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  1 / 8693 MEDLINE  
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PMID:28453684
Autor:Gupta S; De Puysseleyr V; Van der Heyden J; Maddelein D; Lemmens I; Lievens S; Degroeve S; Tavernier J; Martens L
Endereço:Medical Biotechnology Center, VIB, Ghent, Belgium.
Título:MAPPI-DAT: data management and analysis for protein-protein interaction data from the high-throughput MAPPIT cell microarray platform.
Fonte:Bioinformatics; 33(9):1424-1425, 2017 May 01.
ISSN:1367-4811
País de publicação:England
Idioma:eng
Resumo:Summary: Protein-protein interaction (PPI) studies have dramatically expanded our knowledge about cellular behaviour and development in different conditions. A multitude of high-throughput PPI techniques have been developed to achieve proteome-scale coverage for PPI studies, including the microarray based Mammalian Protein-Protein Interaction Trap (MAPPIT) system. Because such high-throughput techniques typically report thousands of interactions, managing and analysing the large amounts of acquired data is a challenge. We have therefore built the MAPPIT cell microArray Protein Protein Interaction-Data management & Analysis Tool (MAPPI-DAT) as an automated data management and analysis tool for MAPPIT cell microarray experiments. MAPPI-DAT stores the experimental data and metadata in a systematic and structured way, automates data analysis and interpretation, and enables the meta-analysis of MAPPIT cell microarray data across all stored experiments. Availability and Implementation: MAPPI-DAT is developed in Python, using R for data analysis and MySQL as data management system. MAPPI-DAT is cross-platform and can be ran on Microsoft Windows, Linux and OS X/macOS. The source code and a Microsoft Windows executable are freely available under the permissive Apache2 open source license at https://github.com/compomics/MAPPI-DAT. Contact: jan.tavernier@vib-ugent.be or lennart.martens@vib-ugent.be. Supplementary information: Supplementary data are available at Bioinformatics online.
Tipo de publicação: JOURNAL ARTICLE


  2 / 8693 MEDLINE  
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PMID:28460635
Autor:Chen I; Mathews-Greiner L; Li D; Abisoye-Ogunniyan A; Ray S; Bian Y; Shukla V; Zhang X; Guha R; Thomas C; Gryder B; Zacharia A; Beane JD; Ravichandran S; Ferrer M; Rudloff U
Endereço:Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA.
Título:Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer.
Fonte:J Transl Med; 15(1):92, 2017 May 01.
ISSN:1479-5876
País de publicação:England
Idioma:eng
Resumo:BACKGROUND: Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease. METHODS: In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells. RESULTS: Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function. CONCLUSION: Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (CDH1 protein, human); 0 (Cadherins); 0 (Diglycerides); 0 (Inositol Phosphates); 0 (inositol 3,4,5-trisphosphate); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)


  3 / 8693 MEDLINE  
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PMID:28460441
Autor:Arora J; Sauer SJ; Tarpley M; Vermeulen P; Rypens C; Van Laere S; Williams KP; Devi GR; Dewhirst MW
Endereço:Duke Cancer Institute, Duke University, Durham, NC, USA.
Título:Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies.
Fonte:Oncotarget; 8(16):25848-25863, 2017 Apr 18.
ISSN:1949-2553
País de publicação:United States
Idioma:eng
Resumo:Inflammatory breast cancer (IBC) is one of the most lethal breast cancer variants; with existing therapy, 5-yr survival rate is only 35%. Current barriers to successful treatment of IBC include frequent infiltration and the presence of tumor cell clusters, termed tumor emboli, within the breast parenchyma and lymphatics. Prior studies have identified the role of anti-apoptotic signaling, in particular hyperactivation of NFκB and its target genes, in IBC pathobiology and therapeutic resistance. The objectives of this study were to: (1) determine if IBC tumor emboli express anti-apoptotic proteins and (2) develop a high content, multiparametric assay to assess the morphology of the IBC 3D spheroids and to optimize a high throughput format to screen for compounds that can inhibit the formation of the IBC tumor clusters/embolic structures. Immunohistochemical analysis of IBC patient tumor samples with documented tumor emboli revealed high NFκB (p65) staining along with expression of XIAP, a potent anti-apoptotic protein known to interact with NFκB signaling in enhancing survival of malignant cells. Subsequently, the high content assay developed allowed for simultaneous imaging and morphometric analysis, including count and viability of spheroids derived from SUM149, rSUM149 and SUM190 cells and its application to evaluate XIAP and NFκB inhibitory agents. We demonstrate the efficacy of the off-patent drug disulfiram when chelated with copper, which we had previously reported to inhibit NFκB signaling, was highly effective in disrupting both IBC spheroids and emboli grown in vitro. Taken together, these results identify a high-throughput approach to target tumor spheroid formation for drug discovery. Finally, disulfiram is a safe and approved drug for management of alcohol abuse, warranting its evaluation for repurposing in IBC therapy.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Apoptosis Regulatory Proteins); 0 (Biomarkers, Tumor); 0 (NF-kappa B); 0 (X-Linked Inhibitor of Apoptosis Protein); 0 (XIAP protein, human); 789U1901C5 (Copper); TR3MLJ1UAI (Disulfiram)


  4 / 8693 MEDLINE  
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PMID:27774815
Autor:Kassegne K; Abe EM; Chen JH; Zhou XN
Endereço:a National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Key Laboratory of Parasite and Vector Biology of the Chinese Ministry of Health , Shanghai ,
Título:Immunomic approaches for antigen discovery of human parasites.
Fonte:Expert Rev Proteomics; 13(12):1091-1101, 2016 12.
ISSN:1744-8387
País de publicação:England
Idioma:eng
Resumo:INTRODUCTION: Genetics combined with proteomics allows for a better understanding of parasite-host interactions and host immune responses. Immunomics elucidates that antigens are targets of induced or naturally acquired immunity (NAI), a promising solution to the challenge of eradicating human infections. High-throughput protein microarrays enhance rapid antigen discovery for the development of serodiagnostic tests/vaccines. Areas covered: This review systematically analyzes the emergence of protein microarrays as a powerful technology for parasite antigen discovery and subsequently summarizes some of the attributes and disadvantages of these approaches. Major insights on novel/validated serological biomarkers or vaccine candidates against malaria and Neglected Tropical Diseases (NTDs) are highlighted. We conclude with a brief description of the processes involved in immunomic protein microarrays. Expert commentary: Interesting discoveries have been made using protein microarrays. However, there is a need to evaluate targets that elicit strong immunogenicity and correlates of protective efficacy to aid prioritization and guide further clinical development. The goal of parasitic disease elimination will be best achieved through an integrated strategy that will incorporate and implement the different control components.
Tipo de publicação: JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Antigens, Helminth); 0 (Vaccines)


  5 / 8693 MEDLINE  
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PMID:29385160
Autor:Just S; Chenard BL; Ceci A; Strassmaier T; Chong JA; Blair NT; Gallaschun RJ; Del Camino D; Cantin S; D'Amours M; Eickmeier C; Fanger CM; Hecker C; Hessler DP; Hengerer B; Kroker KS; Malekiani S; Mihalek R; McLaughlin J; Rast G; Witek J; Sauer A; Pryce CR; Moran MM
Endereço:Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Título:Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice.
Fonte:PLoS One; 13(1):e0191225, 2018.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:BACKGROUND: Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects. HC-070 IN VITRO: To assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070. HC-070 inhibits recombinant TRPC4 and TRPC5 homomultimers in heterologous expression systems with nanomolar potency. It also inhibits TRPC1/5 and TRPC1/4 heteromultimers with similar potency and reduces responses evoked by cholecystokinin tetrapeptide (CCK-4) in the amygdala. The compound is >400-fold selective over a wide range of molecular targets including ion channels, receptors, and kinases. HC-070 IN VIVO: Upon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity. Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Anti-Anxiety Agents); 0 (Antidepressive Agents); 0 (HC-070); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (TRPC Cation Channels); 0 (TRPC4 ion channel); 0 (TRPC5 protein, human); 0 (Trpc5 protein, mouse)


  6 / 8693 MEDLINE  
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PMID:28470618
Autor:Black C; Barker JJ; Hitchman RB; Kwong HS; Festenstein S; Acton TB
Endereço:Evotec Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK.
Título:High-Throughput Production of Proteins in E. coli for Structural Studies.
Fonte:Methods Mol Biol; 1586:359-371, 2017.
ISSN:1940-6029
País de publicação:United States
Idioma:eng
Resumo:We have developed a standardized and efficient workflow for high-throughput (HT) protein expression in E. coli and parallel purification which can be tailored to the downstream application of the target proteins. It includes a one-step purification for the purposes of functional assays and a two-step protocol for crystallographic studies, with the option of on-column tag removal.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Recombinant Proteins)


  7 / 8693 MEDLINE  
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PMID:29305325
Autor:Kurokawa YK; Shang MR; Yin RT; George SC
Endereço:Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States.
Título:Modeling trastuzumab-related cardiotoxicity in vitro using human stem cell-derived cardiomyocytes.
Fonte:Toxicol Lett; 285:74-80, 2018 Mar 15.
ISSN:1879-3169
País de publicação:Netherlands
Idioma:eng
Resumo:Trastuzumab (Herceptin ), a monoclonal antibody against the ErbB2 (HER2) receptor, has significantly improved clinical outcomes for HER2 breast cancer patients. However, the drug also has known cardiotoxic side effects through mechanisms that are not fully understood. Here we utilized human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) to model trastuzumab-related cardiotoxicity in vitro. We demonstrate that cardiotoxic effects of ErbB2 inhibition by trastuzumab can be recapitulated only when the cardioprotective effects of ErbB2/4 signaling is observed. We observed no cardioprotective effects of ErbB2/4 signaling without cellular stress (doxorubicin exposure in this study). In addition to neuregulin-1 (NRG-1), we show that heparin-binding epidermal growth factor-like growth factor (HB-EGF) also provides cardioprotective effects for iPS-CMs. Finally, we demonstrate a simple, high-throughput co-culture platform utilizing iPS-CMs and endothelial cells that is capable of detecting trastuzumab-related cardiotoxicity. We conclude that iPS-CMs can recapitulate trastuzumab-related cardiotoxicity, and may be used to elucidate additional modes of toxicity of trastuzumab and related compounds.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antineoplastic Agents, Immunological); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab)


  8 / 8693 MEDLINE  
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PMID:28470533
Autor:Öz S; Breiling A; Maercker C
Endereço:German Cancer Research Center (DKFZ), Epigenomics and Cancer Risk Factors, Heidelberg, Germany.
Título:Measurement of Cellular Behavior by Electrochemical Impedance Sensing.
Fonte:Methods Mol Biol; 1601:267-273, 2017.
ISSN:1940-6029
País de publicação:United States
Idioma:eng
Resumo:There is a great demand for label-free in vitro assays in a high-throughput context, in order to measure cell viability and analyze cellular functions like cell migration or cell differentiation under noninvasive conditions. Here, we describe impedance measurement to quantify dynamic changes on cell morphology in real time. In order to monitor physiological changes, cells are grown in tissue culture vessels where gold electrodes are incorporated at the bottom. An alternating current signal of several kHz is applied to the electrodes and the resulting voltage is measured to calculate the cellular impedance. Since impedance is closely related to the area of the electrodes covered by the growing cells, parameters such as cell number, size of the cells attached to the electrodes, and cell-cell and cell-substrate/extracellular matrix interactions contribute to the overall impedance values.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:7440-57-5 (Gold)


  9 / 8693 MEDLINE  
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PMID:28470517
Autor:Menzner AK; Gilbert DF
Endereço:Department of Internal Medicine 5, University Medical Center Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Título:A Protocol for In Vitro High-Throughput Chemical Susceptibility Screening in Differentiating NT2 Stem Cells.
Fonte:Methods Mol Biol; 1601:61-70, 2017.
ISSN:1940-6029
País de publicação:United States
Idioma:eng
Resumo:The incidence of neurological diseases including learning and developmental disorders has increased in recent years. Concurrently, the number and volume of worldwide registered and traded chemicals have also increased. There is a broad consensus that the developing brain is particularly sensitive to damage by chemicals and that evaluation of chemicals for developmental toxicity or neurotoxicity is critical to human health. Human pluripotent embryonal carcinoma (NTERA-2 or NT2) cells are increasingly considered as a suitable model for in vitro developmental toxicity and neurotoxicity (DT/DNT) studies as they undergo neuronal differentiation upon stimulation with retinoic acid (RA) and allow toxicity assessment at different stages of maturation. Here we describe a protocol for cell fitness screening in differentiating NT2 cells based on the analysis of intracellular ATP levels allowing for the identification of chemicals which are potentially harmful to the developing brain. The described method is suitable to be adapted to low-, medium-, and high-throughput screening and allows multiplexing with other cell fitness indicators. While the presented protocol focuses on cell fitness screening in human pluripotent stem cells it may also be applied to other in vitro models.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Small Molecule Libraries); 5688UTC01R (Tretinoin); 8L70Q75FXE (Adenosine Triphosphate)


  10 / 8693 MEDLINE  
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PMID:28470516
Autor:Ivanov DP; Grabowska AM; Garnett MC
Endereço:Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK. delyan.ivanov@nottingham.ac.uk.
Título:High-Throughput Spheroid Screens Using Volume, Resazurin Reduction, and Acid Phosphatase Activity.
Fonte:Methods Mol Biol; 1601:43-59, 2017.
ISSN:1940-6029
País de publicação:United States
Idioma:eng
Resumo:Mainstream adoption of physiologically relevant three-dimensional models has been slow in the last 50 years due to long, manual protocols with poor reproducibility, high price, and closed commercial platforms. This chapter describes high-throughput, low-cost, open methods for spheroid viability assessment which use readily available reagents and open-source software to analyze spheroid volume, metabolism, and enzymatic activity. We provide two ImageJ macros for automated spheroid size determination-for both single images and images in stacks. We also share an Excel template spreadsheet allowing users to rapidly process spheroid size data, analyze plate uniformity (such as edge effects and systematic seeding errors), detect outliers, and calculate dose-response. The methods would be useful to researchers in preclinical and translational research planning to move away from simplistic monolayer studies and explore 3D spheroid screens for drug safety and efficacy without substantial investment in money or time.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Indicators and Reagents); 0 (Oxazines); 0 (Xanthenes); 1FN9YD6968 (resazurin); EC 3.1.3.2 (Acid Phosphatase)



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