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Ester Fernandez-Salas, Shaomeng Wang, Arul M Chinnaiyan
Castration resistant prostate cancer (CRPC) is a deadly disease with few therapeutic options once patients become resistant to second generation drugs targeting the AR-transcriptional program. The BET-BRD readers of chromatin are key regulators of AR-, ERG-, and c-Myc-mediated transcription in CRPC. BET-BRD inhibitors have demonstrated pre-clinical efficacy in models of CRPC and are currently being evaluated in several clinical trials. These novel drugs have the potential to transform the way we treat CRPC in the near future...
March 2016: Drug Discovery Today. Technologies
Aaron J Stonestrom, Sarah C Hsu, Michael T Werner, Gerd A Blobel
Pharmacologic inhibitors of the bromodomain and extra-terminal motif (BET) protein family are in clinical trials for the treatment of hematologic malignancies, yet the functions of individual BET proteins remain largely uncharacterized. We review the molecular roles of BETs in the context of erythropoiesis. Studies in this lineage have provided valuable insights into their mechanisms of action, and helped define the individual and overlapping functions of BET protein family members BRD2, BRD3, and BRD4. These studies have important ramifications for our understanding of the molecular and physiologic roles of BET proteins, and provide a framework for elucidating some of the beneficial and adverse effects of pharmacologic inhibitors...
March 2016: Drug Discovery Today. Technologies
Sarah Picaud, Katharina Leonards, Jean-Philippe Lambert, Oliver Dovey, Christopher Wells, Oleg Fedorov, Octovia Monteiro, Takao Fujisawa, Chen-Yi Wang, Hannah Lingard, Cynthia Tallant, Nikzad Nikbin, Lucie Guetzoyan, Richard Ingham, Steven V Ley, Paul Brennan, Susanne Muller, Anastasia Samsonova, Anne-Claude Gingras, Juerg Schwaller, George Vassiliou, Stefan Knapp, Panagis Filippakopoulos
Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function...
October 2016: Science Advances
G M Murray, J P Cassidy, T A Clegg, J A Tratalos, J McClure, R G O'Neill, D J Sammin, M J Casey, M McElroy, B Earley, N Bourke, S J More
Bovine respiratory disease (BRD) is a multifactorial disease and the primary cause of both bovine morbidity and mortality in Ireland. The risk factors associated with a primary necropsy diagnosis of BRD among cattle in the traditional (non-feedlot) husbandry systems prevalent in Ireland have not been investigated previously. The aim of this case-control study was to investigate those risk factors among cattle of all ages over an 8 year period. A total of 3,090 BRD cases and 5,236 controls were matched by submitting veterinary practitioner...
September 15, 2016: Preventive Veterinary Medicine
R Callaby, P Toye, A Jennings, S M Thumbi, J A W Coetzer, I C Conradie Van Wyk, O Hanotte, M N Mbole-Kariuki, B M de C Bronsvoort, L E B Kruuk, M E J Woolhouse, H Kiara
Most studies of infectious diseases in East African cattle have concentrated on gastro-intestinal parasites and vector-borne diseases. As a result, relatively little is known about viral diseases, except for those that are clinically symptomatic or which affect international trade such as foot and mouth disease, bluetongue and epizootic haemorrhagic disease. Here, we investigate the seroprevalence, distribution and relationship between the viruses involved in respiratory disease, infectious bovine rhinotracheitis virus (IBR), bovine parainfluenza virus Type 3 (PIV3) and bovine viral diarrhoea virus (BVDV) in East African Shorthorn Zebu calves...
October 2016: Research in Veterinary Science
Weihong Niu, Xinye Wang, Yao Zhou, Xiayu Li, Guiyuan Li, Ming Zhou
OBJECTIVE: To construct a eukaryotic expression vector of bromodomain-containing protein 7 (BRD7) with deletion of bromodomain (BRD7△brd) using the homologous recombination and reverse PCR amplification techniques. METHODS: The linear DNA fragments of bromodomain-deleted mutation of BRD7 (pIRES2-EGFP- 3Flag/BRD7△brd) were amplified by one pair of reverse PCR primers using high-fidelity enzyme, and then these fragments were transformed into E.coli to obtain the eukaryotic expression vector expressing BRD7△brd protein based on homologous recombination and plasmid cyclization...
September 28, 2016: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
Fade Gong, Li-Ya Chiu, Kyle M Miller
Chromatin-based DNA damage response (DDR) pathways are fundamental for preventing genome and epigenome instability, which are prevalent in cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the addition and removal of acetyl groups on lysine residues, a post-translational modification important for the DDR. Acetylation can alter chromatin structure as well as function by providing binding signals for reader proteins containing acetyl-lysine recognition domains, including the bromodomain (BRD)...
September 2016: PLoS Genetics
Aki Yamada, Kazue Honma, Kazuki Mochizuki, Toshinao Goda
OBJECTIVE: Fructose intake induces hepatic steatosis by activating fat synthesis. In this study, we searched for genes that showed acute induction in the livers of mice force-fed with fructose, and examined how this induction is regulated. MATERIALS/METHODS: We identified genes induced at 6h after the fructose force-feeding using a microarray and quantitative real-time RT-PCR. Histone acetylation and an acetylated histone binding protein bromodomain containing (BRD)4 binding around the fructose-inducible genes were examined using a chromatin immunoprecipitation assay...
October 2016: Metabolism: Clinical and Experimental
Vassilios Myrianthopoulos, Nicolas Gaboriaud-Kolar, Cynthia Tallant, Michelle-Lynn Hall, Stylianos Grigoriou, Peter Moore Brownlee, Oleg Fedorov, Catherine Rogers, David Heidenreich, Marek Wanior, Nikolaos Drosos, Nikitia Mexia, Pavel Savitsky, Tina Bagratuni, Efstathios Kastritis, Evangelos Terpos, Panagis Filippakopoulos, Susanne Müller, Alexios-Leandros Skaltsounis, Jessica Ann Downs, Stefan Knapp, Emmanuel Mikros
Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry...
October 13, 2016: Journal of Medicinal Chemistry
S A Finan, E L Lamkin, A O McKinnon
OBJECTIVE: To investigate the comparative efficacy of BioRelease Deslorelin® (BRD) and Ovuplant® for induction of ovulation in cyclic mares in Australia. METHODS: Ovarian follicular activity of 60 mares for a total of 95 cycles was monitored by ultrasonography until they developed a follicle ≥30 mm and a uterine oedema pattern of 3. Mares were then randomly allocated to one of three treatment groups: (1) treatment with 1.25 mg BRD, (2) a single Ovuplant pellet or (3) 1 mL compound sodium lactate control...
September 2016: Australian Veterinary Journal
Anssi Lipponen, Jussi Paananen, Noora Puhakka, Asla Pitkänen
We aimed to define the chronically altered gene expression signature of traumatic brain injury (TBI-sig) to discover novel treatments to reverse pathologic gene expression or reinforce the expression of recovery-related genes. Genome-wide RNA-sequencing was performed at 3 months post-TBI induced by lateral fluid-percussion injury in rats. We found 4964 regulated genes in the perilesional cortex and 1966 in the thalamus (FDR < 0.05). TBI-sig was used for a LINCS analysis which identified 11 compounds that showed a strong connectivity with the TBI-sig in neuronal cell lines...
2016: Scientific Reports
Keith D DeDonder, Dayna M Harhay, Michael D Apley, Brian V Lubbers, Michael L Clawson, Gennie Schuller, Gregory P Harhay, Brad J White, Robert L Larson, Sarah F Capik, Jim E Riviere, Ted Kalbfleisch, Ronald K Tessman
The objectives of this study were; first, to describe gamithromycin susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni isolated from cattle diagnosed with bovine respiratory disease (BRD) and previously treated with either gamithromycin for control of BRD (mass medication=MM) or sham-saline injected (control=CON); second, to describe the macrolide resistance genes present in genetically typed M. haemolytica isolates; third, use whole-genome sequencing (WGS) to correlate the phenotypic resistance and genetic determinants for resistance among M...
August 30, 2016: Veterinary Microbiology
Zahra Jalali Sefid Dashti, Junaid Gamieldien, Alan Christoffels
BACKGROUND: Iron metabolism and regulation is an indispensable part of species survival, most importantly for blood feeding insects. Iron regulatory proteins are central regulators of iron homeostasis, whose binding to iron response element (IRE) stem-loop structures within the UTRs of genes regulate expression at the post-transcriptional level. Despite the extensive literature on the mechanism of iron regulation in human, less attention has been given to insect and more specifically the blood feeding insects, where research has mainly focused on the characterization of ferritin and transferrin...
2016: BMC Genomics
Junfeng Chen, Chingyuan Yang, Polyana C Tizioto, Huan Huang, Mi O K Lee, Harold R Payne, Sara D Lawhon, Friedhelm Schroeder, Jeremy F Taylor, James E Womack
Unlike the genomes of many mammals that have a single NK-lysin gene, the cattle genome contains a family of four genes, one of which is expressed preferentially in the lung. In this study, we compared the expression of the four bovine NK-lysin genes in healthy animals to animals challenged with pathogens known to be associated with bovine respiratory disease (BRD) using transcriptome sequencing (RNA-seq). The expression of several NK-lysins, especially NK2C, was elevated in challenged relative to control animals...
2016: PloS One
Caroline Berenguer-Daizé, Lucile Astorgues-Xerri, Elodie Odore, Mylène Cayol, Esteban Cvitkovic, Kay Noel, Mohamed Bekradda, Sarah MacKenzie, Keyvan Rezai, François Lokiec, Maria E Riveiro, L'Houcine Ouafik
Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines...
November 1, 2016: International Journal of Cancer. Journal International du Cancer
C Ren, L Zeng, M-M Zhou
The bromodomain (BrD) represents an evolutionarily conserved protein domain whose function mostly is to recognize acetylated lysine residues in histones and nuclear proteins in regulation of gene transcription in chromatin. The highly conserved BrD structure features an unusual left-handed, antiparallel four-helix bundle and a hydrophobic pocket between the interhelical ZA and BC loops important for acetyl-lysine binding. Many proteins, particularly transcriptional activators, contain BrDs, and mutation or deletion of the BrDs impairs the protein function, implying their critical role in human biology and disease...
2016: Methods in Enzymology
Fabian Thieltges, Zengping Liu, Ralf Brinken, Norbert Braun, Warapat Wongsawad, Sudawadee Somboonthanakij, Martina Herwig, Frank G Holz, Boris V Stanzel
PURPOSE: We developed a surgical method for localized and atraumatic removal of the retinal pigment epithelium (RPE) with a novel instrument. METHODS: Bleb retinal detachments (bRD) were raised with balanced salt solution (BSS) following vitrectomy in 27 rabbits. The RPE was scraped with 3 loop variants (polypropylene [PP], 0.1 mm; PP, 0.06 mm; metal, 0.1 mm) of a custom-made instrument. Stabilization of bRDs with BSS or various concentrations (0.1%-0.5%) of hyaluronic acid (HA) was video analyzed...
June 2016: Translational Vision Science & Technology
A Abdallah, J Hewson, D Francoz, H Selim, S Buczinski
BACKGROUND: Bovine respiratory disease (BRD) is a worldwide animal health concern especially in feedlot, dairy, and veal calves. One of the greatest challenges is the absence of a gold standard for achieving an accurate antemortem diagnosis. Various blood markers, including the acute-phase proteins (AAP), have been proposed as potential valuable tools for BRD diagnosis. OBJECTIVES: To perform a systematic review of the literature to assess the accuracy of selected APP (haptoglobin [Hp], serum amyloid A [SAA], and fibrinogen [Fb]) as diagnostic tools for cattle with naturally occurring BRD when compared with clinical reference standards of diagnosis...
July 2016: Journal of Veterinary Internal Medicine
Anna Poghosyan, Jamie K Patel, Rachel L Clifford, Alan J Knox
Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6...
August 5, 2016: Biochemical and Biophysical Research Communications
K E Hay, J M Morton, A C A Clements, T J Mahony, T S Barnes
Bovine respiratory disease (BRD) is the major cause of clinical disease and death in feedlot cattle. A prospective longitudinal study was conducted in a population of Australian feedlot cattle to assess associations between factors related to feedlot management and risk of BRD. In total, 35,131 animals in 170 pens (cohorts) inducted into 14 feedlots were included in statistical analyses. Causal diagrams were used to inform model building to allow separate estimation of total and direct effects. Multilevel mixed effects logistic regression models were fitted within the Bayesian framework...
June 1, 2016: Preventive Veterinary Medicine
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