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Nicole Groh, Christian Seutter von Loetzen, Brinda Subbarayal, Christian Möbs, Lothar Vogel, Andreas Hoffmann, Kay Fötisch, Anna Koutsouridou, Stefanie Randow, Elke Völker, Andreas Reuter, Paul Rösch, Stefan Vieths, Wolfgang Pfützner, Barbara Bohle, Dirk Schiller
BACKGROUND: Allergen-specific immunotherapy (AIT) with birch pollen generates Bet v 1-specific immunoglobulin (Ig)G4 which blocks IgE-mediated hypersensitivity mechanisms. Whether IgG4 specific for Bet v1a competes with IgE for identical epitopes or whether novel epitope specificities of IgG4 antibodies are developed is under debate. OBJECTIVE: We sought to analyze the epitope specificities of IgE and IgG4 antibodies from sera of patients who received AIT. METHODS: 15 sera of patients (13/15 received AIT) with Bet v 1a-specific IgE and IgG4 were analyzed...
October 22, 2016: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
France Lambert, Miljana Bacevic, Pierre Layrolle, Peter Schüpbach, Pierre Drion, Eric Rompen
AIMS: The primary objective of this study was to compare the in vivo performance, namely in terms of quantity of newly formed bone and bone-to-material contact (osteoconductivity), of three hydroxyapatite-based biomaterials (HA) of different origins (natural or synthetic) or manufacturing process in a sinus lift model in rabbits. The secondary objective was to correlate the findings with the physical and topographical characteristics of the biomaterials. MATERIALS AND METHODS: Two bovine HA manufactured with different processes (bovine hydroxyapatites [BHA] and cuttlebone hydroxyapatite [CBHA]) and a synthetic hydroxyapatite (SHA) sintered at high temperature were characterised with scanning electronic microscopy (SEM) and the measurement of specific surface area (BET)...
October 22, 2016: Clinical Oral Implants Research
Somayeh Beirami, Hadi Rahimzadeh Barzoki, Nader Bahramifar
Preconcentration of trace amounts of diazinon by carbon mesoporous CMK-3 in water and biological samples and measurement by high-performance liquid chromatography were investigated. CMK-3, was prepared using hexagonal SBA-15 as the template. The synthesized materials were characterized by XRD, FT-IR, BET, TEM and Boehm titration method. The preconcentration procedure was optimized using a multivariate optimization approach following a two-stage process. Effect of analytical parameters including the amount of the CMK-3 as an adsorbent, pH, type and volume of eluent, flow rate of eluent and sample were studied by screening project, then the effective parameters were optimized by response surface methodology based on central composite design...
October 21, 2016: Biomedical Chromatography: BMC
Daniel Nichol, Mark Robertson-Tessi, Peter Jeavons, Alexander R A Anderson
Non-genetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance in both bacterial infections and cancers. Here, we study how bet-hedging emerges in the genotype-phenotype mapping through a simple interaction model: a molecular switch. We use simple Chemical Reaction Networks to implement stochastic switches that map gene products to phenotypes and investigate the impact of structurally distinct mappings on the evolution of phenotypic heterogeneity. Bet-hedging naturally emerges within this model and is robust to evolutionary loss through mutations to both the expression of individual genes and to the network itself...
October 21, 2016: Genetics
Wylie S Palmer
The entry of small molecule inhibitors of the bromodomain and extra C-terminal domain (BET) family of bromodomains into the clinic has demonstrated the therapeutic potential for this class of epigenetic acetyl-lysine reader proteins. Within the past two years, the development of potent inhibitors for the bromodomain and PHD finger containing protein (BRPF) family and the tripartite motif containing protein 24 (TRIM24) have been reported and are the subject of this review. Both proteins contain other domains with diverse functions and can also be part of a complex of proteins which have implications in epigenetic signaling and disease...
March 2016: Drug Discovery Today. Technologies
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
Srimoyee Ghosh, Jose M Lora
Epigenetic control of gene expression is enforced in part through histone modifications. Bromodomain and extra terminal domain (BET) proteins function as crucial chromatin readers, responsible for interpretation of the chromatin code in diverse cellular contexts, ultimately impacting gene transcription. BET proteins can play a major role in inflammation by profoundly affecting the biology of the Thelper 17 (TH17) lineage. We summarize recent studies focusing on BET inhibition as a viable therapeutic alternative for the control of autoimmune diseases driven by aberrant activation of TH17 cells...
March 2016: Drug Discovery Today. Technologies
Jamel Meslamani, Steven G Smith, Roberto Sanchez, Ming-Ming Zhou
Bromodomains are conserved structural modules responsible for recognizing acetylated-lysine residues on histone tails and other transcription-associated proteins, such as transcription factors and co-factors. Owing to their important functions in the regulation of ordered gene transcription in chromatin, bromodomains of the BET family proteins have recently been shown as druggable targets for a wide array of human diseases, including cancer and inflammation. Here we review the structural and functional features of the bromodomains and their small-molecule inhibitors...
March 2016: Drug Discovery Today. Technologies
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
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
Xiuqing Tian, Rui Guo, Yujiao Zhang, Lingling Xu, Xianbing Liu, Yinglong Hou
OBJECTIVE: To observe the effects of sympathetic overactivity on the immune system involved in the imbalance of T helper (Th) lymphocytes, we investigated the correlation between autonomic dysregulation and the generation of regulatory T (Treg) and Th1 chemokines in patients with acute coronary syndrome (ACS). METHODS: Blood samples obtained from patients with coronary artery disease and controls were analyzed for levels of Th1 and Treg cells and their associated cytokines by flow cytometry...
October 21, 2016: Neuroimmunomodulation
Fuyumi Kato, Francesco Paolo Fiorentino, Andreu Alibés, Manuel Perucho, Montse Sánchez-Céspedes, Takashi Kohno, Jun Yokota
We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification...
October 14, 2016: Oncotarget
Pei Y Liu, Nicholas Sokolowski, Su T Guo, Faraz Siddiqi, Bernard Atmadibrata, Thomas J Telfer, Yuting Sun, Lihong Zhang, Denise Yu, Joshua Mccarroll, Bing Liu, Rui H Yang, Xiang Y Guo, Andrew E Tee, Ken Itoh, Jenny Wang, Maria Kavallaris, Michelle Haber, Murray D Norris, Belamy B Cheung, Jennifer A Byrne, David S Ziegler, Glenn M Marshall, Marcel E Dinger, Rachel Codd, Xu D Zhang, Tao Liu
BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2...
October 13, 2016: Oncotarget
Ke Ren, Wei Zhang, Xiaoqing Chen, Yingyu Ma, Yue Dai, Yimei Fan, Yayi Hou, Ren Xiang Tan, Erguang Li
The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection...
October 2016: PLoS Pathogens
Justus Mahnke, Valéa Schumacher, Stefanie Ahrens, Nadja Käding, Lea Marie Feldhoff, Magdalena Huber, Jan Rupp, Friederike Raczkowski, Hans-Willi Mittrücker
The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for TH2 and TH17 cell formation and controls peripheral CD8(+) T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in TH1 responses. IRF4(-/-) mice generated only marginal numbers of listeria-specific TH1 cells. After transfer into infected mice, IRF4(-/-) CD4(+) T cells failed to differentiate into TH1 cells as indicated by reduced T-bet and IFN-γ expression, and showed limited proliferation...
October 20, 2016: Scientific Reports
Yu Seong Do, Won Hee Lee, Jong Geun Seong, Ju Sung Kim, Ho Hyun Wang, Cara M Doherty, Anita J Hill, Young Moo Lee
Highly permeable, thermally rearranged polymer membranes based on bismaleimide derivatives that exhibit excellent CO2 permeability up to 5440 Barrer with a high BET surface area (1130 m(2) g(-1)) are reported for the first time. In addition, the membranes can be easily used to form semi-interpenetrating networks with other polymers endowing them with superior gas transport properties.
October 20, 2016: Chemical Communications: Chem Comm
Su-Min Lim, Hyun Sik Choi, Jin-Ju Jeong, Seung-Won Han, Dong-Hyun Kim
We investigated the effect of DWac on the gut microbiota composition in mice with 2,3,6-trinitrobenzenesulfonic acid- (TNBS-) induced colitis. Treatment with DWac restored TNBS-disturbed gut microbiota composition and attenuated TNBS-induced colitis. Moreover, we examined the effect of DWac in mice with mesalazine-resistant colitis (MRC). Intrarectal injection of TNBS in MRC mice caused severe colitis, as well as colon shortening, edema, and increased myeloperoxidase activity. Treatment with mesalazine (30 mg/kg) did not attenuate TNBS-induced colitis in MRC mice, whereas treatment with DWac (30 mg/kg) significantly attenuated TNBS-induced colitis...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
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
Eunchong Park, Ju Han Song, Myun Soo Kim, Su-Ho Park, Tae Sung Kim
CD4(+) T cell activation and adequate differentiation into effector T helper (Th) cells are crucial for mediating adaptive immune responses to cope with foreign pathogens. Despite the significant role of Th cells, excessive increases in their numbers result in inflammatory and autoimmune diseases. In this study, we investigated the effects of costunolide, a plant-derived natural compound with an anti-inflammatory activity, in regulating Th cells and the underlying mechanisms. Costunolide significantly decreased cell populations of differentiated Th1, Th2, and Th17 subsets under Th subset-polarizing conditions, while exerting statistically negligible effects on Treg cell differentiation...
October 15, 2016: International Immunopharmacology
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