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https://www.readbyqxmd.com/read/28346811/improved-soluble-scfv-elisa-screening-approach-for-antibody-discovery-using-phage-display-technology
#1
Mohammad R Tohidkia, Maryam Sepehri, Shirin Khajeh, Jaleh Barar, Yadollah Omidi
Phage display technology (PDT) is a powerful tool for the isolation of recombinant antibody (Ab) fragments. Using PDT, target molecule-specific phage-Ab clones are enriched through the "biopanning" process. The individual specific binders are screened by the monoclonal scFv enzyme-linked immunosorbent assay (ELISA) that may associate with inevitable false-negative results. Thus, in this study, three strategies were investigated for optimization of the scFvs screening using Tomlinson I and J libraries, including (1) optimizing the expression of functional scFvs, (2) improving the sensitivity of ELISA, and (3) preparing different samples containing scFvs...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346810/an-automated-multiplexed-hepatotoxicity-and-cyp-induction-assay-using-heparg-cells-in-2d-and-3d
#2
Lindsey M Ott, Karthik Ramachandran, Lisa Stehno-Bittel
Drug-induced liver injury (DILI) and drug-drug interactions (DDIs) are concerns when developing safe and efficacious compounds. We have developed an automated multiplex assay to detect hepatotoxicity (i.e., ATP depletion) and metabolism (i.e., cytochrome P450 1A [CYP1A] and cytochrome P450 3A4 [CYP3A4] enzyme activity) in two-dimensional (2D) and three-dimensional (3D) cell cultures. HepaRG cells were cultured in our proprietary micromold plates and produced spheroids. HepaRG cells, in 2D or 3D, expressed liver-specific proteins throughout the culture period, although 3D cultures consistently exhibited higher albumin secretion and CYP1A/CYP3A4 enzyme activity than 2D cultures...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346786/break-down-in-order-to-build-up-decomposing-small-molecules-for-fragment-based-drug-design-with-emolfrag
#3
Tairan Liu, Misagh Naderi, Chris Alvin, Supratik Mukhopadhyay, Michal Brylinski
Constructing high-quality libraries of molecular building blocks is essential for successful fragment-based drug discovery. In this communication, we describe eMolFrag, a new open-source software to decompose organic compounds into non-redundant fragments retaining molecular connectivity information. Given a collection of molecules, eMolFrag generates a set of unique fragments comprising larger moieties, bricks, and smaller linkers connecting bricks. These building blocks can subsequently be used to construct virtual screening libraries for targeted drug discovery...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28346764/mapping-the-interactions-of-selective-biochemical-probes-of-antibody-conformation-by-hydrogen-deuterium-exchange-mass-spectrometry
#4
Ulrike Leurs, Hermann Beck, Lea Bonnington, Ingo Lindner, Ewa Pol, Kasper Dyrberg Rand
Protein-based pharmaceuticals represent the fastest growing group of drugs in development in the pharmaceutical industry. One of the major challenges in the discovery, development and distribution of biopharmaceuticals is the assessment of changes in their higher-order structure due to chemical modifications. Here, we investigate the interactions of three different biochemical probes (Fabs) generated to detect conformational changes in a therapeutic IgG1 antibody (mAbX) by local hydrogen-deuterium exchange mass spectrometry (HDX-MS)...
March 27, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28346746/simultaneous-determination-of-4-hydroxyphenyl-lactic-acid-4-hydroxyphenyl-acetic-acid-and-3-4-hydroxyphenyl-propionic-acid-in-human-urine-by-ultra-high-performance-liquid-chromatography-with-fluorescence-detection
#5
Yongli Yang, Fan Liu, Yiqun Wan
A simple and reliable method was established for simultaneous determination of 4-hydroxyphenyl acetic acid, 4-hydroxyphenyl lactic acid, and 3-4-hydroxyphenyl propionic acid in human urine by high-performance liquid chromatography with fluorescence detection. Solid-phase extraction was used to eliminate the interferences in urine. The separation of three analytes was achieved using a C18 column and a mobile phase formed by a 95:5 v/v mixture of 50 mmol/L ammonium acetate buffer at pH 6.8 that contained 5 mmol/L tetrabutyl ammonium bromide and acetonitrile...
March 27, 2017: Journal of Separation Science
https://www.readbyqxmd.com/read/28346540/fragment-library-screening-identifies-hits-that-bind-to-the-non-catalytic-surface-of-pseudomonas-aeruginosa-dsba1
#6
Biswaranjan Mohanty, Kieran Rimmer, Róisín M McMahon, Stephen J Headey, Mansha Vazirani, Stephen R Shouldice, Mathieu Coinçon, Stephanie Tay, Craig J Morton, Jamie S Simpson, Jennifer L Martin, Martin J Scanlon
At a time when the antibiotic drug discovery pipeline has stalled, antibiotic resistance is accelerating with catastrophic implications for our ability to treat bacterial infections. Globally we face the prospect of a future when common infections can once again kill. Anti-virulence approaches that target the capacity of the bacterium to cause disease rather than the growth or survival of the bacterium itself offer a tantalizing prospect of novel antimicrobials. They may also reduce the propensity to induce resistance by removing the strong selection pressure imparted by bactericidal or bacteriostatic agents...
2017: PloS One
https://www.readbyqxmd.com/read/28346525/modeling-timelines-for-translational-science-in-cancer-the-impact-of-technological-maturation
#7
Laura M McNamee, Fred D Ledley
This work examines translational science in cancer based on theories of innovation that posit a relationship between the maturation of technologies and their capacity to generate successful products. We examined the growth of technologies associated with 138 anticancer drugs using an analytical model that identifies the point of initiation of exponential growth and the point at which growth slows as the technology becomes established. Approval of targeted and biological products corresponded with technological maturation, with first approval averaging 14 years after the established point and 44 years after initiation of associated technologies...
2017: PloS One
https://www.readbyqxmd.com/read/28346407/insights-into-activity-and-inhibition-from-the-crystal-structure-of-human-o-glcnacase
#8
Nathaniel L Elsen, Sangita B Patel, Rachael E Ford, Dawn L Hall, Fred Hess, Hari Kandula, Maria Kornienko, John Reid, Harold Selnick, Jennifer M Shipman, Sujata Sharma, Kevin J Lumb, Stephen M Soisson, Daniel J Klein
O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346326/sarcomas-with-cic-rearrangements-are-a-distinct-pathologic-entity-with-aggressive-outcome-a-clinicopathologic-and-molecular-study-of-115-cases
#9
Cristina R Antonescu, Adepitan A Owosho, Lei Zhang, Sonja Chen, Kemal Deniz, Joseph M Huryn, Yu-Chien Kao, Shih-Chiang Huang, Samuel Singer, William Tap, Inga-Marie Schaefer, Christopher D Fletcher
CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available...
March 24, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28346318/predictors-of-impaired-hdl-function-in-hiv-1-infected-compared-to-uninfected-individuals
#10
Theodoros Kelesidis, Michael N Oda, Mark S Borja, Yumin Yee, Kit F Ng, Diana Huynh, David Elashoff, Judith S Currier
OBJECTIVE: HDL function rather than absolute level may be a more accurate indicator for cardiovascular disease (CVD). Novel methods can measure HDL function using patient samples. The objective of this study is to identify factors that may contribute to HDL dysfunction in chronic, treated HIV-1 infection. DESIGN: Retrospective study of HDL function measured in two ways in HIV-1 infected males with low overall CVD risk and healthy males with no known CVD risk matched by race to the HIV-1 infected participants...
March 23, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/28346225/long-telomeres-protect-against-age-dependent-cardiac-disease-caused-by-notch1-haploinsufficiency
#11
Christina V Theodoris, Foteini Mourkioti, Yu Huang, Sanjeev S Ranade, Lei Liu, Helen M Blau, Deepak Srivastava
Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascular disease involving premature calcification of the aortic valve, a phenotype that closely mimics human disease caused by NOTCH1 haploinsufficiency...
March 27, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28346107/a-high-throughput-method-for-measuring-drug-residence-time-using-the-transcreener-adp-assay
#12
Meera Kumar, Robert G Lowery
Analysis of drug-target residence times during drug development can result in improved efficacy, increased therapeutic window, and reduced side effects. Residence time can be estimated as the reciprocal of the dissociation rate ( koff) of an inhibitor from its target. The traditional methods for measuring koff require synthesis of labeled ligands or low-throughput label-free methods. To provide an alternative that is better suited to an automated high-throughput screening (HTS) environment, we adapted a classic "jump dilution" catalytic assay method for determination of koff values for kinase inhibitor drugs...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346104/bioengineered-3d-glial-cell-culture-systems-and-applications-for-neurodegeneration-and-neuroinflammation
#13
P Marc D Watson, Edel Kavanagh, Gary Allenby, Matthew Vassey
Neurodegeneration and neuroinflammation are key features in a range of chronic central nervous system (CNS) diseases such as Alzheimer's and Parkinson's disease, as well as acute conditions like stroke and traumatic brain injury, for which there remains significant unmet clinical need. It is now well recognized that current cell culture methodologies are limited in their ability to recapitulate the cellular environment that is present in vivo, and there is a growing body of evidence to show that three-dimensional (3D) culture systems represent a more physiologically accurate model than traditional two-dimensional (2D) cultures...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346103/discovery-of-novel-gq-biased-lpa1-negative-allosteric-modulators
#14
Yuji Shimizu, Masaharu Nakayama
Lysophosphatidic acid (LPA) activates the G-protein-coupled receptor LPA1, which regulates various cellular processes, including cell proliferation and migration. Although LPA1 transduces cellular responses via Gq, Gi, and G12/13, associations between these signaling molecules and cellular phenotypes remain poorly characterized due to the lack of signal-specific pharmacological tools. Here, we characterized novel signal-biased modulators using multiple assays, including label-free impedance assays. LPA caused dramatic changes in cellular impedance in LPA1-expressing recombinant cells, which were susceptible to G-protein and protein kinase inhibitors...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346096/a-novel-multiparametric-drug-scoring-method-for-high-throughput-screening-of-3d-multicellular-tumor-spheroids-using-the-celigo-image-cytometer
#15
Scott Cribbes, Sarah Kessel, Scott McMenemy, Jean Qiu, Leo Li-Ying Chan
Three-dimensional (3D) tumor models have been increasingly used to investigate and characterize cancer drug compounds. The ability to perform high-throughput screening of 3D multicellular tumor spheroids (MCTS) can highly improve the efficiency and cost-effectiveness of discovering potential cancer drug candidates. Previously, the Celigo Image Cytometer has demonstrated a novel method for high-throughput screening of 3D multicellular tumor spheroids. In this work, we employed the Celigo Image Cytometer to examine the effects of 14 cancer drug compounds on 3D MCTS of the glioblastoma cell line U87MG in 384-well plates...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346093/a-label-free-continuous-fluorescence-based-assay-for-monitoring-ornithine-decarboxylase-activity-with-a-synthetic-putrescine-receptor
#16
Mohamed Nilam, Philip Gribbon, Jeanette Reinshagen, Kathrin Cordts, Edzard Schwedhelm, Werner M Nau, Andreas Hennig
Polyamines play an important role in cell growth, differentiation, and cancer development, and the biosynthetic pathway of polyamines is established as a drug target for the treatment of parasitic diseases, neoplasia, and cancer chemoprevention. The key enzyme in polyamine biosynthesis is ornithine decarboxylase (ODC). We report herein an analytical method for the continuous fluorescence monitoring of ODC activity based on the supramolecular receptor cucurbit[6]uril (CB6) and the fluorescent dye trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide (DSMI)...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346088/a-1536-well-3d-viability-assay-to-assess-the-cytotoxic-effect-of-drugs-on-spheroids
#17
Franck Madoux, Allison Tanner, Michelle Vessels, Lynsey Willetts, Shurong Hou, Louis Scampavia, Timothy P Spicer
Evaluation of drug cytotoxicity traditionally relies on use of cell monolayers, which are easily miniaturized to the 1536-well plate format. Three-dimensional (3D) cell culture models have recently gained popularity thanks to their ability to better mimic the complexity of in vivo systems. Despite growing interest in these more physiologically relevant and highly predictive cell-based models for compound profiling and drug discovery, 3D assays are currently performed in a medium- to low-throughput format, either in 96-well or 384-well plates...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346087/pubchem-bioassay
#18
Yanli Wang, Tiejun Cheng, Stephen H Bryant
High-throughput screening (HTS) is now routinely conducted for drug discovery by both pharmaceutical companies and screening centers at academic institutions and universities. Rapid advance in assay development, robot automation, and computer technology has led to the generation of terabytes of data in screening laboratories. Despite the technology development toward HTS productivity, fewer efforts were devoted to HTS data integration and sharing. As a result, the huge amount of HTS data was rarely made available to the public...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346085/slas-discovery
#19
Robert M Campbell
No abstract text is available yet for this article.
January 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346045/a-modular-and-adaptive-mass-spectrometry-based-platform-for-support-of-bioprocess-development-toward-optimal-host-cell-protein-clearance
#20
Donald E Walker, Feng Yang, Joseph Carver, Koman Joe, David A Michels, X Christopher Yu
A modular and adaptive mass spectrometry (MS)-based platform was developed to provide fast, robust and sensitive host cell protein (HCP) analytics to support process development. This platform relies on one-dimensional ultra-high performance liquid chromatography (1D UHPLC) combined with several different MS data acquisition strategies to meet the needs of purification process development. The workflow was designed to allow HCP composition and quantitation for up to 20 samples per day, a throughput considered essential for real time bioprocess development support...
March 27, 2017: MAbs
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