keyword
https://read.qxmd.com/read/32490211/generation-of-an-antibody-recognizing-a-set-of-acetylated-proteins-including-subunits-of-baf-complexes
#21
JOURNAL ARTICLE
Masatoshi Takagi
The aim of this study was to generate an antibody specific to Ki-67 acetylated at lysine 3180, whose existence was reported in an acetylome study (Scholz, C., B.T. Weinert, S.A. Wagner, P. Beli, Y. Miyake, J. Qi, L.J. Jensen, W. Streicher, A.R. McCarthy, N.J. Westwood, S. Lain, J. Cox, P. Matthias, M. Mann, J.E. Bradner, and C. Choudhary. 2015). Rabbits were immunized with a synthetic acetylated peptide corresponding to acetylated lysine 3180 of Ki-67 and the residues flanking it. The obtained antibody, referred to as Ab3180 in this study, was affinity purified with the antigen peptide and characterized...
July 2020: Biochemistry and Biophysics Reports
https://read.qxmd.com/read/32428814/practical-aspects-of-prrsv-rna-detection-in-processing-fluids-collected-in-commercial-swine-farms
#22
JOURNAL ARTICLE
Will A López, Jeffrey J Zimmerman, Phillip C Gauger, Karen M Harmon, Laura Bradner, Min Zhang, Luis Giménez-Lirola, Alejandro Ramirez, Jean Paul Cano, Daniel C L Linhares
Processing fluid samples are easily collected under field conditions and provide the means to test more piglets more frequently in a practical way, thereby improving PRRSV surveillance. However, a deeper understanding of the diagnostic characteristics of this newly described sample type is still required. Therefore, the objective of this field-based study was to determine the relationship between viremic piglets and the detection of PRRSV RNA in processing fluid samples. In two PRRSV-positive breeding herds, processing fluids (n = 77) and individual piglet serum samples (n = 834) were collected from 77 litters in three sampling events and tested for PRRSV RNA...
July 2020: Preventive Veterinary Medicine
https://read.qxmd.com/read/32416067/synthetic-lethal-and-resistance-interactions-with-bet-bromodomain-inhibitors-in-triple-negative-breast-cancer
#23
JOURNAL ARTICLE
Shaokun Shu, Hua-Jun Wu, Jennifer Y Ge, Rhamy Zeid, Isaac S Harris, Bojana Jovanović, Katherine Murphy, Binbin Wang, Xintao Qiu, Jennifer E Endress, Jaime Reyes, Klothilda Lim, Alba Font-Tello, Sudeepa Syamala, Tengfei Xiao, Chandra Sekhar Reddy Chilamakuri, Evangelia K Papachristou, Clive D'Santos, Jayati Anand, Kunihiko Hinohara, Wei Li, Thomas O McDonald, Adrienne Luoma, Rebecca J Modiste, Quang-De Nguyen, Brittany Michel, Paloma Cejas, Cigall Kadoch, Jacob D Jaffe, Kai W Wucherpfennig, Jun Qi, X Shirley Liu, Henry Long, Myles Brown, Jason S Carroll, Joan S Brugge, James Bradner, Franziska Michor, Kornelia Polyak
BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents...
June 18, 2020: Molecular Cell
https://read.qxmd.com/read/32382029/evolutionary-conserved-nsl-complex-brd4-axis-controls-transcription-activation-via-histone-acetylation
#24
JOURNAL ARTICLE
Aline Gaub, Bilal N Sheikh, M Felicia Basilicata, Marie Vincent, Mathilde Nizon, Cindy Colson, Matthew J Bird, James E Bradner, Julien Thevenon, Michael Boutros, Asifa Akhtar
Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex...
May 7, 2020: Nature Communications
https://read.qxmd.com/read/31646949/emergence-of-salmonella-enterica-serovar-4-5-12-i-as-the-primary-serovar-identified-from-swine-clinical-samples-and-development-of-a-multiplex-real-time-pcr-for-improved-salmonella-serovar-level-identification
#25
JOURNAL ARTICLE
Samantha A Naberhaus, Adam C Krull, Laura K Bradner, Karen M Harmon, Paulo Arruda, Bailey L Arruda, Orhan Sahin, Eric R Burrough, Kent J Schwartz, Amanda J Kreuder
Rapid identification of the infecting Salmonella serovar from porcine diagnostic samples is vital to allow implementation of appropriate on-farm treatment and management decisions. Although identification at the serogroup level can be rapidly achieved at most veterinary diagnostic laboratories, final Salmonella serovar identification often takes several weeks because of the limited number of reference laboratories performing the complex task of serotyping. Salmonella serogroup B, currently the dominant serogroup identified from swine clinical samples in the United States, contains serovars that vary from highly pathogenic to minimally pathogenic in swine...
November 2019: Journal of Veterinary Diagnostic Investigation
https://read.qxmd.com/read/31554818/high-fat-diet-fuels-prostate-cancer-progression-by-rewiring-the-metabolome-and-amplifying-the-myc-program
#26
JOURNAL ARTICLE
David P Labbé, Giorgia Zadra, Meng Yang, Jaime M Reyes, Charles Y Lin, Stefano Cacciatore, Ericka M Ebot, Amanda L Creech, Francesca Giunchi, Michelangelo Fiorentino, Habiba Elfandy, Sudeepa Syamala, Edward D Karoly, Mohammed Alshalalfa, Nicholas Erho, Ashley Ross, Edward M Schaeffer, Ewan A Gibb, Mandeep Takhar, Robert B Den, Jonathan Lehrer, R Jeffrey Karnes, Stephen J Freedland, Elai Davicioni, Daniel E Spratt, Leigh Ellis, Jacob D Jaffe, Anthony V DʼAmico, Philip W Kantoff, James E Bradner, Lorelei A Mucci, Jorge E Chavarro, Massimo Loda, Myles Brown
Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden...
September 25, 2019: Nature Communications
https://read.qxmd.com/read/31551018/polioencephalomyelitis-in-domestic-swine-associated-with-porcine-astrovirus-type-3
#27
JOURNAL ARTICLE
Franco S Matias Ferreyra, Laura K Bradner, Eric R Burrough, Vickie L Cooper, Rachel J Derscheid, Phillip C Gauger, Karen M Harmon, Darin Madson, Pablo E Piñeyro, Kent J Schwartz, Gregory W Stevenson, Michel A Zeller, Bailey L Arruda
In the past decade, different members of the genus Mamastrovirus have been associated with outbreaks of neurologic disease in humans, cattle, sheep, mink, and, most recently, porcine astrovirus 3 (PoAstV3) in swine. We performed a retrospective analysis of 50 cases of porcine neurologic disease of undetermined cause but with microscopic lesions compatible with a viral encephalomyelitis to better understand the role and pathogenesis of PoAstV3 infection. Nucleic acid was extracted from formalin-fixed paraffin-embedded (FFPE) tissue for reverse transcription quantitative polymerase chain reaction (RT-qPCR) testing for PoAstV3...
January 2020: Veterinary Pathology
https://read.qxmd.com/read/31126889/the-bet-inhibitor-jq1-attenuates-double-strand-break-repair-and-sensitizes-models-of-pancreatic-ductal-adenocarcinoma-to-parp-inhibitors
#28
JOURNAL ARTICLE
Aubrey L Miller, Samuel C Fehling, Patrick L Garcia, Tracy L Gamblin, Leona N Council, Robert C A M van Waardenburg, Eddy S Yang, James E Bradner, Karina J Yoon
BACKGROUND: DNA repair deficiency accumulates DNA damage and sensitizes tumor cells to PARP inhibitors (PARPi). Based on our observation that the BET inhibitor JQ1 increases levels of DNA damage, we evaluated the efficacy of JQ1 + the PARPi olaparib in preclinical models of pancreatic ductal adenocarcinoma (PDAC). We also addressed the mechanism by which JQ1 increased DNA damage. METHODS: The effect of JQ1 + olaparib on in vivo tumor growth was assessed with patient-derived xenograft (PDX) models of PDAC...
June 2019: EBioMedicine
https://read.qxmd.com/read/30664779/small-molecule-targeting-of-brachyury-transcription-factor-addiction-in-chordoma
#29
JOURNAL ARTICLE
Tanaz Sharifnia, Mathias J Wawer, Ting Chen, Qing-Yuan Huang, Barbara A Weir, Ann Sizemore, Matthew A Lawlor, Amy Goodale, Glenn S Cowley, Francisca Vazquez, Christopher J Ott, Joshua M Francis, Slim Sassi, Patricia Cogswell, Hadley E Sheppard, Tinghu Zhang, Nathanael S Gray, Paul A Clarke, Julian Blagg, Paul Workman, Josh Sommer, Francis Hornicek, David E Root, William C Hahn, James E Bradner, Kwok K Wong, Paul A Clemons, Charles Y Lin, Joanne D Kotz, Stuart L Schreiber
Chordoma is a primary bone cancer with no approved therapy1 . The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3 . Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation...
February 2019: Nature Medicine
https://read.qxmd.com/read/30624860/silk-protein-bioresorbable-drug-eluting-ear-tubes-proof-of-concept
#30
JOURNAL ARTICLE
Sarah A Bradner, Deepa Galaiya, Nikhila Raol, David L Kaplan, Chistopher J Hartnick
Otitis media with effusion (OEM) is a common pediatric pathology treated with topical fluoroquinolones (ear drops) and tympanoplasty tube, also referred to as ear tube, implantation for middle ear drainage. Commercially available ear tubes are fabricated using poly (lactic-co-glycolic acid) synthetic materials that are associated with long-complications due to premature extrusion. Resorbable materials have emerged as desirable alternatives to reduce extrusion-related complications, but often limited by fast resorption rates...
February 2019: Advanced Healthcare Materials
https://read.qxmd.com/read/30590042/non-overlapping-control-of-transcriptome-by-promoter-and-super-enhancer-associated-dependencies-in-multiple-myeloma
#31
JOURNAL ARTICLE
Mariateresa Fulciniti, Charles Y Lin, Mehmet K Samur, Michael A Lopez, Irtisha Singh, Matthew A Lawlor, Raphael E Szalat, Christopher J Ott, Herve' Avet-Loiseau, Kenneth C Anderson, Richard A Young, James E Bradner, Nikhil C Munshi
The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells...
December 26, 2018: Cell Reports
https://read.qxmd.com/read/30587225/efficacy-and-side-effects-of-doxycycline-versus-minocycline-in-the-three-dose-melarsomine-canine-adulticidal-heartworm-treatment-protocol
#32
JOURNAL ARTICLE
Molly D Savadelis, Katherine M Day, Jenna L Bradner, Adrian J Wolstenholme, Michael T Dzimianski, Andrew R Moorhead
BACKGROUND: The American Heartworm Society currently recommends the use of a monthly macrocyclic lactone, a 28-day course of 10 mg/kg doxycycline BID, and the 3-dose protocol of melarsomine dihydrochloride for the treatment of canine heartworm disease. Doxycycline is necessary for the reduction of the bacterium Wolbachia, found in all heartworm life-stages. Previous price increases and decreasing availability prompted us to evaluate alternative tetracycline antibiotics, i.e. minocycline, for the reduction of Wolbachia during canine heartworm treatment...
December 27, 2018: Parasites & Vectors
https://read.qxmd.com/read/30503705/enhancer-architecture-and-essential-core-regulatory-circuitry-of-chronic-lymphocytic-leukemia
#33
JOURNAL ARTICLE
Christopher J Ott, Alexander J Federation, Logan S Schwartz, Siddha Kasar, Josephine L Klitgaard, Romina Lenci, Qiyuan Li, Matthew Lawlor, Stacey M Fernandes, Amanda Souza, Donald Polaski, Deepti Gadi, Matthew L Freedman, Jennifer R Brown, James E Bradner
Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines. With super enhancer-based modeling of regulatory circuits and assessments of transcription factor dependencies, we discover that the essential super enhancer factor PAX5 dominates CLL regulatory nodes and is essential for CLL cell survival...
November 16, 2018: Cancer Cell
https://read.qxmd.com/read/30397315/a-non-canonical-swi-snf-complex-is-a-synthetic-lethal-target-in-cancers-driven-by-baf-complex-perturbation
#34
JOURNAL ARTICLE
Brittany C Michel, Andrew R D'Avino, Seth H Cassel, Nazar Mashtalir, Zachary M McKenzie, Matthew J McBride, Alfredo M Valencia, Qianhe Zhou, Michael Bocker, Luis M M Soares, Joshua Pan, David I Remillard, Caleb A Lareau, Hayley J Zullow, Nora Fortoul, Nathanael S Gray, James E Bradner, Ho Man Chan, Cigall Kadoch
Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation...
December 2018: Nature Cell Biology
https://read.qxmd.com/read/30279226/small-molecule-bcl6-inhibitor-effectively-treats-mice-with-nonsclerodermatous-chronic-graft-versus-host-disease
#35
JOURNAL ARTICLE
Katelyn Paz, Ryan Flynn, Jing Du, Jun Qi, Leo Luznik, Ivan Maillard, Kelli P MacDonald, Geoffrey R Hill, Jonathan S Serody, William J Murphy, Peter T Sage, Arlene H Sharpe, David Miklos, Corey S Cutler, John Koreth, Joseph H Antin, Robert J Soiffer, Jerome Ritz, James E Bradner, Ari M Melnick, Bruce R Blazar
Patient outcomes for steroid-dependent or -refractory chronic graft-versus-host diesease (cGVHD) are poor, and only ibrutinib has been US Food and Drug Administration (FDA) approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B cells to produce antibodies that are associated with disease pathogenesis. The transcriptional corepressor B-cell lymphoma 6 (BCL6) is a member of the Broad-complex, Tramtrack, and Bric-abrac/poxvirus and zinc finger (BTB/POZ) transcription factor family and master regulator of the immune cells in the GC reaction...
January 3, 2019: Blood
https://read.qxmd.com/read/30087114/bet-bromodomain-inhibition-cooperates-with-pd-1-blockade-to-facilitate-antitumor-response-in-kras-mutant-non-small-cell-lung-cancer
#36
JOURNAL ARTICLE
Dennis O Adeegbe, Shengwu Liu, Maureen M Hattersley, Michaela Bowden, Chensheng W Zhou, Shuai Li, Raven Vlahos, Michael Grondine, Igor Dolgalev, Elena V Ivanova, Max M Quinn, Peng Gao, Peter S Hammerman, James E Bradner, J Alan Diehl, Anil K Rustgi, Adam J Bass, Aristotelis Tsirigos, Gordon J Freeman, Huawei Chen, Kwok-Kin Wong
KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS- mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS -mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Treg) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells...
October 2018: Cancer Immunology Research
https://read.qxmd.com/read/29901031/ubiquitous-flame-retardant-toxicants-impair-spermatogenesis-in-a-human-stem-cell-model
#37
JOURNAL ARTICLE
Alyse N Steves, Joshua M Bradner, Kristen L Fowler, Danielle Clarkson-Townsend, Brittany J Gill, Adam C Turry, W Michael Caudle, Gary W Miller, Anthony W S Chan, Charles A Easley
Sperm counts have rapidly declined in Western males over the past four decades. This rapid decline remains largely unexplained, but exposure to environmental toxicants provides one potential explanation for this decline. Flame retardants are highly prevalent and persistent in the environment, but many have not been assessed for their effects on human spermatogenesis. Using a human stem cell-based model of spermatogenesis, we evaluated two major flame retardants, hexabromocyclododecane (HBCDD) and tetrabromobisphenol A (TBBPA), under acute conditions simulating occupational-level exposures...
May 25, 2018: IScience
https://read.qxmd.com/read/29511348/combined-bet-bromodomain-and-cdk2-inhibition-in-myc-driven-medulloblastoma
#38
JOURNAL ARTICLE
Sara Bolin, Anna Borgenvik, Camilla U Persson, Anders Sundström, Jun Qi, James E Bradner, William A Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J Swartling
Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively...
May 2018: Oncogene
https://read.qxmd.com/read/29507391/functional-trim24-degrader-via-conjugation-of-ineffectual-bromodomain-and-vhl-ligands
#39
JOURNAL ARTICLE
Lara N Gechijian, Dennis L Buckley, Matthew A Lawlor, Jaime M Reyes, Joshiawa Paulk, Christopher J Ott, Georg E Winter, Michael A Erb, Thomas G Scott, Mousheng Xu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Nicholas P Kwiatkowski, Jennifer A Perry, Jun Qi, Nathanael S Gray, James E Bradner
The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24...
April 2018: Nature Chemical Biology
https://read.qxmd.com/read/29444854/bet-bromodomain-proteins-regulate-enhancer-function-during-adipogenesis
#40
JOURNAL ARTICLE
Jonathan D Brown, Zachary B Feldman, Sean P Doherty, Jaime M Reyes, Peter B Rahl, Charles Y Lin, Quanhu Sheng, Qiong Duan, Alexander J Federation, Andrew L Kung, Saptarsi M Haldar, Richard A Young, Jorge Plutzky, James E Bradner
Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation...
February 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
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