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https://www.readbyqxmd.com/read/28209615/targeted-degradation-of-bet-proteins-in-triple-negative-breast-cancer
#1
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer L Meagher, Jeanne Stuckey, Daniel F Hayes, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28110784/an-inactivated-influenza-d-virus-vaccine-partially-protects-cattle-from-respiratory-disease-caused-by-homologous-challenge
#2
Ben M Hause, Lucas Huntimer, Shollie Falkenberg, Jamie Henningson, Kelly Lechtenberg, Tom Halbur
Originally isolated from swine, the proposed influenza D virus has since been shown to be common in cattle. Inoculation of IDV to naïve calves resulted in mild respiratory disease histologically characterized by tracheitis. As several studies have associated the presence of IDV with acute bovine respiratory disease (BRD), we sought to investigate the efficacy of an inactivated IDV vaccine. Vaccinated calves seroconverted with hemagglutination inhibition titers 137-169 following two doses. Non-vaccinated calves challenged with a homologous virus exhibited signs of mild respiratory disease from days four to ten post challenge which was significantly different than negative controls at days five and nine post challenge...
February 2017: Veterinary Microbiology
https://www.readbyqxmd.com/read/28093111/efficacy-of-tildipirosin-metaphylaxis-for-the-prevention-of-respiratory-disease-otitis-and-mortality-in-pre-weaned-holstein-calves
#3
A G V Teixeira, J A A McArt, R C Bicalho
The aim of this study was to evaluate the efficacy of two metaphylactic approaches (long acting antibiotic injected once at 10 days of life or twice at 10 and 35 days of life) on the prevention of bovine respiratory disease (BRD), otitis and mortality in high-risk group-housed pre-weaned Holstein heifer calves. The antibiotic of choice for the metaphylactic approach was a long acting macrolide (tildipirosin) administered subcutaneously at the base of the neck at a dose of 1 mL per 45 kg body weight. A clinical trial was carried out on one dairy farm with random allocation of newborn calves to one of three treatments: (1) control (CTR); (2) one injection at 10 days of life (M1); and (3) two injections at 10 and 35 days of life (M2)...
January 2017: Veterinary Journal
https://www.readbyqxmd.com/read/28074713/pathogens-patterns-of-pneumonia-and-epidemiologic-risk-factors-associated-with-respiratory-disease-in-recently-weaned-cattle-in-ireland
#4
Gerard M Murray, Simon J More, Dónal Sammin, Mìcheàl J Casey, Máire C McElroy, Rónan G O'Neill, William J Byrne, Bernadette Earley, Tracy A Clegg, Hywel Ball, Colin J Bell, Joseph P Cassidy
We examined the pathogens, morphologic patterns, and risk factors associated with bovine respiratory disease (BRD) in 136 recently weaned cattle ("weanlings"), 6-12 mo of age, that were submitted for postmortem examination to regional veterinary laboratories in Ireland. A standardized sampling protocol included routine microbiologic investigations as well as polymerase chain reaction and immunohistochemistry. Lungs with histologic lesions were categorized into 1 of 5 morphologic patterns of pneumonia. Fibrinosuppurative bronchopneumonia (49%) and interstitial pneumonia (48%) were the morphologic patterns recorded most frequently...
January 2017: Journal of Veterinary Diagnostic Investigation
https://www.readbyqxmd.com/read/28068087/design-of-a-biased-potent-small-molecule-inhibitor-of-the-bromodomain-and-phd-finger-containing-brpf-proteins-suitable-for-cellular-and-in-vivo-studies
#5
Niall Igoe, Elliott D Bayle, Oleg Fedorov, Cynthia Tallant, Pavel Savitsky, Catherine Rogers, Dafydd R Owen, Gauri Deb, Tim C P Somervaille, David M Andrews, Neil Jones, Anne Cheasty, Hamish Ryder, Paul E Brennan, Susanne Müller, Stefan Knapp, Paul V Fish
The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines...
January 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28064409/assessment-of-nebulisation-of-sodium-ceftiofur-in-the-treatment-of-calves-naturally-infected-with-bovine-respiratory-disease
#6
Vivek Joshi, V K Gupta, U Dimri, O R Vinodh Kumar, D K Sharma, A G Bhanuprakash
Twelve screened cases of bovine respiratory disease (BRD) in calves were enrolled. Six of the calves were treated intramuscularly with sodium ceftiofur (1 mg/kg), and six were treated with nebulised sodium ceftiofur (1 mg/kg). Comparative evaluation of the two therapeutic modalities was based on repetitive analysis of hematological profile of calves on days 0, 5, and 10 post-therapy. The mortality rate in the group of calves treated with the nebulised sodium ceftiofur was significantly (p < 0.001) lower, and their clinical and hematological parameters returned to normal significantly (p < 0...
January 7, 2017: Tropical Animal Health and Production
https://www.readbyqxmd.com/read/28058252/risk-assessment-in-the-recovery-of-food-for-social-solidarity-purposes-preliminary-data
#7
Vesna Milicevic, Giampaolo Colavita, Marta Castrica, Sabrina Ratti, Antonella Baldi, Claudia M Balzaretti
The most recent study, conducted by Politecnico of Milan, on food surplus management in Italy shows that in the Italian food supply chain the food surplus is around 5.5 million tons/year, and the amount of food wasted is around 5.1 million tons/year. During 2015, the charitable organizations (COs) belonging to the Italian Food Bank Network, active in recovering and distributing food for social solidarity's purposes, reused 381,345 tons of food from 2292 donors. The main supplying sources of the Banco Alimentare Network are: food industries, organized large-scale retail trade and collective catering service...
September 20, 2016: Italian Journal of Food Safety
https://www.readbyqxmd.com/read/28053347/functions-of-bromodomain-containing-proteins-and-their-roles-in-homeostasis-and-cancer
#8
REVIEW
Takao Fujisawa, Panagis Filippakopoulos
Bromodomains (BRDs) are evolutionarily conserved protein-protein interaction modules that are found in a wide range of proteins with diverse catalytic and scaffolding functions and are present in most tissues. BRDs selectively recognize and bind to acetylated Lys residues - particularly in histones - and thereby have important roles in the regulation of gene expression. BRD-containing proteins are frequently dysregulated in cancer, they participate in gene fusions that generate diverse, frequently oncogenic proteins, and many cancer-causing mutations have been mapped to the BRDs themselves...
January 5, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28046137/rapid-communication-variance-component-estimates-for-charolais-sired-fed-cattle-and-relative-economic-impact-of-bovine-respiratory-disease
#9
J W Buchanan, M D MacNeil, R C Raymond, A R McClain, A L Van Eenennaam
Variance components were estimated and relative economic importance of bovine respiratory disease (BRD) was derived from 3 yr of performance, morbidity, and mortality data collected from a single beef cattle finishing operation. One thousand one hundred eighty nine of 12,812 Charolais-sired calves were treated for BRD during the finishing period. Weaning weight (WW), DMI, days to harvest (D2H), HCW, yield grade (YG), and marbling score determined by image analysis (MARB) were collected to quantify the economic impact associated with treatment for BRD...
December 2016: Journal of Animal Science
https://www.readbyqxmd.com/read/28032455/in-silico-design-and-bioevaluation-of-selective-benzotriazepine-brd4-inhibitors-with-potent-antiosteoclastogenic-activity
#10
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/27988122/deciphering-upper-respiratory-tract-microbiota-complexity-in-healthy-calves-and-calves-that-develop-respiratory-disease-using-shotgun-metagenomics
#11
Natália C Gaeta, Svetlana F Lima, Andre G Teixeira, Erika K Ganda, Georgios Oikonomou, Lilian Gregory, Rodrigo C Bicalho
Bovine respiratory disease (BRD) is a multifactorial disorder responsible for severe economic losses in dairy and feedlot herds. Advances in next-generation sequencing mean that microbial communities in clinical samples, including non-culturable bacteria, can be characterized. Our aim was to evaluate the microbiota of the upper respiratory tract of healthy calves and calves with BRD using whole-genome sequencing (shotgun metagenomics). We performed deep nasopharyngeal swabs on 16 Holstein heifer calves (10 healthy and 6 diagnosed with BRD during the study) at 14 and 28 d of life in 1 dairy herd near Ithaca, New York...
February 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/27983764/bendamustine-lenalidomide-and-dexamethasone-brd-has-high-activity-as-2-nd-line-therapy-for-relapsed-and-refractory-multiple-myeloma-a-phase-ii-trial
#12
Ulrich J M Mey, Wolfram Brugger, Heike Schwarb, Stefanie Pederiva, Andreas Schwarzer, Tobias Dechow, Paul Jehner, Jacqueline Rauh, Christian J Taverna, Mathias Schmid, Martin Schmidt-Hieber, Steffen Doerfel, Natalie Fischer, Axel Ruefer, Carsten Ziske, Wolfgang Knauf, Richard Cathomas, Roger von Moos, Felicitas Hitz, Rafael Sauter, Elke Hiendlmeyer, Nathan Cantoni, Mario Bargetzi, Christoph Driessen
The combination of lenalidomide (Revlimid(®) , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations...
March 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/27980108/dual-hdac-and-pi3k-inhibitor-cudc-907-downregulates-myc-and-suppresses-growth-of-myc-dependent-cancers
#13
Kaiming Sun, Ruzanna Atoyan, Mylissa A Borek, Steven DellaRocca, Maria Elena S Samson, Anna W Ma, Guang-Xin Xu, Troy Patterson, David P Tuck, Jaye L Viner, Ali Fattaey, Jing Wang
Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDACs) and phosphoinositide 3-kinases (PI3Ks), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear...
December 15, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27966810/discovery-of-a-pcaf-bromodomain-chemical-probe
#14
Moses Moustakim, Peter G K Clark, Laura Trulli, Angel L Fuentes de Arriba, Matthias T Ehebauer, Apirat Chaikuad, Emma J Murphy, Jacqui Mendez-Johnson, Danette Daniels, Chun-Feng D Hou, Yu-Hui Lin, John R Walker, Raymond Hui, Hongbing Yang, Lucy Dorrell, Catherine M Rogers, Octovia P Monteiro, Oleg Fedorov, Kilian V M Huber, Stefan Knapp, Jag Heer, Darren J Dixon, Paul E Brennan
The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3...
December 14, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27931931/diagnostic-accuracy-of-clinical-illness-for-bovine-respiratory-disease-brd-diagnosis-in-beef-cattle-placed-in-feedlots-a-systematic-literature-review-and-hierarchical-bayesian-latent-class-meta-analysis
#15
E Timsit, N Dendukuri, I Schiller, S Buczinski
Diagnosis of bovine respiratory disease (BRD) in beef cattle placed in feedlots is typically based on clinical illness (CI) detected by pen-checkers. Unfortunately, the accuracy of this diagnostic approach (namely, sensitivity [Se] and specificity [Sp]) remains poorly understood, in part due to the absence of a reference test for ante-mortem diagnosis of BRD. Our objective was to pool available estimates of CI's diagnostic accuracy for BRD diagnosis in feedlot beef cattle while adjusting for the inaccuracy in the reference test...
December 1, 2016: Preventive Veterinary Medicine
https://www.readbyqxmd.com/read/27926874/multivalent-histone-and-dna-engagement-by-a-phd-brd-pwwp-triple-reader-cassette-recruits-zmynd8-to-k14ac-rich-chromatin
#16
Pavel Savitsky, Tobias Krojer, Takao Fujisawa, Jean-Philippe Lambert, Sarah Picaud, Chen-Yi Wang, Erin K Shanle, Krzysztof Krajewski, Hans Friedrichsen, Alexander Kanapin, Colin Goding, Matthieu Schapira, Anastasia Samsonova, Brian D Strahl, Anne-Claude Gingras, Panagis Filippakopoulos
Elucidation of interactions involving DNA and histone post-translational-modifications (PTMs) is essential for providing insights into complex biological functions. Reader assemblies connected by flexible linkages facilitate avidity and increase affinity; however, little is known about the contribution to the recognition process of multiple PTMs because of rigidity in the absence of conformational flexibility. Here, we resolve the crystal structure of the triple reader module (PHD-BRD-PWWP) of ZMYND8, which forms a stable unit capable of simultaneously recognizing multiple histone PTMs while presenting a charged platform for association with DNA...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27898956/effect-of-timing-of-challenge-following-short-term-natural-exposure-to-bovine-viral-diarrhea-virus-type-1b-on-animal-performance-and-immune-response-in-beef-steers
#17
L Carlos-Valdez, B K Wilson, L O Burciaga-Robles, D L Step, B P Holland, C J Richards, M A Montelongo, A W Confer, R W Fulton, C R Krehbiel
Bovine respiratory disease (BRD) is the most common and economically detrimental disease of beef cattle during the postweaning period, causing the majority of morbidity and mortality in feedlots. The pathogenesis of this disease often includes an initial viral infection, which can predispose cattle to a secondary bacterial infection. The objective of this experiment was to determine the effects of timing of an intratracheal (MH) challenge relative to 72 h of natural exposure to bovine viral diarrhea virus (BVDV) type 1b persistently infected (PI) calves on performance, serum antibody production, total and differential white blood cell (WBC) count, rectal temperature, clinical severity score (CS), and haptoglobin (Hp)...
November 2016: Journal of Animal Science
https://www.readbyqxmd.com/read/27898899/fever-feeding-and-grooming-behavior-around-peak-clinical-signs-in-bovine-respiratory-disease
#18
R L Toaff-Rosenstein, L J Gershwin, C B Tucker
Feedlot cattle are monitored for the sickness response, both physiological and behavioral, to detect bovine respiratory disease (BRD), but this method can be inaccurate. Diagnostic accuracy may improve if the BRD sickness response is better understood. We hypothesized that steers around peak BRD would have fever, anorexia, and less grooming than controls. We also expected sickness response magnitude to be greater as clinical and pathological severity increased. Unvaccinated steers were assigned to challenge with 1 of 5 BRD viruses or bacteria (BRD challenge; = 4/pathogen; 20 total), based on susceptibility as determined by serology...
September 2016: Journal of Animal Science
https://www.readbyqxmd.com/read/27810220/evolving-views-on-bovine-respiratory-disease-an-appraisal-of-selected-key-pathogens-part-1
#19
REVIEW
Gerard M Murray, Rónan G O'Neill, Simon J More, Máire C McElroy, Bernadette Earley, Joseph P Cassidy
Bovine respiratory disease (BRD) is one of the most commonly diagnosed causes of morbidity and mortality in cattle and interactions of factors associated with the animal, the pathogen and the environment are central to its pathogenesis. Emerging knowledge of a role for pathogens traditionally assumed to be minor players in the pathogenesis of BRD reflects an increasingly complex situation that will necessitate regular reappraisal of BRD pathogenesis and control. This review appraises the role of selected key pathogens implicated in BRD pathogenesis to assess how our understanding of their role has evolved in recent years...
November 2016: Veterinary Journal
https://www.readbyqxmd.com/read/27810216/evolving-views-on-bovine-respiratory-disease-an-appraisal-of-selected-control-measures-part-2
#20
REVIEW
Gerard M Murray, Rónan G O'Neill, Simon J More, Máire C McElroy, Bernadette Earley, Joseph P Cassidy
Bovine respiratory disease (BRD) control poses significant challenges to the cattle industry worldwide. The sometimes complex interactions of factors associated with the animal, the pathogen and the environment complicate the implementation of effective control measures. Blanket vaccination or mass medication provides inconsistent control and the effective tackling of BRD will require innovative, evidence-based and targeted interventions which, if employed sensibly, offer useful alternatives for addressing this disease...
November 2016: Veterinary Journal
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