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actionable mutation

Ana S C Valdeira, Daniel A Ritt, Deborah K Morrison, James B McMahon, Kirk R Gustafson, Jorge A R Salvador
In the present study, a series of novel madecassic acid derivatives was synthesized and screened against the National Cancer Institute's 60 human cancer cell line panel. Among them, compounds 5 , 12 , and 17 displayed potent and highly differential antiproliferative activity against 80% of the tumor cells harboring the B-RafV600E mutation within the nanomolar range. Structure-activity analysis revealed that a 5-membered A ring containing an α,β-unsaturated aldehyde substituted at C-23 with a 2-furoyl group seems to be crucial to produce this particular growth inhibition signature...
2018: Frontiers in Chemistry
Moses Koobotse, Jeff Holly, Claire Perks
Within populations carrying the same genetic predisposition, the penetrance of BRCA1 mutations has increased over time. Although linked to changes in lifestyle factors associated with energy metabolism, these observations cannot be explained by the established role of BRCA1 in DNA repair alone. We manipulated BRCA1 expression using tetracycline in the UBR60-bcl2 cell line (which has an inducible, tetracycline-regulated BRCA1 expression) and siRNA in oestrogen receptor(ER)-positive MCF7 and T47D breast cancer cells...
September 11, 2018: Oncotarget
Matthias Richard, Ana Victoria Gutiérrez, Albertus Viljoen, Daniela Rodriguez-Rincon, Françoise Roquet-Baneres, Mickael Blaise, Isobel Everall, Julian Parkhill, R Andres Floto, Laurent Kremer
New therapeutic approaches are needed against Mycobacterium abscessus , a respiratory mycobacterial pathogen that evades efforts to successfully treat infected patients. Clofazimine and bedaquiline, two drugs used for the treatment of multi-drug resistant tuberculosis, are being considered as alternatives for the treatment in lung diseases caused by M. abscessus With the aim to understand the mechanism of action of these agents in M. abscessus , we sought herein to determine the means by which M. abscessus can develop resistance...
October 15, 2018: Antimicrobial Agents and Chemotherapy
Matthew P McCusker, Daniela Alves Ferreira, Donal Cooney, Bruno Martins Alves, Seámus Fanning, Jean-Marie Pagès, Marta Martins, Anne Davin-Regli
PURPOSE: The main focus of this study was to evaluate the antimicrobial susceptibility profiles of a selected number of human clinical isolates of Enterobacter aerogenes and explore the effects of selected chemosensitisers on the reversal of the resistant phenotype of these isolates. METHODOLOGY: This study design was accomplished by: (i) characterising several multidrug resistant (MDR) E. aerogenes clinical isolates; (ii) evaluating the contribution of target gene mutations to the resistance phenotype focusing on fluoroquinolones and chloramphenicol only; (iii) evaluating the contribution of membrane permeability and efflux to the MDR phenotype; (iv) assessing the combined action of selected antimicrobials and chemosensitisers (to identify combinations with synergistic effects and able to reduce the MIC); (v) understand how these combinations can modulate the permeability or efflux on these isolates...
October 12, 2018: Journal of Global Antimicrobial Resistance
Danil Pupov, Ivan Petushkov, Daria Esyunina, Katsuhiko S Murakami, Andrey Kulbachinskiy
The σ factor drives promoter recognition by bacterial RNA polymerase (RNAP) and is also essential for later steps of transcription initiation, including RNA priming and promoter escape. Conserved region 3.2 of the primary σ factor ('σ finger') directly contacts the template DNA strand in the open promoter complex and facilitates initiating NTP binding in the active center of RNAP. Ribosomal RNA promoters are responsible for most RNA synthesis during exponential growth but should be silenced during the stationary phase to save cell resources...
October 13, 2018: Nucleic Acids Research
Agustin Lage, Teresa Romero
Cancer control is a wider concept than oncology, and includes comprehensive actions for prevention, early diagnosis, treatment, services organization, and education, aiming to modify hard indicators such as incidence, mortality rates, and survival at a population scale. Based on these concepts, organized national cancer programs appeared in several countries in the second half of the 20th century. But at the same time, scientific efforts began to modify the landscape of cancer control. Evidence of mortality reductions began to appear, cancer-driving mutations became measurable, many novel drugs were registered, the methodology of clinical trials spread through health systems, targeted drugs and immunotherapy entered into the mainstream of therapeutics, and treatment goals started to shift from cure to chronic control...
January 2018: Seminars in Oncology
Samantha N McNulty, Katherine Schwetye, Michael Goldstein, Jamal Carter, Robert E Schmidt, George Ansstas, Christina I Tsien, Albert H Kim, Sonika Dahiya
Meningiomas are among the most common tumors of the adult central nervous system (CNS). They are classified by the World Health Organization into three pathologic grades with increasing severity: grade I are benign with favorable treatment outcomes and low recurrence rates while grade III display malignant behavior and poor progression-free survival. Previous studies have shown that inactivation of NF-2 is the most common genetic event in high-grade meningioma; however, there is dearth of molecular data to distinguish grade II (AM-II) from the even more aggressive grade III (AM-III)...
October 11, 2018: Experimental and Molecular Pathology
Verena Schöning, Stephan Krähenbühl, Jürgen Drewe
Protein kinases (PKs) play a role in many pivotal aspects of cellular function. Dysregulation and mutations of protein kinases are involved in the development of different diseases, which might be treated by inhibition of the corresponding kinase. Protein kinase inhibitors (PKIs) are generally well tolerated, but unexpected and serious adverse events on the heart, lung, kidney and liver were observed clinically. In this study, the structure-activity relationship of PKIs in relation to hepatotoxicity was investigated...
October 10, 2018: Toxicology Letters
Aditya Iyer, Mireille M A E Claessens
Alpha synuclein (αS) is a ~14 kDa intrinsically disordered protein. Decades of research have increased our knowledge on αS yet its physiological function remains largely elusive. The conversion of monomeric αS into oligomers and amyloid fibrils is believed to play a central role of the pathology of Parkinson's disease (PD). It is becoming increasingly clear that the interactions of αS with cellular membranes are important for both αS's functional and pathogenic actions. Therefore, understanding interactions of αS with membranes seems critical to uncover functional or pathological mechanisms...
October 10, 2018: Biochimica et biophysica acta. Proteins and proteomics
Bogdan I Fedeles, John M Essigmann
In a multicellular organism, somatic mutations represent a permanent record of the past chemical and biochemical perturbations experienced by a cell in its local microenvironment. Akin to a perpetual recording device, with every replication, genomic DNA accumulates mutations in patterns that reflect: i) the sequence context-dependent formation of DNA damage, due to environmental or endogenous reactive species, including spontaneous processes; ii) the activity of DNA repair pathways, which, depending on the type of lesion, can erase, ignore or exacerbate the mutagenic consequences of that DNA damage; and iii) the choice of replication machinery that synthesizes the nascent genomic copy...
August 25, 2018: DNA Repair
Marian Vincenzi, Flavia Anna Mercurio, Marilisa Leone
BACKGROUND: The sterile alpha motif (Sam) domain is a small helical protein module able to undergo homo- and hetero-oligomerization as well as polymerization thus forming different types of protein architectures. A few Sam domains are involved in pathological processes and consequently, they represent valuable targets for the development of new potential therapeutic routes. This study intends to collect state-of-the-art knowledge on the different modes by which Sam domains can favor disease onset and progression...
October 9, 2018: Current Medicinal Chemistry
Kotaro Shide
One of the main molecular features of myeloproliferative neoplasms (MPNs) is the high frequency of JAK2V617F or CALRexon 9 mutations. The mouse models driven by these mutations suggest that they are the direct cause of MPNs and that the expression levels of mutated genes define the disease phenotype. The function of MPN-initiating cells was also elucidated using these mouse models. Furthermore, these mouse models play important roles as disease models to investigate the effects and mechanisms of action of therapeutic drugs such as JAK2 inhibitors and interferon α against MPNs...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Kasey Jividen, Katarzyna Z Kedzierska, Chun-Song Yang, Karol Szlachta, Aakrosh Ratan, Bryce M Paschal
BACKGROUND: The cellular effects of androgen are transduced through the androgen receptor, which controls the expression of genes that regulate biosynthetic processes, cell growth, and metabolism. Androgen signaling also impacts DNA damage signaling through mechanisms involving gene expression and transcription-associated DNA damaging events. Defining the contributions of androgen signaling to DNA repair is important for understanding androgen receptor function, and it also has translational implications...
October 10, 2018: BMC Cancer
Saad Alzahrani, Paul R Ebert
Phosphine is the only fumigant approved globally for general use to control insect pests in stored grain. Due to the emergence of resistance among insect pests and the lack of suitable alternative fumigants, we are investigating ways to synergistically enhance phosphine toxicity, by studying the mechanism of action of known synergists, such as oxygen, temperature, and arsenite. Under normoxia, exposure of the model organism C. elegans for 24 hours at 20 °C to 70 ppm phosphine resulted in 10% mortality, but nearly 100% mortality if the oxygen concentration was increased to 80%...
October 10, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Zuzana Kosutzka, Stephen Tisch, Cecilia Bonnet, Marta Ruiz, Elodie Hainque, Marie-Laure Welter, Francois Viallet, Carine Karachi, Soledad Navarro, Marjan Jahanshahi, Sophie Rivaud-Pechoux, David Grabli, Emmanuel Roze, Marie Vidailhet
BACKGROUND: Good short-term results of pallidal deep brain stimulation have been reported in myoclonus-dystonia. Efficacy and safety in the long term remain to be established. In addition, the actual impact of DBS treatment on social inclusion is unknown. The objective of this study was to assess the long-term clinical outcome, quality of life, and social adjustment of GPi-DBS in patients with ε-sarcoglycan (DYT11)-positive myoclonus-dystonia. METHODS: Consecutive myoclonus-dystonia patients with ε-sarcoglycan mutations who underwent GPi-DBS were evaluated at least 5 years postoperatively...
October 9, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Zahra Mortezaei, Jean-Baptiste Cazier, Ali Ashraf Mehrabi, Chao Cheng, Ali Masoudi-Nejad
Understanding the genetic causes of neurodegenerative disease (ND) can be useful for their prevention and treatment. Among the genetic variations responsible for ND, heritable germline variants have been discovered in genome-wide association studies (GWAS), and nonheritable somatic mutations have been discovered in sequencing projects. Distinguishing the important initiating genes in ND and comparing the importance of heritable and nonheritable genetic variants for treating ND are important challenges. In this study, we analysed GWAS results, somatic mutations and drug targets of ND from large databanks by performing directed network-based analysis considering a randomised network hypothesis testing procedure...
October 9, 2018: Journal of Cellular Biochemistry
Erik M Larsen, R Jeremy Johnson
The rise of antibiotic resistance necessitates the search for new platforms for drug development. Prodrugs are common tools for overcoming drawbacks typically associated with drug formulation and delivery, with ester prodrugs providing a classic strategy for masking polar alcohol and carboxylic acid functionalities and improving cell permeability. Ester prodrugs are normally designed to have simple ester groups, as they are expected to be cleaved and reactivated by a wide spectrum of cellular esterases. However, a number of pathogenic and commensal microbial esterases have been found to possess significant substrate specificity and can play an unexpected role in drug metabolism...
October 10, 2018: Drug Development Research
Giulio Riva, Christine Mian, Claudio Luchini, Ilaria Girolami, Claudio Ghimenton, Luca Cima, Luca Novelli, Esther Hanspeter, Guido Mazzoleni, Christine Schwienbacher, Stefan Pycha, Carolina D'Elia, Emanuela Trenti, Armin Pycha, Guido Martignoni, Ondrej Hes, Albino Eccher, Gabriella Nesi, Matteo Brunelli
Urachal carcinoma (UrC) is an exceedingly rare neoplasm that develops from the urachus, an embryologic remnant of the urogenital sinus and allantois. The most commonly encountered histologic subtype is adenocarcinoma. The aim of this study is to characterize a series of UrC by morphology, immunohistochemistry, and molecular analysis. We retrospectively investigated seven cases of UrCs and assessed patient symptoms, imaging, histologic features, immunohistochemical profile, molecular characteristics, pathologic stages, and type of treatment...
October 9, 2018: Virchows Archiv: An International Journal of Pathology
Hamid R Noori, Christian Mücksch, Valentina Vengeliene, Kai Schönig, Tatiane T Takahashi, Nuriya Mukhtasimova, Maryam Bagher Oskouei, Matias Mosqueira, Dusan Bartsch, Rainer Fink, Herbert M Urbassek, Rainer Spanagel, Steven M Sine
Alcohol consumption affects many organs and tissues, including skeletal muscle. However, the molecular mechanism of ethanol action on skeletal muscle remains unclear. Here, using molecular dynamics simulations and single channel recordings, we show that ethanol interacts with a negatively charged amino acid within an extracellular region of the neuromuscular nicotinic acetylcholine receptor (nAChR), thereby altering its global conformation and reducing the single channel current amplitude. Charge reversal of the negatively charged amino acid abolishes the nAChR-ethanol interaction...
2018: Communications biology
James M Bogenberger, Thomas T DeLeon, Mansi Arora, Daniel H Ahn, Mitesh J Borad
Biliary tracts cancers (BTCs) are a diverse group of aggressive malignancies with an overall poor prognosis. Genomic characterization has uncovered many putative clinically actionable aberrations that can also facilitate the prognostication of patients. As such, comprehensive genomic profiling is playing a growing role in the clinical management of BTCs. Currently however, there is only one precision medicine approved by the US Food and Drug Administration (FDA) for the treatment of BTCs. Herein, we highlight the prevalence and prognostic, diagnostic, and predictive significance of recurrent mutations and other genomic aberrations with current clinical implications or emerging relevance to clinical practice...
2018: NPJ precision oncology
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