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https://www.readbyqxmd.com/read/28806746/selective-small-chemical-inhibitors-of-protein-arginine-methyltransferase-5-with-anti-lung-cancer-activity
#1
Gui-Mei Kong, Min Yu, Zhongping Gu, Zhi Chen, Rui-Ming Xu, Deon O'Bryant, Zhengxin Wang
Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation...
2017: PloS One
https://www.readbyqxmd.com/read/28806587/elucidation-of-host-pathogen-protein-protein-interactions-to-uncover-mechanisms-of-host-cell-rewiring
#2
REVIEW
Charlotte Nicod, Amir Banaei-Esfahani, Ben C Collins
Infectious diseases are the result of molecular cross-talks between hosts and their pathogens. These cross-talks are in part mediated by host-pathogen protein-protein interactions (HP-PPI). HP-PPI play crucial roles in infections, as they may tilt the balance either in favor of the pathogens' spread or their clearance. The identification of host proteins targeted by viral or bacterial pathogenic proteins necessary for the infection can provide insights into their underlying molecular mechanisms of pathogenicity, and potentially even single out pharmacological intervention targets...
August 11, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/28806393/craf-gene-fusions-in-pediatric-low-grade-gliomas-define-a-distinct-drug-response-based-on-dimerization-profiles
#3
P Jain, T M Fierst, H J Han, T E Smith, A Vakil, P J Storm, A C Resnick, A J Waanders
Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28806262/an-unusual-case-of-penile-prostate-cancer-uncovered-by-multiparametric-mri-and-psma-targeted-18f-dcfpyl-pet-ct
#4
Steven P Rowe, Michael A Gorin, Linda C Chu, Kenneth J Pienta, Martin G Pomper, Ashley E Ross, Katarzyna J Macura
Multiparametric MRI (mpMRI) is currently the test of choice for imaging sites of prostate cancer located within the pelvis. However, molecular imaging with PET radiotracers that bind to prostate-specific membrane antigen is increasingly being used for this purpose and may compliment mpMRI findings. We present a case of a 59-year-old man with elevated postprostatectomy serum prostate-specific antigen level who was found on both mpMRI and prostate-specific membrane antigen-targeted PET to harbor residual prostate cancer in the corpus spongiosum along the proximal urethra...
August 12, 2017: Clinical Nuclear Medicine
https://www.readbyqxmd.com/read/28806136/harnessing-olig2-function-in-tumorigenicity-and-plasticity-to-target-malignant-gliomas
#5
Jennifer Kosty, Fanghui Lu, Robert Kupp, Shwetal Mehta, Q Richard Lu
Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix-loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity...
August 14, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28806065/synthesis-characterization-and-selective-delivery-of-darpin-gold-nanoparticle-conjugates-to-cancer-cells
#6
Sergey Deyev, Galina Proshkina, Anastasiya Ryabova, Francesco Tavanti, Maria Cristina Menziani, Gennady Eidelshtein, Gabriel Avishai, Alexander B Kotlyar
We demonstrate that the designed ankyril repeat protein (DARPin) _9-29, which specifically targets human epidermal growth factor receptor 2 (HER 2), binds tightly to gold nanoparticles (GNPs). Binding of the protein strongly increases the colloidal stability of the particles. The results of experimental analysis and molecular dynamics simulations show that approximately 35 DARPin _9-29 molecules are bound to the surface of a 5 nm GNP and that the binding does not involve the receptor-binding domain of the protein...
August 14, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28806060/a-smart-dna-machine-for-carcinoembryonic-antigen-detection-by-exonuclease-iii-assisted-target-recycling-and-dna-walker-cascade-amplification
#7
Mengqi He, Kun Wang, Wen-Jing Wang, Yong-Liang Yu, Jian-Hua Wang
Synthetic DNA machine performs quasi-mechanical movements in response to external intervention, suggesting the promise of constructing sensitive and specific biosensors. Herein, a smart DNA walker biosensor for label-free detection of carcinoembryonic antigen (CEA) is developed for the first time by a novel cascade amplification strategy of exonuclease (Exo) III-assisted target recycling (ERA) and DNA walker. ERA as the first stage of amplification generates the walker-DNA, while the autonomous traveling of the walker-DNA on the substrate-modified silica microspheres as the second stage of amplification produces an ultrasensitive fluorescent signal with the help of N-methylmesoporphyrin IX (NMM)...
August 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28806050/linking-high-throughput-screens-to-identify-moas-and-novel-inhibitors-of-mycobacterium-tuberculosis-dihydrofolate-reductase
#8
John P Santa Maria, Yumi Park, Lihu Yang, Nicholas Murgolo, Michael D Altman, Paul Zuck, Greg Adam, Chad Chamberlin, Peter Saradjian, Peter Dandliker, Helena I M Boshoff, Clifton E Barry, Charles Garlisi, David B Olsen, Katherine Young, Meir Glick, Elliott Nickbarg, Peter S Kutchukian
Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for mechanism of action (MoA) and reveal actionable chemical matter. Here we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning is employed to identify chemical features with predicted efficacy targets for a given phenotypic screen...
August 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28805986/histiocytic-sarcoma-new-insights-into-fna-cytomorphology-and-molecular-characteristics
#9
Yin P Hung, Scott B Lovitch, Xiaohua Qian
BACKGROUND: Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes. Molecular characteristics of HS and fine-needle aspiration (FNA) criteria for its diagnosis have not been established. METHODS: A case series of HS in 8 FNA samples from 6 patients was reviewed along with histopathologic and clinical data. Immunohistochemistry was performed on cell blocks (3 cases), core biopsies (5 cases), and surgical specimens (4 cases)...
August 2017: Cancer
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#10
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805741/alcohol-and-cancer-mechanisms-and-therapies
#11
REVIEW
Anuradha Ratna, Pranoti Mandrekar
Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1)-mediated generation of reactive oxygen species, aberrant metabolism of folate and retinoids, increased estrogen, and genetic polymorphisms. Here, we summarize the impact of alcohol drinking on the risk of cancer development and potential underlying molecular mechanisms...
August 14, 2017: Biomolecules
https://www.readbyqxmd.com/read/28805498/gingiskhan%C3%A2-protease-cleavage-allows-a-high-throughput-antibody-to-fab-conversion-enabling-direct-functional-assessment-during-lead-identification-of-human-monoclonal-and-bispecific-igg1-antibodies
#12
Jörg Moelleken, Manuel Endesfelder, Christian Gassner, Sabine Lingke, Simone Tomaschek, Oksana Tyshchuk, Stefan Lorenz, Ulrike Reiff, Michael Mølhøj
The determination of the binding strength of immunoglobulins (IgGs) to targets can be influenced by avidity when the targets are soluble di- or multimeric proteins, or associated to cell surfaces, including surfaces introduced from heterogeneous assays. However, for the understanding of the contribution of a second drug-to-target binding site in molecular design, or for ranking of monovalent binders during lead identification, affinity-based assessment of the binding strength is required. Typically, monovalent binders like antigen-binding fragments (Fabs) are generated by proteolytic cleavage with papain, which often results in a combination of under- and over-digestion, and requires specific optimization and chromatographic purification of the desired Fabs...
August 14, 2017: MAbs
https://www.readbyqxmd.com/read/28805387/polymyxin-binding-to-the-bacterial-outer-membrane-reveals-cation-displacement-and-increasing-membrane-curvature-in-susceptible-but-not-in-resistant-lps-chemotypes
#13
Denys Ewerton da Silva Santos, Laércio Pol-Fachin, Roberto D Lins, Thereza A Soares
Lipid-A is the causative agent of Gram-negative sepsis and responsible for increasingly high mortality rate among hospitalized patients. Compounds that bind Lipid-A can limit this inflammatory process. The cationic antimicrobial peptide polymyxin B (Pmx-B) is one of the simplest molecules capable of selectively bind to Lipid-A, and may serve as a model for further development of Lipid-A binding agents. Gram-negative bacteria resistance to Pmx-B relies on the upregulation of a number of regulatory systems, which promote chemical modifications of the LPS structure, and leads to major changes in the physical-chemical properties of the outer membrane...
August 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28805201/-osteoporosis-and-vascular-calcification-in-rheumatoid-arthritis-the-role-of-osteoprotegerin-and-sclerostin
#14
REVIEW
Magdalena Krajewska-Włodarczyk, Tomasz Stompór
Disorders of bone tissue metabolism and increased frequency of cardiovascular diseases are among the well-known, extra-articular complications of rheumatoid arthritis (ra). The mechanisms leading to local and generalized loss of bone tissue as well as those promoting calcification of vessels are similar. Recently, a great interest has aroused among the studies related to the meaning of the RANKL/RANK/OPG system and the Wnt/β-catenin signaling pathway, as biological links between the bone and vascular systems...
July 21, 2017: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
https://www.readbyqxmd.com/read/28805144/a-qm-protein-ligand-investigation-of-anti-psychotic-drugs-with-the-dopamine-d2-receptor-d2r
#15
Ramin Ekhteiari Salmas, Yusuf Serhat Is, Serdar Durdagi, Matthias Stein, Mine Yurtsever
The dopamine D2 Receptor (D2R) is a member of the G-Protein Coupled Receptor (GPCR) family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson's disease. D2R is the target protein of the commonly used anti-psychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone and quetiapine. Due to their significant side effects and nonselective profiles, the discovery of novel drugs has become a challenge for researchers working in this field...
August 14, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28805061/a-triple-helix-molecular-switch-electrochemical-ratiometric-biosensor-for-ultrasensitive-detection-of-nucleic-acids
#16
Erhu Xiong, Zhenzhen Li, Xiaohua Zhang, Jiawan Zhou, Xiaoxia Yan, Yunqing Liu, Jinhua Chen
Biomolecular receptors such as nucleic acids that switch between two or more conformations upon binding to a specific target can be used to build specific and sensitive biosensors. In this work, based on the electrochemical dual-signaling ratiometric strategy and triple-helix molecular switch, we developed a selective, reusable, and simple electrochemical DNA (E-DNA) biosensor for target DNA (T-DNA) detection. A hairpin DNA capture probe labeled with methylene blue (MB-DNA) self-assembles on the surface of gold electrode (GE) through Au-S bond, and then a single-strand DNA modified with two ferrocenes (Fc-DNA) on each end to enhance the oxidation signal hybridizes with the MB-DNA to form a triple-helix conformation...
August 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28804866/virally-vectored-vaccine-delivery-medical-needs-mechanisms-advantages-and-challenges
#17
Daniel D Pinschewer
Vaccines represent one of the most successful chapters in the history of medicine. Over the past decades, the advent of recombinant cDNA technology has enabled the biomedical community to genetically engineer viruses for vaccine delivery purposes. As a starting point, this review evaluates the unmet medical needs, which drive scientists and industry to exploit such fundamentally new technology for human vaccination. The author discusses the molecular functioning, production and safety profile of replication-competent and -deficient viral vector systems, representing two fundamentally distinct classes of "genetic vaccines"...
August 14, 2017: Swiss Medical Weekly
https://www.readbyqxmd.com/read/28804757/one-aptamer-two-functions-the-full-length-aptamer-inhibits-ampa-receptors-while-the-short-one-inhibits-both-ampa-and-kainate-receptors
#18
William J Jaremko, Zhen Huang, Wei Wen, Andrew Wu, Nicholas Karl, Li Niu
AMPA and kainate receptors, along with NMDA receptors, are distinct subtypes of glutamate ion channels. Excessive activity of AMPA and kainate receptors has been implicated in neurological diseases, such as epilepsy and neuropathic pain. Antagonists that block their activities are therefore potential drug candidates. In a recent article in the Journal of Biological Chemistry by Jaremko et al. 2017, we have reported on the discovery and molecular characterization of an RNA aptamer of a dual functionality: the full-length RNA (101 nucleotide) inhibits AMPA receptors while the truncated or the short (55 nucleotide) RNA inhibits both the AMPA and kainate receptors...
2017: RNA & Disease
https://www.readbyqxmd.com/read/28804599/circulating-exosome-microrna-associated-with-heart-failure-secondary-to-myxomatous-mitral-valve-disease-in-a-naturally-occurring-canine-model
#19
Vicky K Yang, Kerry A Loughran, Dawn M Meola, Christine M Juhr, Kristen E Thane, Airiel M Davis, Andrew M Hoffman
Myxomatous mitral valve disease (MMVD) is functionally and histologically identical to mitral valve prolapse (MVP) in humans. Currently, there are no medical treatments that can delay the progression of this valvular disease or associated cardiac remodelling. Therefore, there is a need to understand the molecular pathology associated with MMVD and MVP better, and thus identify potential therapeutic targets. Circulating exosomes contain small RNA, including miRNA, which reflect cell physiology and pathology...
2017: Journal of Extracellular Vesicles
https://www.readbyqxmd.com/read/28804562/premature-exhaustion-of-mesenchymal-stromal-cells-from-myelodysplastic-syndrome-patients
#20
Yanbin Pang, Chengxin Deng, Suxia Geng, Jianyu Weng, Peilong Lai, Pengjun Liao, Lingji Zeng, Zesheng Lu, Jing Zhang, Xin Du
Myelodysplastic syndrome (MDS) predominantly occurs in aging people. Over the past decades, the cellular and molecular pathologies of MDS cells have been intensively investigated. However, how the bone marrow stromal niches are altered during MDS development remains elusive. In this study, we attempted to isolate and characterize mesenchymal stromal cells (MSCs) from 30 MDS patients. We observed that only 9/30 bone marrow aspirations from MDS patients successfully formed a monolayer in vitro, while 17/17 bone marrow aspirations from normal donors (median age 45 years, range: 22-73 years) succeeded in this process...
2017: American Journal of Translational Research
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