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actionable mutation

Kate Baker, Sarah L Gordon, Holly Melland, Fabian Bumbak, Daniel J Scott, Tess J Jiang, David Owen, Bradley J Turner, Stewart G Boyd, Mari Rossi, Mohammed Al-Raqad, Orly Elpeleg, Dawn Peck, Grazia M S Mancini, Martina Wilke, Marcella Zollino, Giuseppe Marangi, Heike Weigand, Ingo Borggraefe, Tobias Haack, Zornitza Stark, Simon Sadedin, Tiong Yang Tan, Yunyun Jiang, Richard A Gibbs, Sara Ellingwood, Michelle Amaral, Whitley Kelley, Manju A Kurian, Michael A Cousin, F Lucy Raymond
Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound...
August 13, 2018: Brain: a Journal of Neurology
Emily Langron, Stella Prins, Paola Vergani
BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a debilitating hereditary disease caused by mutations in the CFTR gene, which encodes an anion channel. WT-CFTR gating is a non-equilibrium process. After ATP binding, CFTR enters a stable open state (O1 ). ATP hydrolysis leads it to a short-lived post-hydrolytic open state (O2 ), from which channels close. Here we use mutations to probe the mechanism of VX-770, the first compound directly targeting the CFTR protein approved for treatment of CF...
August 14, 2018: British Journal of Pharmacology
Kevin M Sullivan, Heidi L Kenerson, Venu G Pillarisetty, Kimberly J Riehle, Raymond S Yeung
With the widespread adoption of molecular profiling in clinical oncology practice, many physicians are faced with making therapeutic decisions based upon isolated genomic alterations. For example, epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are effective in EGFR-mutant non-small cell lung cancers (NSCLC) while anti-EGFR monoclonal antibodies are ineffective in Ras-mutant colorectal cancers. The matching of mutations with drugs aimed at their respective gene products represents the current state of "precision" oncology...
July 2018: Annals of Translational Medicine
Paola Pontieri, Hans Hartings, Marco Di Salvo, Domenica R Massardo, Mario De Stefano, Graziano Pizzolante, Roberta Romano, Jacopo Troisi, Angelica Del Giudice, Pietro Alifano, Luigi Del Giudice
A considerable body of evidence links together mitochondrial dysfunctions, toxic action of metalloid oxyanions, and system and neurodegenerative disorders. In this study we have used the model yeast Saccharomyces cerevisiae to investigate the genetic determinants associated with tellurite resistance/sensitivity. Nitrosoguanidine-induced K2 TeO3 -resistant mutants were isolated, and one of these mutants, named Sc57-Te5 R , was characterized. Both random spore analysis and tetrad analysis and growth of heterozygous (TeS /Te5 R ) diploid from Sc57-Te5 R mutant revealed that nuclear and recessive mutation(s) was responsible for the resistance...
August 13, 2018: Scientific Reports
Robert L Anderson, Darshan V Trivedi, Saswata S Sarkar, Marcus Henze, Weikang Ma, Henry Gong, Christopher S Rogers, Joshua M Gorham, Fiona L Wong, Makenna M Morck, Jonathan G Seidman, Kathleen M Ruppel, Thomas C Irving, Roger Cooke, Eric M Green, James A Spudich
Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin...
August 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Morgana Favero, Nathaniel P Sotuyo, Emily Lopez, Jennifer A Kearney, Ethan M Goldberg
Dravet syndrome is a severe childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene SCN1A , which encodes the type 1 neuronal voltage gated sodium (Na+ ) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome ( Scn1a +/- mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cells (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1...
August 13, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Mirco Friedrich, Lukas Bunse, Wolfgang Wick, Michael Platten
PURPOSE OF REVIEW: The present review introduces recent progress in eliciting the role of mutant isocitrate dehydrogenase (IDH) in gliomas, especially regarding its mode of action as a modulator of antitumor immune response, and provides rationales for targeting mutant IDH in glioma immunotherapy. Both the development of small molecule inhibitors repressing the enzymatic activity of mutant IDH and novel, mechanism-led combination immunotherapies are discussed. RECENT FINDINGS: Since the discovery of highly frequent IDH mutations in low-grade gliomas and nonsolid malignancies, its tumor cell-intrinsic effects have been intensively investigated...
August 9, 2018: Current Opinion in Oncology
Erica L Rosenthal, Sandra de Castro Buffington, Galen Cole
Background: The topic of breast cancer genetics entered the public discourse following Angelina Jolie's 2013 announcement that she carries the BRCA1 mutation and underwent a prophylactic double mastectomy to reduce her breast cancer risk. A year prior to Jolie's announcement, the teen drama 90210 ran an eight-episode story arc on the BRCA gene mutations. This study focuses on an evaluation of the impact of this particular media text within the broader context of research on the persuasive effects of entertainment narratives (i...
2018: Journal of Communication in Healthcare
Martina Kaniakova, Lenka Kleteckova, Katarina Lichnerova, Kristina Holubova, Kristyna Skrenkova, Miloslav Korinek, Jan Krusek, Tereza Smejkalova, Jan Korabecny, Karel Vales, Ondrej Soukup, Martin Horak
N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory neurotransmission in the mammalian central nervous system (CNS), and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials (including memantine) and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine (tacrine; THA) was the first approved drug for Alzheimer's disease (AD) treatment...
August 9, 2018: Neuropharmacology
Michal Kostas, Agata Lampart, Joanna Bober, Antoni Wiedlocha, Justyna Tomala, Daniel Krowarsch, Jacek Otlewski, Malgorzata Zakrzewska
FGF1 and FGF2 bind to specific cell-surface tyrosine kinase receptors (FGFRs) and activate intracellular signaling that leads to proliferation, migration or differentiation of many cell types. Besides this classical mode of action, under stress conditions FGF1 and FGF2 are translocated in a receptor dependent-manner via the endosomal membrane into the cytosol and nucleus of the cell. However, despite many years of research, the role of translocated FGF1 and FGF2 inside the cell remains unclear. Here, we reveal an anti-apoptotic activity of intracellular FGF1 and FGF2, which is independent of FGFR activation and downstream signaling...
August 9, 2018: Journal of Molecular Biology
Xiujuan Zhang, Xiaohui Ding, Yuanmei Zhu, Huihui Chong, Sheng Cui, Jinsheng He, Xinquan Wang, Yuxian He
OBJECTIVE: The peptide drug T20 (enfuvirtide), derived from the C-terminal heptad repeat region of HIV-1 gp41, is the only membrane fusion inhibitor available for treatment of viral infection; however, its mechanism of action remains elusive and its structural basis is lacking. DESIGN: We focused on determining the crystal structure of T20 in complex with N39, a target mimic peptide derived from the N-terminal heptad repeat region of gp41. Based on the structural information, the mechanisms of action of T20 and its resistance were further characterized...
August 8, 2018: AIDS
Albert Wiegman
PURPOSE OF REVIEW: To create awareness for the devastating influence of high cholesterol in familial hypercholesterolaemia (FH) on vessel walls. Persons with high LDL-C and a known mutation associated with FH have a 22-fold increase in CVD compared with those with a normal LDL-C and no genetic mutation. If the awareness of the need to diagnose and treat this genetic disorder at an early stage increases, great atherosclerotic impact later in life could be avoided. Every minute a child with heterozygous FH is born somewhere in the world and every day a child with homozygous FH is born...
August 9, 2018: Current Cardiology Reports
Xuejie Chen, Da-Yun Jin, Darrel W Stafford, Jian-Ke Tie
Warfarin, acenocoumarol, phenprocoumon, and fluindione are commonly prescribed oral anticoagulants for the prevention and treatment of thromboembolic disorders. These anticoagulants function by impairing the biosynthesis of active vitamin K-dependent coagulation factors through the inhibition of vitamin K epoxide reductase (VKOR). Genetic variations in VKOR have been closely associated with the resistant phenotype of oral anticoagulation therapy. However, the relative efficacy of these anticoagulants, their mechanisms of action, and their resistance variations among naturally occurring VKOR mutations remain elusive...
August 8, 2018: Blood
Rebecca L Cunningham, Amy L Herbert, Breanne L Harty, Sarah D Ackerman, Kelly R Monk
BACKGROUND: In the peripheral nervous system (PNS), specialized glial cells called Schwann cells produce myelin, a lipid-rich insulating sheath that surrounds axons and promotes rapid action potential propagation. During development, Schwann cells must undergo extensive cytoskeletal rearrangements in order to become mature, myelinating Schwann cells. The intracellular mechanisms that drive Schwann cell development, myelination, and accompanying cell shape changes are poorly understood...
August 8, 2018: Neural Development
Claes Søndergaard Wassmann, Lars Christian Lund, Mette Thorsing, Sabrina Prehn Lauritzen, Hans Jørn Kolmos, Birgitte Haahr Kallipolitis, Janne Kudsk Klitgaard
Staphylococcus aureus has developed resistance towards the most commonly used anti-staphylococcal antibiotics. Therefore, there is an urgent need to find new treatment opportunities. A new approach relies on the use of helper compounds, which are able to potentiate the effect of antibiotics. A well-studied helper compound is thioridazine, which potentiates the effect of the β-lactam antibiotic dicloxacillin against Methicillin-resistant Staphylococcus aureus (MRSA). In order to identify thioridazine's mechanism of action and how it potentiates the effect of dicloxacillin, we generated thioridazine resistant strains of MRSA USA300 by serial passage experiments...
2018: PloS One
Oz Mordechai, Myriam Weyl-Ben-Arush
OBJECTIVE: To date, the understanding of pediatric tumor genomics and how these genetic aberrations correlate with clinical outcome is lacking. Here, we report our experience with the next-generation sequencing (NGS) test program and discuss implications for the inclusion of molecular profiling into clinical pediatric oncology trials. We also aimed to explore studies on NGS in pediatric cancers and to quantify the variability of finding actionable mutations and the clinical implications...
July 30, 2018: Rambam Maimonides Medical Journal
Amanda I McColl, Mark R Bleackley, Marilyn A Anderson, Rohan G T Lowe
Over the last few decades, the emergence of resistance to commonly used antifungal molecules has become a major barrier to effective treatment of recurrent life-threatening fungal diseases. Resistance combined with the increased incidence of fungal diseases has created the need for new antifungals, such as the plant defensin NaD1, with different mechanisms of action to broaden treatment options. Antimicrobial peptides produced in plants and animals are promising new molecules in the arsenal of antifungal agents because they have different mechanisms of action to current antifungals and are often targeted specifically to fungal pathogens (van der Weerden et al...
2018: Frontiers in Microbiology
Lisa De Lorenzi, Silvana Arrighi, Debora Groppetti, Stefania Bonacina, Pietro Parma
In mammals, the regression of the müllerian ducts is regulated by the action of the AMH hormone which is produced by testes during embryonic development. The action of this hormone is mediated by the only known receptor AMHR2. Mutations occurring in the AHM hormone and/or in the AMHR2 receptor gene cause the lack of regression of müllerian ducts, which may therefore persist even in male embryos carrying a XY chromosomal arrangement. This is known as the persistent müllerian duct syndrome (PMDS). A female German Shepherd dog was referred to the veterinary clinic because of urinary incontinence...
August 8, 2018: Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation
Tsukasa Kanetake, Takayuki Sassa, Koki Nojiri, Megumi Sawai, Satoko Hattori, Tsuyoshi Miyakawa, Takuya Kitamura, Akio Kihara
Insulation by myelin lipids is essential to fast action potential conductivity: changes in their quality or amount can cause several neurologic disorders. Sjögren-Larsson syndrome (SLS) is one such disorder, which is caused by mutations in the fatty aldehyde dehydrogenase ALDH3A2. To date, the molecular mechanism underlying SLS pathology has remained unknown. In this study, we found that Aldh3a2 is expressed in oligodendrocytes and neurons in the mouse brain, and neurons of Aldh3a2 knockout (KO) mice exhibited impaired metabolism of the long-chain base, a component of sphingolipids...
August 7, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Alessia Finotti, Matteo Allegretti, Jessica Gasparello, Patrizio Giacomini, Demetrios A Spandidos, Giuseppe Spoto, Roberto Gambari
In oncology, liquid biopsy is used in the detection of next-generation analytes, such as tumor cells, cell-free nucleic acids and exosomes in peripheral blood and other body fluids from cancer patients. It is considered one of the most advanced non-invasive diagnostic systems to enable clinically relevant actions and implement precision medicine. Medical actions include, but are not limited to, early diagnosis, staging, prognosis, anticipation (lead time) and the prediction of therapy responses, as well as follow-up...
October 2018: International Journal of Oncology
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