applications can lead to suboptimal data quality due to compound carryover or precipitation during the dilution steps. In cell-based assays, this effect is worsened by the unpredictable physical characteristics of compounds and the low DMSO tolerance within the assay. In some cases, the conventional approaches using manual or automated liquid handling resulted in variable IC50 dose responses. This study examines the cause of this variability and evaluates the accuracy of screening data in these case studies. A number of liquid-handling options have been explored to address the issues and establish a generic compound-handling workflow to support cell-based screening across our screening functions. The authors discuss the validation of the Labcyte Echo reformatter as an effective noncontact solution for generic compound-handling applications against diverse compound classes using triple-quad liquid chromatography/mass spectrometry. The successful validation and implementation challenges of this technology for direct dosing onto cells in cell-based screening is discussed.

    Publication / Type:
    Journal of Biomolecular Screening 2009:452-459
    Related Subject:
    Concentration Cell-Based Acoustic Droplet Ejection
    Link:
    http://jbx.sagepub.com/content/14/5/452.abstract
  • Proteomic Analysis Illuminates a Novel Structural Definition of the Claustrum and Insula Mathur B N, Caprioli R M, Deutch A Y.

    Institution: Vanderbilt University

    Publication: Cereb Cortex. 2009 19 (10)2372-2379.

    2009 abstract

    The claustrum is a prominent but ill-defined forebrain structure that has been suggested to integrate multisensory information and perhaps transform percepts into consciousness. The claustrum's shape and vague borders have hampered experimental assessment of its functions. We used matrix-assisted laser desorption ionization-imaging mass spectrometry to reveal a novel protein marker, G-protein gamma2 subunit (Gng2), which is enriched in the claustrum but not adjacent structures of the rat forebrain. The spatial pattern of Gng2 expression suggests key differences from commonly held views of the claustrum's structure. Using anatomical methods, we found that the rat claustrum is present only at striatal levels of the telencephalon and does not extend to frontal cortical territories. Moreover, the claustrum is surrounded on all sides by layer VI insular cortex cells in both the rat and primate. Using these defining characteristics of the claustrum, we found that the claustrum projects to cortical but not to subcortical sites. The definition of the claustrum as a cortical site is considered. The identification of a claustrum-specific protein opens the door to selective molecular lesions and the subsequent evaluation of the role of the claustrum in cognition.

    Publication / Type:
    Cereb Cortex. 2009 19 (10)2372-2379.
    Related Subject:
    Proteomic Claustrum Insula
    Link:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742595/
  • Extraction, Identification, and Functional Characterization of a Bioactive Substance From Automated Compound-Handling Plastic Tips Watson J, Greenough E, Leet J, Ford M, Drexler D, Belcastro J, Herbst J, Chatterjee M, Banks M

    Institution: Bristol-Myers Squibb Company

    Publication: J Biomol Screen June 2009 vol. 14 no. 5 566-572, 10.1177/1087057109336594

    2009 abstract

    Disposable plastic labware is ubiquitous in contemporary pharmaceutical research laboratories. Plastic labware is routinely used for chemical compound storage and during automated liquid-handling processes that support assay development, high-throughput screening, structure-activity determinations, and liability profiling. However, there is little information available in the literature on the contaminants released from plastic labware upon DMSO exposure and their resultant effects on specific biological assays. The authors report here the extraction, by simple DMSO washing, of a biologically active substance from one particular size of disposable plastic tips used in automated compound handling. The active contaminant was identified as erucamide ((Z)-docos-13-enamide), a long-chain mono-unsaturated fatty acid amide commonly used in plastics manufacturing, by gas chromatography/mass spectroscopy analysis of the DMSO-extracted material. Tip extracts prepared in DMSO, as well as a commercially obtained sample of erucamide, were active in a functional bioassay of a known G-protein-coupled fatty acid receptor. A sample of a different disposable tip product from the same vendor did not release detectable erucamide following solvent extraction, and DMSO extracts prepared from this product were inactive in the receptor functional assay. These results demonstrate that solvent-extractable contaminants from some plastic labware used in the contemporary pharmaceutical research and development (R&D) environment can be introduced into physical and biological assays during routine compound management liquid-handling processes. These contaminants may further possess biological activity and are therefore a potential source of assay-specific confounding artifacts.

    Publication / Type:
    J Biomol Screen June 2009 vol. 14 no. 5 566-572, 10.1177/1087057109336594
    Related Subject:
    Bioactive Automated Compound-Handling Plastic Tips
    Link:
    http://jbx.sagepub.com/content/14/5/566
  • Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2 Delpire E, Days E, Lewis L, Mi D, Kim J, Lindsley C, Weaver C

    Institution: Vanderbilt University

    Publication: Proc Natl Acad Sci U S A. 2009 March 31; 106(13): 5383–5388,10.1073/pnas.0812756106

    2009 abstract

    KCC2, a neuronal-specific K-Cl cotransporter, plays a major role in maintaining intracellular Cl− concentration in neurons below its electrochemical equilibrium potential, thus favoring robust GABA hyperpolarizing or inhibitory responses. The pharmacology of the K-Cl cotransporter is dominated by loop diuretics such as furosemide and bumetanide, molecules used in clinical medicine because they inhibit the loop of Henle Na-K-2Cl cotransporter with much higher affinity. To identify molecules that affect KCC2 activity, we developed a fluorescence-based assay suitable for high-throughput screening (HTS) and used the assay to screen a library of 234,000 small molecules. We identified a large number of molecules that either decrease or increase the activity of the cotransporter. Here, we report the characterization of a small number of inhibitors, some of which inhibit KCC2 activity in the submicromolar range without substantially affecting NKCC1 activity. Using medicinal chemistry, we synthesized a number of variants, tested their effect on KCC2 function, and provide an analysis of structure/activity relationships. We also used one of the compounds to demonstrate competitive inhibition in regard to external [K+] versus noncompetitive inhibition in respect to external [Cl−].

    Publication / Type:
    Proc Natl Acad Sci U S A. 2009 March 31; 106(13): 5383–5388,10.1073/pnas.0812756106
    Related Subject:
    fluorescence, high-throughput screening, Na-K-2Cl cotransporter, thallium, HEK293, transporter
    Link:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654392/?tool=pmcentrez
  • Optimizing the Profiling of Protein Kinases Dimond P

    Institution: Life Science Consultant

    Publication: Genetic Engineering and Biotechnologies News, Vol 28, No. 10 (May 15, 2008)

    2008 abstract

    Protein kinases comprise the largest family of mammalian enzymes, totaling at least 500. These ubiquitous enzymes play key roles in cellular regulation by catalyzing the reversible phosphorylation of more than 10,000 proteins.

    Dysfunctional intracellular signaling through protein kinases is associated with about 400 human diseases, most notably cancers. As a result of the clinical success of the p210 Bcr-Abl inhibitor (Novartis’ Gleevec) for treatment of chronic myelogenous leukemia, pharma companies have applied massive resources to finding the next blockbuster kinase activity-modulating drug. And, as kinase-focused drug discovery enterprises expand, so does the need for discovery tools that automate and scale them.

    At the Society for Biomolecular Screening’s (SBS) annual meeting held last month, companies collaborated in workshops, combining their technologies to address formidable challenges in kinase profiling and to facilitate selection of appropriate assay options.

    In a workshop entitled “Assay Optimization and Kinase Profiling in micro HTS Format,” Labcyte (www.labcyte.com), Deerac Fluidics (www.deerac.com), Promega (www.promega.com), Corning Life Sciences (www.corning.com), and BMG Labtech (www.bmglabtech.com) teamed up to present a complete platform approach for kinase-assay development.

    Using Labcyte’s ultralow volume-test technology, Corning Life Sciences’ specially developed dual assay plates, luminescent kinase-assay technology from Promega, Deerac Fluidics’ reagent-dispensing technology, and BMG Labtech’s PHERAstar luminescent-detection instrumentation, these companies demonstrated the complementarity and adaptability of their diverse technologies for the development of extremely low-volume, protein-kinase assays.

    Publication / Type:
    Genetic Engineering and Biotechnologies News, Vol 28, No. 10 (May 15, 2008)
    Related Subject:
    kinase, miniaturization, Z', "z-prime", touchless, precision, accuracy, throughput, assay development
    Link:
    http://www.genengnews.com/gen-articles/optimizing-the-profiling-of-protein-kinases/2476/?page=1
  • Assay Sciences: A Model for Improving Efficiency Through Centralization Wingfield J, Jones D, Clark R, Simpson P

    Institution: AstraZeneca

    Publication:

    2007 PDF abstract

    The pharmaceutical industry is facing increasing external market pressures to reduce costs and deliver the next generation of therapeutics cost effectively. Pharmaceutical R&D faces the challenge of streamlining all stages of the drug discovery process. Delivering high quality decision-making data at the earliest opportunity serves to accelerate research and maintain product pipelines that are critical to business success. Reducing the time between Hit to Lead, whilst operating in an increasingly challenging business environment requires a different approach when deploying resources.

    Secondary screening in the pharmaceutical industry has traditionally been carried out within project teams, in many cases biochemical and cell screening are carried out by the same bioscience resource. This typically results in a serial approach to screening where biochemical data is gathered before or during the development of any cellular assays. In a post high throughput (HTS) environment the level of automation applied to support screening has often been quite limited as there is no perceived benefit of automation when screening smaller numbers of samples. This model has the potential to delay project screening once the primary screening campaign has been completed, partly due to a hand over phase and repeat validation when the assay is handed back to project bioscientists. In some cases, screening may need to be suspended while adequate bioscience resource is redeployed from other on-going project support work. Moving away from the traditional project-centric lead identification to a centralised capability offers many advantages to both the bioscience and chemistry communities. Centralisation of both biochemical and cellular secondary screening activities enables flexible use of resources, allowing rapid responses to changing business demands.

    Centralisation permits testing across multiple targets and increases the speed that data is generated. In addition focusing a small team on one aspect of drug discovery enables them to standardise the automation, technology, process and adopt best practices. This can result in a flexible, agile work team that can respond effectively to changing demand. Focusing teams in this way provides clarity around their expected delivery, which helps individuals maintain drive. On the counter side, there is a need to manage the perceived loss of project ownership of the assays that are centralised. The centralised team need to understand that their output will be subject to additional scrutiny. Initially there will need to be a considerable investment of time in managing customer interactions during the establishment of the capability, building customer confidence. Having a clear service level agreement (SLA) between the central screening team and each customer, which specifies the turn round time for data delivery, stringent QC process for data analysis, roles and responsibilities for individuals is important. The screening team then have to deliver against these SLA's.

    Related Subject:
    high throughput, drug discovery
  • A High-Content Glucocorticoid Receptor Translocation Assay for Compound Mechanism-of-Action Evaluation Agler M, Prack M, Zhu Y, Kolb J, Nowak K, Ryseck R, Shen D, Cvijic M, Somerville J, Nadler S, Chen T

    Institution: Bristol-Myers Squibb, St. Jude Children's Hospital

    Publication: J Biomol Screen December 207 vol. 12 no. 8 1029-1041, 10.1177/1087057107309353

    2007 abstract

    Ligand-induced cytoplasm to nucleus translocation is a critical event in the nuclear receptor (NR) signal transduction cascade. The development of green fluorescent proteins and their color variants fused with NRs, along with the recent developments in automated cellular imaging technologies, has provided unique tools to monitor and quantify the NR translocation events. These technology developments have important implications in the mechanistic evaluation of NR signaling and provide a powerful tool for drug discovery. The unique challenges for developing a robust NR translocation assay include cytotoxicity accompanied with chronic overexpression of NRs, basal translocation induced by serum present in culture medium, and interference from endogenous NRs, as well as subcellular dynamics. The authors have developed a robust assay system for the glucocorticoid receptor (GR) that was applied to a panel of nuclear receptor ligands. Using a high-content imaging system, ligand-induced, dose-dependent GR nuclear translocation was quantified and a correlation with other conventional assays established.

    Publication / Type:
    J Biomol Screen December 207 vol. 12 no. 8 1029-1041, 10.1177/1087057107309353
    Related Subject:
    glucocorticoid receptor, nuclear translocation, high content screening, green fluorescent proteins, androgen receptor, mechanism of action
    Link:
    http://jbx.sagepub.com/content/12/8/1029.full.pdf+html
  • Keeping DMSO Concentration Below 0.5% to Minimize its Effect in HTS Assays Gallagher A, Koechlein D, Shieh J

    Institution: Deerac Fluidics, Labcyte Inc.

    Publication: J Biomol Screen December 207 vol. 12 no. 8 1029-1041, 10.1177/1087057107309353

    2007 PDF abstract

    Dimethyl sulfoxide (DMSO) is a commonly used solvent for compounds. DMSO accelerates protein unfolding and weakens the binding between small molecules and proteins. Consequently researchers keep DMSO concentrations as low as possible, especially for sensitive assays. To keep the DMSO concentration at less than one percent of the final assay volume has been difficult due to the lack of reliable nanoliter-range liquid handlers. Intermediate aqueous dilution steps can cause the compound to “crash out” of solution. The requirement to keep compounds dissolved while keeping DMSO concentration low in the final assay is especially critical when preparing compound activity curves. The Labcyte Echo™ 550 liquid handler utilizes acoustic drop ejection (ADE) to transfer 2.5-250 nL of compounds in DMSO directly from storage plates to assay plates. Deerac Fluidics Latitude™ bulk dispenser, which uses “spot-on” technology, can precisely deliver as low as 50 nL. The Latitude can be used to rapidly add pure DMSO to specific wells so that all assay wells have the same DMSO concentration. Here we demonstrate the use of these two technologies in combination for keeping final DMSO concentration under 0.5% in HTS assays.

    Publication / Type:
    J Biomol Screen December 207 vol. 12 no. 8 1029-1041, 10.1177/1087057107309353
    Related Subject:
    DMSO Concentration Below 0.5% Minimize Effect HTS Assays
  • Debunking the Myth: Validation of Fluorescein for Testing the Precision of Nanoliter Dispensing Harris D, Mutz M

    Institution: Labcyte Inc., Institute for Molecular Medicine Finland, FIMM, University of Helsinki

    Publication: (JALA 2006;11:233–9) DOI: 10.1016/j.jala.2006.05.006

    2006 abstract

    Acoustic energy can precisely and accurately eject a droplet of liquid from a reservoir, enabling delivery of picoliter and nanoliter volumes. Acoustic droplet ejection has been shown to be extremely precise (coefficients of variation !2%) over a wide range of dispensed volumes. However, measuring the performance of low-volume fluid transfers can be difficult because the data are often masked by variability in bulk dispensers and fluorescence readers used as part of the overall measurement process. The fluorophore used must also be stable so that thermal bleaching and photobleaching do not contribute additional variability to the measurements. This study assesses the suitability of fluorescein to measure the precision of fluid transfers of 2.5-nL DMSO droplets. The short-term and long-term stabilities of fluorescein are first qualified using a reference standard. Next, we determine the noise contribution of the filler and reader. Lastly, data are presented for the precision of 5- and 50-nL fluid transfers using this fluorescein measurement process.

    Publication / Type:
    (JALA 2006;11:233–9) DOI: 10.1016/j.jala.2006.05.006
    Related Subject:
    Fluorescein Precision Nanoliter Dispensing
    Link:
    http://jla.sagepub.com/content/11/4/233.short
  • The Effects of Small Molecule and Protein Solutes on Acoustic Drop Ejection Shieh J, Ellson R, Olechno J

    Institution: Labcyte Inc.

    Publication: Journal of Laboratory AutomationAugust 2006 vol. 11 no. 4 227-232, 10.1016/j.jala.2006.06.005

    2006 abstract

    Increasing the solute concentration of a solution alters the speed of sound in the solution in addition to changing the fluid viscosity and surface tension. For liquid handling devices that transfer fluids with acoustic energy, the change in sound speed can impact the focus of the acoustic energy and ultimately the accuracy of the transfer volume. To determine the effects of increasing solute concentration on transfer accuracy and precision, we studied the change in sound speed in dimethyl sulfoxide with the addition of low-molecular weight compounds and in phosphate-buffered saline with protein. The impact of compound and protein concentration on transfer precision and accuracy was found to be minimal and ADE can be used to transfer fluids regardless of these additions.

    Publication / Type:
    Journal of Laboratory AutomationAugust 2006 vol. 11 no. 4 227-232, 10.1016/j.jala.2006.06.005
    Related Subject:
    .
    Link:
    http://jla.sagepub.com/content/11/4/227.full
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