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https://www.readbyqxmd.com/read/28938529/defining-a-therapeutic-window-for-kinase-inhibitors-in-leukemia-to-avoid-neutropenia
#1
Kate McArthur, Akshay A D'Cruz, David Segal, Kurt Lackovic, Andrew F Wilks, Joanne A O'Donnell, Cameron J Nowell, Motti Gerlic, David C S Huang, Christopher J Burns, Ben A Croker
Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938072/machine-learning-for-silver-nanoparticle-electron-transfer-property-prediction
#2
Baichuan Sun, Michael Fernandez, Amanda S Barnard
Nanoparticles exhibit diverse structural and morphological features that are often inter-connected, making the correlation of structure/property relationships challenging. In this study a multi-structure/single-property relationship of silver nanoparticles is developed for the energy of Fermi level, which can be tuned to improve the transfer of electrons in a variety of applications. By combining different machine learning analytical algorithms, including k-mean, logistic regression and random forest with electronic structure simulations, we find that the degree of twinning (characterised by the fraction of hexagonal closed packed atoms) and the population of {111} facet (characterized by a surface coordination number of 9) are strongly correlated to the Fermi energy of silver nanoparticles...
September 22, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28937750/active-site-metal-identity-alters-hdac8-substrate-selectivity-a-potential-novel-regulatory-mechanism
#3
Carol Ann Castaneda, Jeffrey E Lopez, Caleb G Joseph, Michael D Scholle, Milan Mrksich, Carol A Fierke
Histone deacetylase 8 (HDAC8) is a well-characterized member of the class I acetyl-lysine deacetylase (HDAC) family and previous work has shown that the effi-ciency of HDAC8-catalyzed deacetylation of a methylcoumarin peptide varies depending on the identity of the divalent metal ion in the HDAC8 active site. Here we demonstrate that both HDAC8 activity and substrate selectivity for a diverse range of peptide substrates depends on the identity of the active site metal ion. Varied deacetylase activities of Fe(II)- and Zn(II)-HDAC8 toward an array of peptide substrates were identified using a high-throughput Self-Assembled Monolayers for MALDI-TOF Mass Spectrometry (SAMDI) mass spectrometry screen...
September 22, 2017: Biochemistry
https://www.readbyqxmd.com/read/28937220/a-fluorescence-polarization-activity-based-protein-profiling-assay-in-the-discovery-of-potent-selective-inhibitors-for-human-non-lysosomal-glucosylceramidase
#4
Daniel Lahav, Bing Liu, Richard J B H N van den Berg, Adrianus M C H van den Nieuwendijk, Tom Wennekes, Amar T Ghisaidoobe, Imogen Breen, Maria J Ferraz, Chi-Lin Kuo, Liang Wu, Paul P Geurink, Huib Ovaa, Gijsbert A van der Marel, Mario van der Stelt, Rolf G Boot, Gideon J Davies, Johannes M F G Aerts, Herman S Overkleeft
Human non-lysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA) and the cytosolic retaining β-glucosidase, GBA3...
September 22, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28937207/a-facile-and-sensitive-method-for-protein-kinase-a-activity-assay-based-on-fluorescent-off-on-polyu-peptide-assembly
#5
Yanhui Xu, Wen Shi, Xinyuan He, Xiaofeng Wu, Xiaohua Li, Huimin Ma
Phosphorylation mediated by protein kinases plays a pivotal role in metabolic and cell-signaling processes, and the dysfunction of protein kinases such as protein kinase A (PKA) may induce several human diseases. Therefore it is of great significance to develop a facile and effective method for PKA activity assay and high-throughput screening of inhibitors. Herein, we develop a new fluorescent off-on method for PKA assay based on the assembly of anionic polyuridylic acid (polyU) and cationic fluorescent peptide...
September 22, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28936274/a-review-on-wax-printed-microfluidic-paper-based-devices-for-international-health
#6
REVIEW
S Altundemir, A K Uguz, K Ulgen
Paper-based microfluidics has attracted attention for the last ten years due to its advantages such as low sample volume requirement, ease of use, portability, high sensitivity, and no necessity to well-equipped laboratory equipment and well-trained manpower. These characteristics have made paper platforms a promising alternative for a variety of applications such as clinical diagnosis and quantitative analysis of chemical and biological substances. Among the wide range of fabrication methods for microfluidic paper-based analytical devices (μPADs), the wax printing method is suitable for high throughput production and requires only a commercial printer and a heating source to fabricate complex two or three-dimensional structures for multipurpose systems...
July 2017: Biomicrofluidics
https://www.readbyqxmd.com/read/28935948/novel-scaffolds-for-inhibition-of-cruzipain-identified-from-high-throughput-screening-of-anti-kinetoplastid-chemical-boxes
#7
Emir Salas-Sarduy, Lionel Urán Landaburu, Joel X Karpiak, Kevin P Madauss, Juan José Cazzulo, Fernán Agüero, Vanina Eder Alvarez
American Trypanosomiasis or Chagas disease is a prevalent, neglected and serious debilitating illness caused by the kinetoplastid protozoan parasite Trypanosoma cruzi. The current chemotherapy is limited only to nifurtimox and benznidazole, two drugs that have poor efficacy in the chronic phase and are rather toxic. In this scenario, more efficacious and safer drugs, preferentially acting through a different mechanism of action and directed against novel targets, are particularly welcome. Cruzipain, the main papain-like cysteine peptidase of T...
September 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28935105/structure-guided-directed-evolution-of-glycosidases-a-case-study-in-engineering-a-blood-group-antigen-cleaving-enzyme
#8
David H Kwan
Directed evolution is an incredibly powerful strategy for engineering enzyme function. Applying this approach to glycosidases offers enormous potential for the development of highly specialized tools in chemical glycobiology. Performing enzyme directed evolution requires the generation, by random mutagenesis, of mutant libraries from which large numbers of variant enzymes must be screened in high-throughput assays. A structure-guided "semirational" method for library creation allows researchers to target specific amino acid positions for mutagenesis, concentrating mutations where they might be most effective in order to produce mutant libraries of a manageable size, minimizing screening effort while maximizing the chances of finding improved mutants...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28934395/abnormal-polyamine-metabolism-is-unique-to-the-neuropathic-forms-of-mps-potential-for-biomarker-development-and-insight-into-pathogenesis
#9
Christian Hinderer, Nathan Katz, Jean-Pierre Louboutin, Peter Bell, Jakub Tolar, Paul J Orchard, Troy C Lund, Mohamad Nayal, Liwei Weng, Clementina Mesaros, Carolina F M de Souza, Amauri Dalla Corte, Roberto Giugliani, James M Wilson
The mucopolysaccharidoses (MPS) are rare genetic disorders marked by severe somatic and neurological symptoms. Development of treatments for the neurological manifestations of MPS has been hindered by the lack of objective measures of central nervous system disease burden. Identification of biomarkers for central nervous system disease in MPS patients would facilitate the evaluation of new agents in clinical trials. High throughput metabolite screening of cerebrospinal fluid (CSF) samples from a canine model of MPS I revealed a marked elevation of the polyamine, spermine, in affected animals, and gene therapy studies demonstrated that reduction of CSF spermine reflects correction of brain lesions in these animals...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28933752/graphene-field-effect-transistors-for-biomedical-applications-current-status-and-future-prospects
#10
REVIEW
Rhiannan Forsyth, Anitha Devadoss, Owen J Guy
Since the discovery of the two-dimensional (2D) carbon material, graphene, just over a decade ago, the development of graphene-based field effect transistors (G-FETs) has become a widely researched area, particularly for use in point-of-care biomedical applications. G-FETs are particularly attractive as next generation bioelectronics due to their mass-scalability and low cost of the technology's manufacture. Furthermore, G-FETs offer the potential to complete label-free, rapid, and highly sensitive analysis coupled with a high sample throughput...
July 26, 2017: Diagnostics
https://www.readbyqxmd.com/read/28933746/evaluation-of-novel-dual-acetyl-and-butyrylcholinesterase-inhibitors-as-potential-anti-alzheimer-s-disease-agents-using-pharmacophore-3d-qsar-and-molecular-docking-approaches
#11
Xiaocong Pang, Hui Fu, Shilun Yang, Lin Wang, Ai-Lin Liu, Song Wu, Guan-Hua Du
DL0410, containing biphenyl and piperidine skeletons, was identified as an acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor through high-throughput screening assays, and further studies affirmed its efficacy and safety for Alzheimer's disease treatment. In our study, a series of novel DL0410 derivatives were evaluated for inhibitory activities towards AChE and BuChE. Among these derivatives, compounds 6-1 and 7-6 showed stronger AChE and BuChE inhibitory activities than DL0410. Then, pharmacophore modeling and three-dimensional quantitative structure activity relationship (3D-QSAR) models were performed...
July 26, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28933684/screening-of-primary-gp120-immunogens-to-formulate-the-next-generation-polyvalent-dna-prime-protein-boost-hiv-1-vaccines
#12
Shixia Wang, Te-Hui Wu, Anthony Hackett, Veronica Efros, Yan Wang, Dong Han, Aaron Wallace, Yuxin Chen, Guangnan Hu, Shuying Liu, Paul Clapham, James Arthos, David Montefiori, Shan Lu
Our previous preclinical studies and a Phase I clinical trial DP6-001 have indicated that a polyvalent Env formulation was able to elicit broadly reactive antibody responses including low titer neutralizing antibody responses against viral isolates of subtypes A, B, C and AE. In the current report, a panel of 62 gp120 immunogens were screened in a rabbit model to identify gp120 immunogens that can elicit improved binding and neutralizing antibody responses and some of them can be included in the next polyvalent formulation...
September 21, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28933630/going-native-direct-high-throughput-screening-of-secreted-full-length-igg-antibodies-against-cell-membrane-proteins
#13
Yongliang Fang, Thach H Chu, Margaret E Ackerman, Karl E Griswold
Gel microdroplet - fluorescence activated cell sorting (GMD-FACS) is an innovative high throughput screening platform for recombinant protein libraries, and we show here that GMD-FACS can overcome many of the limitations associated with conventional screening methods for antibody libraries. For example, phage and cell surface display benefit from exceptionally high throughput, but generally require high quality, soluble antigen target and necessitate the use of anchored antibody fragments. In contrast, the GMD-FACS assay can screen for soluble, secreted, full-length IgGs at rates of several thousand clones per second, and the technique enables direct screening against membrane protein targets in their native cellular context...
September 21, 2017: MAbs
https://www.readbyqxmd.com/read/28933584/circular-rna-hsa_circ_0001982-promotes-breast-cancer-cell-carcinogenesis-through-decreasing-mir-143
#14
Yi-Yin Tang, Ping Zhao, Tian-Ning Zou, Jia-Jun Duan, Rong Zhi, Si-Yuan Yang, De-Chun Yang, Xiao-Li Wang
Circular RNAs (circRNAs) are a type of noncoding RNAs generated from back-splicing, which have been verified to mediate multiple tumorigenesis. With the development of high-throughput sequencing, massive circRNAs are discovered in tumorous tissue. However, the potential physiological effect of circRNAs in breast cancer is still unknown. The purpose of this study is to investigate the expression profile of circRNA in breast cancer tissue and explore the in-depth regulatory mechanism in breast cancer tumorigenesis...
September 21, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/28932179/non-invasive-real-time-monitoring-of-yeast-volatilome-by-ptr-tof-ms
#15
Iuliia Khomenko, Irene Stefanini, Luca Cappellin, Valentina Cappelletti, Pietro Franceschi, Duccio Cavalieri, Tilmann D Märk, Franco Biasioli
INTRODUCTION: Producing a wide range of volatile secondary metabolites Saccharomyces cerevisiae influences wine, beer, and bread sensory quality and hence selection of strains based on their volatilome becomes pivotal. A rapid on-line method for volatilome assessing of strains growing on standard solid media is still missing. OBJECTIVES: Methodologically, the aim of this study was to demonstrate the automatic, real-time, direct, and non-invasive monitoring of yeast volatilome in order to rapidly produce a robust large data set encompassing measurements relative to many strains, replicates and time points...
2017: Metabolomics: Official Journal of the Metabolomic Society
https://www.readbyqxmd.com/read/28931934/identification-and-correction-of-spatial-bias-are-essential-for-obtaining-quality-data-in-high-throughput-screening-technologies
#16
Bogdan Mazoure, Robert Nadon, Vladimir Makarenkov
Spatial bias continues to be a major challenge in high-throughput screening technologies. Its successful detection and elimination are critical for identifying the most promising drug candidates. Here, we examine experimental small molecule assays from the popular ChemBank database and show that screening data are widely affected by both assay-specific and plate-specific spatial biases. Importantly, the bias affecting screening data can fit an additive or multiplicative model. We show that the use of appropriate statistical methods is essential for improving the quality of experimental screening data...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28931883/high-throughput-targeted-screening-in-triple-negative-breast-cancer-cells-identifies-wnt-inhibiting-activities-in-pacific-brittle-stars
#17
Artem Blagodatski, Vsevolod Cherepanov, Alexey Koval, Vladimir I Kharlamenko, Yuri S Khotimchenko, Vladimir L Katanaev
Pro-proliferative oncogenic signaling is one of the hallmarks of cancer. Specific targeting of such signaling pathways is one of the main approaches to modern anti-cancer drug discovery, as opposed to more traditional search for general cytotoxic agents. Natural products, especially from marine sources, represent a largely untapped source of chemical diversity, which so far have mostly been screened for cytotoxicity. Here we present a pioneering pipeline of high-throughput screening of marine-based activities targeted against the Wnt signaling pathway, which is one of the key factors in oncogenic transformation, growth and metastasis in different cancers, including the devastating triple-negative breast cancer (TNBC) currently lacking any targeted therapies...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28931839/multiwell-capillarity-based-microfluidic-device-for-the-study-of-3d-tumour-tissue-2d-endothelium-interactions-and-drug-screening-in-co-culture-models
#18
María Virumbrales-Muñoz, José María Ayuso, Marta Olave, Rosa Monge, Diego de Miguel, Luis Martínez-Lostao, Séverine Le Gac, Manuel Doblare, Ignacio Ochoa, Luis J Fernandez
The tumour microenvironment is very complex, and essential in tumour development and drug resistance. The endothelium is critical in the tumour microenvironment: it provides nutrients and oxygen to the tumour and is essential for systemic drug delivery. Therefore, we report a simple, user-friendly microfluidic device for co-culture of a 3D breast tumour model and a 2D endothelium model for cross-talk and drug delivery studies. First, we demonstrated the endothelium was functional, whereas the tumour model exhibited in vivo features, e...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28931623/small-molecule-screens-a-gateway-to-cancer-therapeutic-agents-with-case-studies-of-food-and-drug-administration-approved-drugs
#19
REVIEW
Nathan P Coussens, John C Braisted, Tyler Peryea, G Sitta Sittampalam, Anton Simeonov, Matthew D Hall
High-throughput screening (HTS) of small-molecule libraries accelerates the discovery of chemical leads to serve as starting points for probe or therapeutic development. With this approach, thousands of unique small molecules, representing a diverse chemical space, can be rapidly evaluated by biologically and physiologically relevant assays. The origins of numerous United States Food and Drug Administration-approved cancer drugs are linked to HTS, which emphasizes the value in this methodology. The National Institutes of Health Molecular Libraries Program made HTS accessible to the public sector, enabling the development of chemical probes and drug-repurposing initiatives...
October 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/28931578/lipid-topology-and-electrostatic-interactions-underpin-lytic-activity-of-linear-cationic-antimicrobial-peptides-in-membranes
#20
David J Paterson, Manlio Tassieri, Julien Reboud, Rab Wilson, Jonathan M Cooper
Linear cationic antimicrobial peptides are a diverse class of molecules that interact with a wide range of cell membranes. Many of these peptides disrupt cell integrity by forming membrane-spanning pores that ultimately lead to their death. Despite these peptides high potency and ability to evade acquired bacterial drug resistance, there is a lack of knowledge on their selectivity and activity mechanisms. Such an understanding would provide an informative framework for rational design and could lead to potential antimicrobial therapeutic targets...
September 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
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