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https://www.readbyqxmd.com/read/28211522/structure-and-polymorphisms-of-the-major-histocompatibility-complex-in-the-oriental-stork-ciconia-boyciana
#1
Hiroki Tsuji, Yukio Taniguchi, Shintaro Ishizuka, Hirokazu Matsuda, Takahisa Yamada, Kazuaki Naito, Hiroaki Iwaisaki
The major histocompatibility complex (MHC) is highly polymorphic and plays a central role in the vertebrate immune system. Despite its functional consistency, the MHC genomic structure differs substantially among organisms. In birds, the MHCs of Galliformes and the Japanese crested ibis (Pelecaniformes) are well-characterized, but information about other avian MHCs remains scarce. The Oriental stork (Ciconia boyciana, order Ciconiiformes) is a large endangered migrant. The current Japanese population of this bird originates from a few founders; thus, understanding the genetic diversity among them is critical for effective population management...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28194432/bet-inhibitors-block-pancreatic-stellate-cell-collagen-i-production-and-attenuate-fibrosis-in-vivo
#2
Krishan Kumar, Brian T DeCant, Paul J Grippo, Rosa F Hwang, David J Bentrem, Kazumi Ebine, Hidayatullah G Munshi
The fibrotic reaction, which can account for over 70%-80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28173625/bet-proteins-an-approach-to-future-therapies-in-transplantation
#3
Beatriz Suarez-Álvarez, Ramón M Rodríguez, Marta Ruiz-Ortega, Carlos López-Larrea
In order to develop new efficient therapies for organ transplantation it is essential to acquire a comprehensive knowledge of the molecular mechanisms and processes, such as immune activation, chronic inflammation and fibrosis that lead to rejection and long-term graft loss. Recent efforts have shed some light on the epigenetic regulation associated with these processes. In this context, the bromo and extraterminal (BET) family of bromodomain proteins (BRD2, BRD3, BRD4 and BRDT) have emerged as major epigenetic players, connecting chromatin structure with gene expression changes...
February 7, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28161994/conformation-dependent-qsar-approach-for-the-prediction-of-inhibitory-activity-of-bromodomain-modulators
#4
C R García-Jacas, K Martinez-Mayorga, Y Marrero-Ponce, J L Medina-Franco
Epigenetic drug discovery is a promising research field with growing interest in the scientific community, as evidenced by the number of publications and the large amount of structure-epigenetic activity information currently available in the public domain. Computational methods are valuable tools to analyse and understand the activity of large compound collections from their structural information. In this manuscript, QSAR models to predict the inhibitory activity of a diverse and heterogeneous set of 88 organic molecules against the bromodomains BRD2, BRD3 and BRD4 are presented...
February 6, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28107481/bet-inhibitors-disrupt-rad21-dependent-conformational-control-of-kshv-latency
#5
Horng-Shen Chen, Alessandra De Leo, Zhuo Wang, Andrew Kerekovic, Robert Hills, Paul M Lieberman
Kaposi's Sarcoma-associated Herpesvirus (KSHV) establishes stable latent infection in B-lymphocytes and pleural effusion lymphomas (PELs). During latency, the viral genome persists as an epigenetically constrained episome with restricted gene expression programs. To identify epigenetic regulators of KSHV latency, we screened a focused small molecule library containing known inhibitors of epigenetic factors. We identified JQ1, a Bromodomain and Extended Terminal (BET) protein inhibitor, as a potent activator of KSHV lytic reactivation from B-cells carrying episomal KSHV...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28096419/stromal-cues-regulate-the-pancreatic-cancer-epigenome-and-metabolome
#6
Mara H Sherman, Ruth T Yu, Tiffany W Tseng, Cristovao M Sousa, Sihao Liu, Morgan L Truitt, Nanhai He, Ning Ding, Christopher Liddle, Annette R Atkins, Mathias Leblanc, Eric A Collisson, John M Asara, Alec C Kimmelman, Michael Downes, Ronald M Evans
A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28032455/in-silico-design-and-bioevaluation-of-selective-benzotriazepine-brd4-inhibitors-with-potent-antiosteoclastogenic-activity
#7
Vishwa Deepak, Binglin Wang, Dwayne Koot, Abe Kasonga, Xiao Xing Stander, Magdalena Coetzee, Andre Stander
The bromodomain (BRD) and extra-terminal domain (BET) protein family binds to acetylated histones on lysine residues and act as epigenetic readers. Recently, the role of this protein family in bone loss has been gaining attention. Earlier studies have reported that benzotriazepine (Bzt) derivatives could be effective inhibitors of BET proteins. In this study by using in silico tools we designed three Bzt analogs (W49, W51, and W52). By docking, molecular simulations and chemiluminescent alpha screen binding assay we show that the studied analogs were selective at inhibiting BRD4 when compared to BRD2...
December 29, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28008999/genetic-architecture-differences-between-pediatric-and-adult-onset-inflammatory-bowel-diseases-in-the-polish-population
#8
Jerzy Ostrowski, Agnieszka Paziewska, Izabella Lazowska, Filip Ambrozkiewicz, Krzysztof Goryca, Maria Kulecka, Tomasz Rawa, Jakub Karczmarski, Michalina Dabrowska, Natalia Zeber-Lubecka, Roman Tomecki, Anna Kluska, Aneta Balabas, Magdalena Piatkowska, Katarzyna Paczkowska, Jaroslaw Kierkus, Piotr Socha, Michal Lodyga, Grazyna Rydzewska, Maria Klopocka, Grazyna Mierzwa, Barbara Iwanczak, Elzbieta Krzesiek, Katarzyna Bak-Drabik, Jaroslaw Walkowiak, Beata Klincewicz, Piotr Radwan, Urszula Grzybowska-Chlebowczyk, Piotr Landowski, Agnieszka Jankowska, Bartosz Korczowski, Teresa Starzynska, Piotr Albrecht, Michal Mikula
Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn's disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping...
December 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27997612/signatures-of-crested-ibis-mhc-revealed-by-recombination-screening-and-short-reads-assembly-strategy
#9
Liao Chang, Shiyang He, Danqing Mao, Yuanhong Liu, Zijun Xiong, Dongke Fu, Bo Li, Shuguang Wei, Xun Xu, Shengbin Li, Hui Yuan
Whole-genome shotgun (WGS) sequencing has become a routine method in genome research over the past decade. However, the assembly of highly polymorphic regions in WGS projects remains a challenge, especially for large genomes. Employing BAC library constructing, PCR screening and Sanger sequencing, traditional strategy is laborious and expensive, which hampers research on polymorphic genomic regions. As one of the most highly polymorphic regions, the major histocompatibility complex (MHC) plays a central role in the adaptive immunity of all jawed vertebrates...
2016: PloS One
https://www.readbyqxmd.com/read/27991587/a-bromodomain-dna-interaction-facilitates-acetylation-dependent-bivalent-nucleosome-recognition-by-the-bet-protein-brdt
#10
Thomas C R Miller, Bernd Simon, Vladimir Rybin, Helga Grötsch, Sandrine Curtet, Saadi Khochbin, Teresa Carlomagno, Christoph W Müller
Bromodomains are critical components of many chromatin modifying/remodelling proteins and are emerging therapeutic targets, yet how they interact with nucleosomes, rather than acetylated peptides, remains unclear. Using BRDT as a model, we characterized how the BET family of bromodomains interacts with site-specifically acetylated nucleosomes. Here we report that BRDT interacts with nucleosomes through its first (BD1), but not second (BD2) bromodomain, and that acetylated histone recognition by BD1 is complemented by a bromodomain-DNA interaction...
December 19, 2016: Nature Communications
https://www.readbyqxmd.com/read/27903752/hexim1-as-a-robust-pharmacodynamic-marker-for-monitoring-target-engagement-of-bet-family-bromodomain-inhibitors-in-tumors-and-surrogate-tissues
#11
Xiaoyu Lin, Xiaoli Huang, Tamar Uziel, Paul Hessler, Daniel H Albert, Lisa A Roberts-Rapp, Keith F McDaniel, Warren M Kati, Yu Shen
An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET bromodomain inhibitor OTX015 using literature-described putative pharmacodynamic (PD) markers such as c-Myc, BRD2, etc. failed to detect PD marker responses in AML patients treated at active dose and those with clinical responses. Here we report the identification and characterization of HEXIM1 and other genes as robust PD markers for BET inhibitors...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27898717/gene-based-genome-wide-association-analysis-in-european-and-asian-populations-identified-novel-genes-for-rheumatoid-arthritis
#12
Hong Zhu, Wei Xia, Xing-Bo Mo, Xiang Lin, Ying-Hua Qiu, Neng-Jun Yi, Yong-Hong Zhang, Fei-Yan Deng, Shu-Feng Lei
OBJECTIVE: Rheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations. METHODS: Gene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects)...
2016: PloS One
https://www.readbyqxmd.com/read/27865874/bromodomain-containing-protein-2-induces-insulin-resistance-via-the-mtor-akt-signaling-pathway-and-an-inflammatory-response-in-adipose-tissue
#13
Ruixin Sun, Yi Wu, Weihua Hou, Zujun Sun, Yuxiong Wang, Huanhuan Wei, Wei Mo, Min Yu
Insulin resistance is a major metabolic abnormality in a large majority of patients with type II diabetes. Bromodomain-containing protein 2 (Brd2), a transcriptional co-activator/co-repressor with switch mating type/sucrose non-fermenting (SWI/SNF)-like functions that regulates chromatin, suppresses adipocyte differentiation and regulates pancreatic β-cell biology. However, the effects of Brd2 on insulin resistance remain unknown. Here, overexpression of Brd2 in white adipose tissue of wild-type (WT) mice led to insulin resistance...
January 2017: Cellular Signalling
https://www.readbyqxmd.com/read/27835869/otx015-mk-8628-a-novel-bet-inhibitor-exhibits-antitumor-activity-in-non-small-cell-and-small-cell-lung-cancer-models-harboring-different-oncogenic-mutations
#14
Maria E Riveiro, Lucile Astorgues-Xerri, Ramiro Vazquez, Roberta Frapolli, Ivo Kwee, Andrea Rinaldi, Elodie Odore, Keyvan Rezai, Mohamed Bekradda, Giorgio Inghirami, Maurizio D'Incalci, Kay Noel, Esteban Cvitkovic, Eric Raymond, Francesco Bertoni
Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#15
REVIEW
Yasushi Taniguchi
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code...
November 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27783056/metabolic-response-to-xd14-treatment-in-human-breast-cancer-cell-line-mcf-7
#16
Daqiang Pan, Michel Kather, Lucas Willmann, Manuel Schlimpert, Christoph Bauer, Simon Lagies, Karin Schmidtkunz, Steffen U Eisenhardt, Manfred Jung, Stefan Günther, Bernd Kammerer
XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells...
October 24, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27769357/clinical-trials-for-bet-inhibitors-run-ahead-of-the-science
#17
REVIEW
Guillaume Andrieu, Anna C Belkina, Gerald V Denis
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27769353/erythropoiesis-provides-a-brd-s-eye-view-of-bet-protein-function
#18
REVIEW
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
https://www.readbyqxmd.com/read/27769352/phospho-brd4-transcription-plasticity-and-drug-targeting
#19
REVIEW
Cheng-Ming Chiang
BRD4 is an epigenetic regulator and transcription cofactor whose phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. While the bromodomains of BET family proteins, including BRD4, BRD2, BRD3 and BRDT, have been the primary targets of small compounds such as JQ1, I-BET and MS417 that show promising anticancer effects against some hematopoietic cancer and solid tumors, drug resistance upon prolonged treatment necessitates a better understanding of alternative pathways underlying not only the resistance but also persistent BET protein dependence for identifying new targets and effective combination therapy strategies...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27651315/brd4-regulates-breast-cancer-dissemination-through-jagged1-notch1-signaling
#20
Guillaume Andrieu, Anna H Tran, Katherine J Strissel, Gerald V Denis
The bromodomain and extraterminal (BET) proteins are epigenetic "readers" of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear how individual family members participate in cancer progression and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here, we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative breast cancer migration and invasion...
November 15, 2016: Cancer Research
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