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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
  • A Chemical Genomics Screen to Discover Genes That Modulate Neural Stem Cell Differentiation Kim K J, Wang J, Xu X, Wu S, Zhang W, Qin Z, Wu F, Liu A, Zhao Y, Fang H, Zhu M, Zhao J, Zhong Z

    Institution: GlaxoSmithKline

    Publication: J Biomol Screen February 2012 vol. 17 no. 2 129-139

    2012 abstract

    The authors designed a chemical genomics screen with the aim of understanding genes and pathways that modulate neural stem/precursor cell differentiation. Multipotent mouse neural precursor cells isolated from cortices of embryonic day 12 (E12) embryos were subjected to spontaneous differentiation triggered by growth factor withdrawal. A quantitative whole-well immunofluorescence assay was set up to screen tool compound sets to identify small molecules with potent, dose-dependent, and reproducible effects on increasing neural stem cell differentiation toward neuronal lineage. Among the pro-neuronal compounds, kinase inhibitors were shown to exert pro-neuronal effect via a signaling pathway associated with the kinase. The global effect of hit compounds on modulating neuronal differentiation was confirmed by an in vivo mouse study and human neural stem cells culture. This study demonstrates that a phenotypic assay using cell type–specific antibody markers can be used for a large-scale compound screen to discover targets and pathways with impacts on differentiation of lineage-restricted precursor cells toward specific lineages.

    Publication / Type:
    J Biomol Screen February 2012 vol. 17 no. 2 129-139
    Related Subject:
    Chemical Genomics Screen Neural Stem Cell Differentiation
    Link:
    http://jbx.sagepub.com/content/17/2/129.abstract
  • Implementation and Development of an Automated, Ultra-High-Capacity, Acoustic, Flexible Dispensing Platform for Assay-Ready Plate Delivery Griffith D, Northwood R, Owen P, Simkiss E, Brierley A, Cross K, Slaney A, Davis M, Bath C

    Institution: AstraZeneca

    Publication: Journal of Laboratory Automation October 2012 vol. 17 no. 5 348-358 10.1177/2211068212457159

    2012 abstract

    Compound management faces the daily challenge of providing high-quality samples to drug discovery. The advent of new screening technologies has seen demand for liquid samples move toward nanoliter ranges, dispensed by contactless acoustic droplet ejection. Within AstraZeneca, a totally integrated assay-ready plate production platform has been created to fully exploit the advantages of this technology. This enables compound management to efficiently deliver large throughputs demanded by high-throughput screening while maintaining regular delivery of smaller numbers of compounds in varying plate formats for cellular or biochemical concentration-response curves in support of hit and lead optimization (structure-activity relationship screening). The automation solution, CODA, has the capability to deliver compounds on demand for single- and multiple-concentration ranges, in batch sizes ranging from 1 sample to 2 million samples, integrating seamlessly into local compound and test management systems. The software handles compound orders intelligently, grouping test requests together dependent on output plate type and serial dilution ranges so that source compound vessels are shared among numerous tests, ensuring conservation of sample, reduced labware and costs, and efficiency of work cell logistics. We describe the development of CODA to address the customer demand, challenges experienced, learning made, and subsequent enhancements.

    Publication / Type:
    Journal of Laboratory Automation October 2012 vol. 17 no. 5 348-358 10.1177/2211068212457159
    Related Subject:
    Automated Ultra-High-Capacity Acoustic Flexible Dispensing Platform Assay-Ready
    Link:
    http://jla.sagepub.com/content/17/5/348.abstract
  • Development and Validation of Reagents and Assays for EZH2 Peptide and Nucleosome High-Throughput Screens Diaz E, Machutta C A, Chen S, Jiang Y, Nixon C, Hoffman G, Key D, Sweitzer S, Patel M, Wu Z, Creasy

    Institution: GlaxoSmithKline

    Publication: J Biomol Screen. 2012 Dec;17(10):1279-92. doi: 10.1177/1087057112453765

    2012 abstract

    Histone methyltransferases (HMT) catalyze the methylation of histone tail lysines, resulting in changes in gene transcription. Misregulation of these enzymes has been associated with various forms of cancer, making this target class a potential new area for the development of novel chemotherapeutics. EZH2 is the catalytic component of the polycomb group repressive complex (PRC2), which selectively methylates histone H3 lysine 27 (H3K27). EZH2 is overexpressed in prostate, breast, bladder, brain, and other tumor types and is recognized as a molecular marker for cancer progression and aggressiveness. Several new reagents and assays were developed to aid in the identification of EZH2 inhibitors, and these were used to execute two high-throughput screening campaigns. Activity assays using either an H3K27 peptide or nucleosomes as substrates for methylation are described. The strategy to screen EZH2 with either a surrogate peptide or a natural substrate led to the identification of the same tractable series. Compounds from this series are reversible, are [3H]-S-adenosyl-L-methionine competitive, and display biochemical inhibition of H3K27 methylation.

    Publication / Type:
    J Biomol Screen. 2012 Dec;17(10):1279-92. doi: 10.1177/1087057112453765
    Related Subject:
    EZH2 Peptide Nucleosome
    Link:
    http://jbx.sagepub.com/content/17/10/1279.abstract
  • Development of a High-Throughput Calcium Flux Assay for Identification of All Ligand Types Including Positive, Negative, and Silent Allosteric Modulators for G Protein-Coupled Receptors Noblin D, Bertekap R L, Burford N T, Hendricson A, Zhang L, Knox R, Banks M, O'Connell J, and Alt A

    Institution: Yale University, Bristol-Myers Squibb

    Publication: ASSAY and Drug Development Technologies. October 2012, 10(5): 457-467. doi:10.1089/adt.2011.443

    2012 abstract

    In recent years, the increased use of cell-based fun​ctional assays for G protein-coupled receptors in high-throughput screening has enabled the design of robust assays to identify allosteric modulators (AMs) in addition to the more traditional orthosteric agonists and antagonists. In this article, the authors describe a screening format able to identify all ligand types using a triple-add assay that measures changes in cytosolic calcium concentration with three separate additions and reads in the same assay plate. This triple-add assay captures more small molecule ligand types than previously described assay formats without a significant increase in screening cost. Finally, the customizability of the triple-add assay to suit the needs of various AM screening programs is demonstrated.

    Publication / Type:
    ASSAY and Drug Development Technologies. October 2012, 10(5): 457-467. doi:10.1089/adt.2011.443
    Related Subject:
    Calcium Flux Positive Negative Silent Allosteric Modulators G Protein-Coupled Receptors
    Link:
    http://online.liebertpub.com/doi/abs/10.1089/adt.2011.443
  • Proteomic analysis of formalin-fixed paraffin embedded tissue by MALDI imaging mass spectrometry Casadonte R, Caprioli R M

    Institution: Mass Spectrometry Research Center, Department of Biochemistry, Vanderbilt University

    Publication: Nat Protoc. 2011 October 13; 6(11): 1695–1709.  doi:  10.1038/nprot.2011.388

    2011 abstract

    Archived formalin-fixed paraffin-embedded (FFPE) tissue collections represent a valuable informational resource for proteomic studies. Multiple FFPE core biopsies can be assembled in a single block to form tissue microarrays (TMAs). We describe a protocol for analyzing protein in FFPE -TMAs using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). The workflow incorporates an antigen retrieval step following deparaffinization, in situ trypsin digestion, matrix application and then mass spectrometry signal acquisition. The direct analysis of FFPE -TMA tissue using IMS allows direct analysis of multiple tissue samples in a single experiment without extraction and purification of proteins. The advantages of high speed and throughput, easy sample handling and excellent reproducibility make this technology a favorable approach for the proteomic analysis of clinical research cohorts with large sample numbers. For example, TMA analysis of 300 FFPE cores would typically require 6 h of total time through data acquisition, not including data analysis.

    Publication / Type:
    Nat Protoc. 2011 October 13; 6(11): 1695–1709.  doi:  10.1038/nprot.2011.388
    Related Subject:
    Proteomic formalin-fixed paraffin MALDI mass spectrometry
    Link:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516368/
  • Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay Pantel J, Williams S Y, Mi D, Sebag J, Corbin J D, Weaver C D, Cone R D

    Institution: Department of Molecular Physiology and Biophysics, Vanderbilt University

    Publication: European Journal of Pharmacology, 660, 139-147, 2011

    2011 abstract

    The melanocortin MC4 receptor is a potential target for the development of drugs for both obesity and cachexia. Melanocortin MC4 receptor ligands known thus far are orthosteric agonists or antagonists, however the agonists, in particular, have generally exhibited unwanted side effects. For some receptors, allosteric modulators are expected to reduce side-effect profiles. To identify allosteric modulators of the melanocortin MC4 receptor, we created HEK293 cell lines coexpressing the human melanocortin MC4 receptor and a modified luciferase-based cAMP sensor. Monitoring luminescence as a readout of real-time intracellular cAMP concentration, we demonstrate that this cell line is able to report melanocortin agonist responses, as well as inverse agonist response to the physiological AgRP peptide. Based on the MC4R-GLO cell line, we developed an assay that was shown to meet HTS standards (Z′ = 0.50). A pilot screen run on the Microsource Spectrum compound library (n = 2000) successfully identified 62 positive modulators. This screen identified predicted families of compounds: β2AR agonists – the β2AR being endogenously expressed in HEK293 cells, an adenylyl cyclase activator and finally a distribution of phosphodiesterase (PDE) inhibitors well characterized or recently identified. In this last category, we identified a structural family of coumarin-derived compounds (imperatorin, osthol and prenyletin), along with deracoxib, a drug in veterinary use for its COX2 inhibitory properties. This latter finding unveiled a new off-target mechanism of action for deracoxib as a PDE inhibitor. Overall, these data are the first report of a HTS for allosteric modulators for a Gs protein coupled receptor.

    Publication / Type:
    European Journal of Pharmacology, 660, 139-147, 2011
    Related Subject:
    allosteric melanocortin-4 receptor cAMP
    Link:
    http://dx.doi.org/10.1016/j.ejphar.2011.01.031
  • A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway Mao X, Cao B, Wood T E, Hurren R, Tong J, Wang X, Wang W, Li J, Jin Y, Sun W, Spagnuolo P A, MacLean

    Institution: University of Toronto

    Publication: Blood February 10, 2011 vol. 117 no. 6 1986-1997

    2011 abstract

    D-cyclins are universally dysregulated in multiple myeloma and frequently overexpressed in leukemia. To better understand the role and impact of dysregulated D-cyclins in hematologic malignancies, we conducted a high-throughput screen for inhibitors of cyclin D2 transactivation and identified 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161), which inhibited the expression of cyclins D1, D2, and D3 and arrested cells at the G0/G1 phase. After D-cyclin suppression, S14161 induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of leukemia, S14161 inhibited tumor growth without evidence of weight loss or gross organ toxicity. Mechanistically, S14161 inhibited the activity of phosphoinositide 3-kinase in intact cells and the activity of the phosphoinositide 3-kinases α, β, δ, and γ in a cell-free enzymatic assay. In contrast, it did not inhibit the enzymatic activities of other related kinases, including the mammalian target of rapamycin, the DNA-dependent protein kinase catalytic subunit, and phosphoinositide-dependent kinase-1. Thus, we identified a novel chemical compound that inhibits D-cyclin transactivation via the phosphoinositide 3-kinase/protein kinase B signaling pathway. Given its potent antileukemia and antimyeloma activity and minimal toxicity, S14161 could be developed as a novel agent for blood cancer therapy.

    Publication / Type:
    Blood February 10, 2011 vol. 117 no. 6 1986-1997
    Related Subject:
    small-molecule inhibitor D-cyclin myeloma leukemia phosphoinositide 3-kinase
    Link:
    http://171.66.121.249/content/117/6/1986.full
  • Development and Validation of a Simple Cell-Based Fluorescence Assay for Dipeptidyl Peptidase 1 (DPP1) Activity Thong B, Pilling J, Ainscow E, Beri R, Unitt J

    Institution:

    Publication: J Biomol Screen January 2011 vol. 16 no. 1 36-43

    2011 abstract

    Dipeptidyl peptidase 1 (DPP1) (EC 3.4.14.1; also known as cathepsin C, cathepsin J, dipeptidyl aminopeptidase, and dipeptidyl aminotransferase) is a lysosomal cysteinyl protease of the papain family involved in the intracellular degradation of proteins. Isolated enzyme assays for DPP1 activity using a variety of synthetic substrates such as dipeptide or peptide linked to amino-methyl-coumarin (AMC) or other fluorophores are well established. There is, however, no report of a simple whole-cell-based assay for measuring lysosomal DPP1 activity other than the use of flow cytometry (fluorescence-activated cell sorting) or the use of invasive activity-based probes or the production of physiological products such as neutrophil elastase. The authors investigated a number of DPP1 fluorogenic substrates that have the potential to access the lysosome and enable the measurement of DPP1 enzyme activity in situ. They describe the development and evaluation of a simple noninvasive fluorescence assay for measuring DPP1 activity in fresh or cryopreserved human THP-1 cells using the substrate H-Gly-Phe-AFC (amino-fluoro-coumarin). This cell-based fluorescence assay can be performed in a 96-well plate format and is ideally suited for determining the cell potency of potential DPP1 enzyme inhibitors.

    Publication / Type:
    J Biomol Screen January 2011 vol. 16 no. 1 36-43
    Related Subject:
    Simple Cell-Based Fluorescence Dipeptidyl Peptidase 1 (DPP1)
    Link:
    http://jbx.sagepub.com/content/16/1/36.short
  • Protein signatures for survival and recurrence in metastatic melanoma Hardesty W M, Kelley M C, Mi D, Low R L, Caprioli R M

    Institution: Vanderbilt University

    Publication: J Proteomics. 2011 June 10; 74(7): 1002–1014.  doi:  10.1016/j.jprot.2011.04.013

    2011 abstract

    atients with melanoma metastatic to regional lymph nodes exhibit a range in tumor progression, survival, and treatment. Current approaches to stratify patients with this stage of disease predominantly involve clinical and histological methods. Molecular classification thus far has focused almost exclusively on genetic mutations. In this study, proteomic data from 69 melanoma lymph node metastases and 17 disease free lymph nodes acquired by histology-directed MALDI imaging mass spectrometry were used to classify tumor from control lymph node and to molecularly sub-classify patients with stage III disease. From these data, 12 survival associated protein signals and 3 recurrence associated signals in the acquired mass spectra were combined to generate a multiplex molecular signature to group patients into either poor or favorable groups for recurrence and survival. Proteins represented in the signature include cytochrome c, s100 A6, histone H4, and cleaved forms of thymosin β-4, thymosin β-10, and ubiquitin. In total over 40 protein signals from the tissue were identified.

    Publication / Type:
    J Proteomics. 2011 June 10; 74(7): 1002–1014.  doi:  10.1016/j.jprot.2011.04.013
    Related Subject:
    Protein signatures survival recurrence metastatic melanoma
    Link:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178099/
  • Spatial mapping by Imaging Mass Spectrometry offers advancements for rapid definition of human skin proteomic signatures Taverna D, Nanney L B, Pollins A C, Sindona G, Caprioli R

    Institution: Vanderbilt University

    Publication: Exp Dermatol. 2011 August; 20(8): 642–647.  doi:  10.1111/j.1600-0625.2011.01289.x

    2011 abstract

    Investigations of the human skin proteome by classical analytical procedures have not addressed spatial molecular distributions in whole skin biopsies. The aim of this study was to develop methods for detection of protein signatures and their spatial disposition in human skin using advanced molecular imaging technology based on mass spectrometry technologies. This technology allows for the generation of protein images at specific molecular weight values without the use of antibody while maintaining tissue architecture. Two experimental approaches were employed: MALDI-MS profiling, where mass spectra were taken from discrete locations based on histology, and MALDI-IMS imaging, where complete molecular images were obtained at various MW values. In addition, proteins were identified by in situ tryptic digestion, sequence analysis of the fragment peptides, and protein database searching. We have detected patterns of protein differences that exist between epidermis and dermis as well as subtle regional differences between the papillary and reticular dermis. Furthermore, we were able to detect proteins that are constitutive features of human skin as well as those associated with unique markers of individual variability.

    Publication / Type:
    Exp Dermatol. 2011 August; 20(8): 642–647.  doi:  10.1111/j.1600-0625.2011.01289.x
    Related Subject:
    Spatial mapping Imaging Spectrometry rapid human skin proteomic
    Link:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135742/
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