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Target tractability

Timothy Chao, Emma E Furth, Robert H Vonderheide
Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas...
October 13, 2016: Cancer Immunology Research
Henrike Knacke, Maik Pietzner, Kieu Trinh Do, Werner Römisch-Margl, Gabi Kastenmüller, Uwe Völker, Henry Völzke, Jan Krumsiek, Anna Artati, Henri Wallaschofski, Matthias Nauck, Karsten Suhre, Jerzy Adamski, Nele Friedrich
OBJECTIVE: Insulin-like Growth Factor (IGF-I) is known for its various physiological and severe pathophysiological effects on human metabolism, however underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time we associated serum IGF-I levels with multi-fluid untargeted metabolomics data. METHODS: Plasma/urine samples of 995 non-diabetic participants of the Study of Health in Pomerania (SHIP-TREND) were characterized by mass spectrometry...
October 6, 2016: Journal of Clinical Endocrinology and Metabolism
S M Dieter, C Heining, A Agaimy, D Huebschmann, D Bonekamp, B Hutter, K R Ehrenberg, M Fröhlich, M Schlesner, C Scholl, H-P Schlemmer, S Wolf, A Mavratzas, C S Jung, S Gröschel, C V Kalle, R Eils, B Brors, R Penzel, M Kriegsmann, D E Reuss, P Schirmacher, A Stenzinger, P A Federspil, W Weichert, H Glimm, S Fröhling
BACKGROUND: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Zhilan Feng, Andrew N Hill, Aaron T Curns, John W Glasser
Among the several means by which heterogeneity can be modeled, Levins' (1969) meta-population approach preserves the most analytical tractability, a virtue to the extent that generality is desirable. When model populations are stratified, contacts among their respective sub-populations must be described. Using a simple meta-population model, Feng et al. (2015) showed that mixing among sub-populations, as well as heterogeneity in characteristics affecting sub-population reproduction numbers, must be considered when evaluating public health interventions to prevent or control infectious disease outbreaks...
September 23, 2016: Mathematical Biosciences
Esben G Poulsen, Sofie V Nielsen, Elin J Pietras, Jens V Johansen, Cornelia Steinhauer, Rasmus Hartmann-Petersen
The ubiquitin-proteasome system is the major pathway for intracellular protein degradation in eukaryotic cells. Due to the large number of genes dedicated to the ubiquitin-proteasome system, mapping degradation pathways for short lived proteins is a daunting task, in particular in mammalian cells that are not genetically tractable as, for instance, a yeast model system. Here, we describe a method relying on high-throughput cellular imaging of cells transfected with a targeted siRNA library to screen for components involved in degradation of a protein of interest...
2016: Methods in Molecular Biology
Simon J Bulley, Alaa Droubi, Jonathan H Clarke, Karen E Anderson, Len R Stephens, Phillip T Hawkins, Robin F Irvine
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic lipid kinases with physiological functions that are incompletely understood, not the least because genetic deletion and cell transfection have led to contradictory data. Here, we used the genetic tractability of DT40 cells to create cell lines in which endogenous PI5P4Kα was removed, either stably by genetic deletion or transiently (within 1 h) by tagging the endogenous protein genomically with the auxin degron. In both cases, removal impacted Akt phosphorylation, and by leaving one PI5P4Kα allele present but mutating it to be kinase-dead or have PI4P 5-kinase activity, we show that all of the effects on Akt phosphorylation were dependent on the ability of PI5P4Kα to synthesize phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] rather than to remove PI5P...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Robin M Hallett, Alex B K Seong, David R Kaplan, Meredith S Irwin
BACKGROUND: In the pediatric cancer neuroblastoma (NB), patients are stratified into low, intermediate or high-risk subsets based in part on MYCN amplification status. While MYCN amplification in general predicts unfavorable outcome, no clinical or genomic factors have been identified that predict outcome within these cohorts of high-risk patients. In particular, it is currently not possible at diagnosis to determine which high-risk neuroblastoma patients will ultimately fail upfront therapy...
November 2016: Molecular Oncology
Donal M O'Sullivan, Deepti Angra
Vicia faba L, is a globally important grain legume whose main centers of diversity are the Fertile Crescent and Mediterranean basin. Because of its small number (six) of exceptionally large and easily observed chromosomes it became a model species for plant cytogenetics the 70s and 80s. It is somewhat ironic therefore, that the emergence of more genomically tractable model plant species such as Arabidopsis and Medicago coincided with a marked decline in genome research on the formerly favored plant cytogenetic model...
2016: Frontiers in Genetics
E A Ross, A J Naylor, J D O'Neil, T Crowley, M L Ridley, J Crowe, T Smallie, T J Tang, J D Turner, L V Norling, S Dominguez, H Perlman, N M Verrills, G Kollias, M P Vitek, A Filer, C D Buckley, J L Dean, A R Clark
OBJECTIVES: Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP...
September 5, 2016: Annals of the Rheumatic Diseases
Hongxing He, Hengrui Fang, Mitchell D Miller, George N Phillips, Wu Pei Su
An iterative transform method proposed previously for direct phasing of high-solvent-content protein crystals is employed for enhancing the molecular-replacement (MR) algorithm in protein crystallography. Target structures that are resistant to conventional MR due to insufficient similarity between the template and target structures might be tractable with this modified phasing method. Trial calculations involving three different structures are described to test and illustrate the methodology. The relationship of the approach to PHENIX Phaser-MR and MR-Rosetta is discussed...
September 1, 2016: Acta Crystallographica. Section A, Foundations and Advances
Joseph G Jardine, Devin Sok, Jean-Philippe Julien, Bryan Briney, Anita Sarkar, Chi-Hui Liang, Erin A Scherer, Carole J Henry Dunand, Yumiko Adachi, Devan Diwanji, Jessica Hsueh, Meaghan Jones, Oleksandr Kalyuzhniy, Michael Kubitz, Skye Spencer, Matthias Pauthner, Karen L Saye-Francisco, Fabian Sesterhenn, Patrick C Wilson, Denise M Galloway, Robyn L Stanfield, Ian A Wilson, Dennis R Burton, William R Schief
An optimal HIV vaccine should induce broadly neutralizing antibodies (bnAbs) that neutralize diverse viral strains and subtypes. However, potent bnAbs develop in only a small fraction of HIV-infected individuals, all contain rare features such as extensive mutation, insertions, deletions, and/or long complementarity-determining regions, and some are polyreactive, casting doubt on whether bnAbs to HIV can be reliably induced by vaccination. We engineered two potent VRC01-class bnAbs that minimized rare features...
August 2016: PLoS Pathogens
Muhammad Baghdadi, Haruka Wada, Sayaka Nakanishi, Hirotake Abe, Nanumi Han, Wira Eka Putra, Daisuke Endo, Hidemichi Watari, Noriaki Sakuragi, Yasuhiro Hida, Kichizo Kaga, Yohei Miyagi, Tomoyuki Yokose, Atsushi Takano, Yataro Daigo, Ken-Ichiro Seino
The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling...
October 15, 2016: Cancer Research
Katherine Martin, James Pritchett, Jessica Llewellyn, Aoibheann F Mullan, Varinder S Athwal, Ross Dobie, Emma Harvey, Leo Zeef, Stuart Farrow, Charles Streuli, Neil C Henderson, Scott L Friedman, Neil A Hanley, Karen Piper Hanley
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts...
2016: Nature Communications
Phani Ghanakota, Heather Ann Carlson
Identifying binding hotspots on protein surfaces is of prime interest in structure-based drug discovery, either to assess the tractability of pursuing a protein target or to drive improved potency of lead compounds. Computational approaches to detect such regions have traditionally relied on energy minimization of probe molecules onto static protein conformations in the absence of the natural water environment. Advances in high performance computing now allow us to assess hotspots using molecular dynamics (MD) simulations...
August 3, 2016: Journal of Medicinal Chemistry
Jennifer Hanisak, W Michael Seganish, William T McElroy, Haiquin Tang, Rui Zhang, Hon-Chung Tsui, Theirry Fischmann, Deen Tulshian, James Tata, Christopher Sondey, Kristine Devito, James Fossetta, Charles G Garlisi, Daniel Lundell, Xiaoda Niu
IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR...
September 1, 2016: Bioorganic & Medicinal Chemistry Letters
Barbara A Fox, Kiah L Sanders, Leah M Rommereim, Rebekah B Guevara, David J Bzik
Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells...
July 2016: PLoS Genetics
J Ablain, L I Zon
The zebrafish has been a powerful model in forward genetic screens to identify genes essential for organogenesis and embryonic development. Conversely, using reverse genetics to investigate specific gene function requires phenotypic analysis of complete gene inactivation. Despite the availability and efficacy of morpholinos, the lack of tractable and efficient knockout technologies has impeded reverse genetic studies in the zebrafish, particularly in adult animals. The recent development of genome-editing technologies such as CRISPR/Cas9 greatly widened the scope of loss-of-function studies in the zebrafish, allowing for the rapid phenotypic assessment of gene silencing in embryos, the generation of knockout lines, and large-scale reverse genetic screens...
2016: Methods in Cell Biology
David Rodríguez, Saibal Chakraborty, Eugene Warnick, Steven Crane, Zhan-Guo Gao, Robert O'Connor, Kenneth A Jacobson, Jens Carlsson
Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis...
October 21, 2016: ACS Chemical Biology
John Ferguson, Alberto Alvarez-Iglesias, John Newell, John Hinde, Martin O'Donnell
Chronic diseases tend to depend on a large number of risk factors, both environmental and genetic. Average attributable fractions were introduced by Eide and Gefeller as a way of partitioning overall disease burden into contributions from individual risk factors; this may be useful in deciding which risk factors to target in disease interventions. Here, we introduce new estimation methods for average attributable fractions that are appropriate for both case-control designs and prospective studies. Confidence intervals, derived using Monte Carlo simulation, are also described...
June 24, 2016: Statistical Methods in Medical Research
Quan Zeng, Zhihai Wang, Chuan Liu, Zhitao Gong, Li Yang, Liang Jiang, Zuxia Ma, Yi Qian, Yucheng Yang, Houyong Kang, Suling Hong, Youquan Bu, Guohua Hu
Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer that is prevalent among people of southern Chinese ancestry in southern China and Southeast Asia. Radiotherapy and cisplatin (CDDP)-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to CDDP and radiotherapy. NFBD1 functions in cell cycle checkpoint activation and DNA repair following DNA damage. In this study, we identified the NFBD1 as a tractable molecular target to chemosensitize NPC cells...
July 2016: Molecular and Cellular Biochemistry
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