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https://www.readbyqxmd.com/read/28734965/enhanced-immunostimulatory-activity-of-in-silico-discovered-agonists-of-toll-like-receptor-2-tlr2
#1
M S Murgueitio, S Ebner, P Hörtnagl, C Rakers, R Bruckner, P Henneke, G Wolber, S Santos-Sierra
BACKGROUND: Emergent therapies in anticancer vaccination use Toll-like receptors (TLRs) agonists as dendritic cell (DC) vaccine adjuvants. DCs from the patient are isolated, stimulated with TLR agonists and tumor antigens ex vivo and then infused back into the patient. Although some TLR ligands have been tested in clinical trials, novel TLR agonists with improved immunomodulatory properties are essential to optimize treatment success. We report on the discovery of small-molecule TLR2 agonists, with favorable properties as synthetic adjuvants...
July 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28734794/botulinum-toxin-a-is-effective-to-treat-tension-type-headache-caused-by-hemifacial-spasm
#2
Atsushi Mizuma, Eiichiro Nagata, Takashi Yasuda, Maiko Kouchi, Taira Nakayama, Kazunari Honma, Kentaro Tokuoka, Yasuhisa Kitagawa, Shigeru Nogawa, Shunya Takizawa
OBJECTIVE: We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH. METHODS: Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients' characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined...
July 19, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28734350/dried-urine-spots-a-novel-sampling-technique-for-comprehensive-lc-ms-n-drug-screening
#3
Julian A Michely, Markus R Meyer, Hans H Maurer
Dried matrix spot (DMS) technique as alternative sampling strategy, especially dried urine spots (DUS), might be an alternative for drug screening. So far only particular drugs or drug classes were covered in DMS screenings. Therefore, workup of DUS for a broad comprehensive library-based LC-MS(n) screening was developed. It consisted of enzymatic on-spot deconjugation followed by liquid extraction and LC-MS(n) analysis. This workup was compared to established urine precipitation (UP) and validated according to international guidelines for qualitative approaches, using exemplary compounds of several drug classes (antidepressants, benzodiazepines, cardiovascular drugs, neuroleptics, opioids, stimulants, etc...
August 22, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/28734205/identification-of-mycobacterium-tuberculosis-enoyl-acyl-carrier-protein-reductase-inhibitors-a-combined-in-silico-and-in-vitro-analysis
#4
Mohsin Y Lone, Mohd Athar, Vivek K Gupta, Prakash C Jha
Mycobacterium tuberculosis (Mtb), had developed evolutionary changes in its genome to adapt for survival and thereby generated multi-drug resistant strains. However, novel drug targets that remained unchanged for their biochemical role has impressed the research community to target such proteins. The comprehensive analysis of multiple protein targets has influenced us to make a consensus structural rule exploited by pharmacophore and other allied techniques from a large repository of protein structures. In this pursuit, we made a retrospective analysis of pharmacophores mapped from the tuberculosis structural proteome and identified unique patterns that can be employed for the novel molecules design...
July 14, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28733251/rna-binding-protein-raly-promotes-protein-arginine-methyltransferase-1-alternatively-spliced-isoform-v2-relative-expression-and-metastatic-potential-in-breast-cancer-cells
#5
Emma Bondy-Chorney, R Mitchell Baldwin, Andréanne Didillon, Benoît Chabot, Bernard J Jasmin, Jocelyn Côté
Aberrant expression of Protein Arginine Methyltransferases (PRMTs) has been observed in several cancer types, including breast cancer. We previously reported that the PRMT1v2 isoform, which is generated through inclusion of alternative exon 2, is overexpressed in breast cancer cells and promotes their invasiveness. However, the precise mechanism by which expression of this isoform is controlled and how it is dysregulated in breast cancer remains unknown. Using a custom RNA interference-based screen, we identified several RNA binding proteins (RBP) which, when knocked down, altered the relative abundance of the alternatively spliced PRMT1v2 isoform...
July 18, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28733082/effects-of-novel-triple-stage-antimalarial-ionic-liquids-on-lipid-membrane-models
#6
Ricardo Ferraz, Marina Pinheiro, Ana Gomes, Cátia Teixeira, Cristina Prudêncio, Salette Reis, Paula Gomes
Primaquine-based ionic liquids, obtained by acid-base reaction between parent primaquine and cinnamic acids, were recently found as triple-stage antimalarial hits. These ionic compounds displayed significant activity against both liver- and blood-stage Plasmodium parasites, as well as against stage V P. falciparum parasites. Remarkably, blood-stage activity of the ionic liquids against both chloroquine-sensitive (3D7) and resistant (Dd2) P. falciparum strains was clearly superior to those of the respective covalent (amide) analogues and of parent primaquine...
July 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28732272/screening-of-the-open-scaffolds-collection-from-compounds-australia-identifies-a-new-chemical-entity-with-anthelmintic-activities-against-different-developmental-stages-of-the-barber-s-pole-worm-and-other-parasitic-nematodes
#7
Sarah Preston, Yaqing Jiao, Jonathan B Baell, Jennifer Keiser, Simon Crawford, Anson V Koehler, Tao Wang, Moana M Simpson, Ray M Kaplan, Karla J Cowley, Kaylene J Simpson, Andreas Hofmann, Abdul Jabbar, Robin B Gasser
The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the 'Open Scaffolds' collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the 'Open Scaffolds' collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays...
May 28, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28732184/high-throughput-identification-of-mir-596-inducing-p53-mediated-apoptosis-in-hela-and-hct116-cells-using-cell-microarray
#8
Ming Ma, Junyu Yang, Bolun Wang, Zhihua Zhao, Jianzhong Jeff Xi
miRNAs play a key role in the regulation of gene networks in mammalian cells. However, little is known about their roles and functions in the apoptosis pathway. Here, we conducted a whole-genome miRNA screening for apoptosis and identified more than 100 miRNAs as apoptosis inducers. To further explain the roles of these mRNAs in apoptosis, a second round of screening was conducted between p53 +/+ and -/- cells. Among the hits, miR-596 was identified as a regulator of p53. The overexpression of miR-596 significantly increased p53 at the protein level, thereby inducing apoptosis...
July 1, 2017: SLAS Technology
https://www.readbyqxmd.com/read/28731783/identification-of-sppl2a-inhibitors-by-multiparametric-analysis-of-a-high-content-ultra-high-throughput-screen
#9
Xian Zhang, Marjo Götte, Yvonne Ibig-Rehm, Ansgar Schuffenhauer, Marion Kamke, Dan Beisner, Danilo Guerini, Daniela Siebert, Ghislain M C Bonamy, Daniela Gabriel, Ursula Bodendorf
The intramembrane protease signal peptide peptidase-like 2a (SPPL2a) is a potential drug target for the treatment of autoimmune diseases due to an essential role in B cells and dendritic cells. To screen a library of 1.4 million compounds for inhibitors of SPPL2a, we developed an imaging assay detecting nuclear translocation of the proteolytically released cytosolic substrate fragment. The state-of-the-art hit calling approach based on nuclear translocation resulted in numerous false-positive hits, mainly interrupting intracellular protein trafficking...
July 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28730642/myc-expression-and-translocation-analyses-in-low-grade-and-transformed-follicular-lymphoma
#10
S M Aukema, R van Pel, I Nagel, S Bens, R Siebert, S Rosati, E van den Berg, A G Bosga-Bouwer, R E Kibbelaar, M Hoogendoorn, G W van Imhoff, J C Kluin-Nelemans, P M Kluin, M Nijland
Low grade follicular lymphoma (FL1/2) has an annual risk of transformation of approximately 3% which is associated with aberrations in CDKN2A/B, TP53 and MYC. Like in DLBCL high MYC expression in transformed FL (tFL) might predict a MYC breakpoint. We quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in 4 isolated biopsies of tFL. As controls 28 biopsies of FL1/2 without transformation (median follow up 105 months) and 9 FL3A/B were analyzed...
July 21, 2017: Histopathology
https://www.readbyqxmd.com/read/28730478/high-content-imaging-and-rnai-screens-for-investigating-kinase-network-plasticity
#11
Simon R Stockwell, Sibylle Mittnacht
High-content imaging connects the information-rich method of microscopy with the systematic objective principles of software-driven analysis. Suited to automation and, therefore, considerable scale-up of study size, this approach can deliver multiparametric data over cell populations or at the level of the individual cell and has found considerable utility in reverse genetic and pharmacological screens. Here we present a method to screen small interfering RNA (siRNA) libraries allowing subsequent observation of the impact of each knockdown on two interlinked, high-content, G1-/S-phase cell cycle transition assays related to cyclin-dependent kinase (CDK) 2 activity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28730442/chitosan-nanoparticles-for-mirna-delivery
#12
Merve Denizli, Burcu Aslan, Lingegowda S Mangala, Dahai Jiang, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K Sood
RNA interference techniques represent a promising strategy for therapeutic applications. In addition to small interfering RNA-based approaches, which have been widely studied and translated into clinical investigations, microRNA-based approaches are attractive owing to their "one hit, multiple targets" concept. To overcome challenges with in vivo delivery of microRNAs related to stability, cellular uptake, and specific delivery, our group has developed and characterized chitosan nanoparticles for nucleotide delivery...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28729956/predicting-the-host-of-influenza-viruses-based-on-the-word-vector
#13
Beibei Xu, Zhiying Tan, Kenli Li, Taijiao Jiang, Yousong Peng
Newly emerging influenza viruses continue to threaten public health. A rapid determination of the host range of newly discovered influenza viruses would assist in early assessment of their risk. Here, we attempted to predict the host of influenza viruses using the Support Vector Machine (SVM) classifier based on the word vector, a new representation and feature extraction method for biological sequences. The results show that the length of the word within the word vector, the sequence type (DNA or protein) and the species from which the sequences were derived for generating the word vector all influence the performance of models in predicting the host of influenza viruses...
2017: PeerJ
https://www.readbyqxmd.com/read/28729943/relationship-between-cerebellar-structure-and-emotional-memory-in-depression
#14
Li-Yan Xu, Fang-Cheng Xu, Can Liu, Yi-Fu Ji, Jin-Min Wu, Ying Wang, Hai-Bao Wang, Yong-Qiang Yu
BACKGROUND: A few studies have been conducted on the relationship between cerebellar volume and emotional memory or clinical severity in major depressive disorder (MDD). In this study, we aimed to compare the volume and density of the cerebellar gray matter (GM) in patients with MDD and in healthy controls (HCs) and explore the association between these cerebellar parameters and measurements of emotional memory and clinical severity. METHOD: Voxel-based morphometry (VBM) and Individual Brain Atlases using Statistical Parametric Mapping (IBASPM) were used to assess GM density and volume in the cerebellum, respectively, in patients with MDD and the HCs...
July 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28729623/3d-qsar-studies-on-maslinic-acid-analogs-for-anticancer-activity-against-breast-cancer-cell-line-mcf-7
#15
Sarfaraz Alam, Feroz Khan
Global prevalence of breast cancer and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of field based 3D-QSAR model based on human breast cancer cell line MCF7 in vitro anticancer activity, which defines the molecular level understanding and regions of structure-activity relationship for triterpene maslinic acid and its analogs. The key features such as average shape, hydrophobic regions and electrostatic patterns of active compounds were mined and mapped to virtually screen potential analogs...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28729055/novel-1-2-dihydroquinazolin-2-ones-design-synthesis-and-biological-evaluation-against-trypanosoma-brucei
#16
ThanhTruc Pham, Madeline Walden, Christopher Butler, Rosario Diaz-Gonzalez, Guiomar Pérez-Moreno, Gloria Ceballos-Pérez, Veronica Gomez-Pérez, Raquel García-Hernández, Henry Zecca, Emma Krakoff, Brian Kopec, Ogar Ichire, Caden Mackenzie, Marika Pitot, Luis Miguel Ruiz, Francisco Gamarro, Dolores González-Pacanowska, Miguel Navarro, Amy B Dounay
In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to-lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability...
July 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28728898/kbe009-an-antimalarial-bestatin-like-inhibitor-of-the-plasmodium-falciparum-m1-aminopeptidase-discovered-in-an-ugi-multicomponent-reaction-derived-peptidomimetic-library
#17
Jorge González-Bacerio, Sarah El Chamy Maluf, Yanira Méndez, Isel Pascual, Isabelle Florent, Pollyana M S Melo, Alexandre Budu, Juliana C Ferreira, Ernesto Moreno, Adriana K Carmona, Daniel G Rivera, Maday Alonso Del Rivero, Marcos L Gazarini
Malaria is a global human parasitic disease mainly caused by the protozoon Plasmodium falciparum. Increased parasite resistance to current drugs determines the relevance of finding new treatments against new targets. A novel target is the M1 alanyl-aminopeptidase from P. falciparum (PfA-M1), which is essential for parasite development in human erythrocytes and is inhibited by the pseudo-peptide bestatin. In this work, we used a combinatorial multicomponent approach to produce a library of peptidomimetics and screened it for the inhibition of recombinant PfA-M1 (rPfA-M1) and the in vitro growth of P...
July 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28728785/operative-strategies-to-reduce-cerebral-embolic-events-during-on-and-off-pump-coronary-artery-bypass-surgery-a-stratified-prospective-randomized-trial
#18
Michael E Halkos, Aaron Anderson, Jose Nilo G Binongo, Anthony Stringer, Yi Lasanajak, Vinod H Thourani, Omar M Lattouf, Robert A Guyton, Kim T Baio, Eric Sarin, William B Keeling, N Renee Cook, Katherine Carssow, Alexis Neill, Kathryn E Glas, John D Puskas
OBJECTIVE: To determine the impact of different aortic clamping strategies on the incidence of cerebral embolic events during coronary artery bypass grafting (CABG). METHODS: Between 2012 and 2015, 142 patients with low-grade aortic disease (epiaortic ultrasound grade I/II) undergoing primary isolated CABG were studied. Those undergoing off-pump CABG were randomized to a partial clamp (n = 36) or clampless facilitating device (CFD; n = 36) strategy. Those undergoing on-pump CABG were randomized to a single-clamp (n = 34) or double-clamp (n = 36) strategy...
June 16, 2017: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/28727445/an-antibiotic-that-inhibits-the-atpase-activity-of-an-abc-transporter-by-binding-to-a-remote-extracellular-site
#19
Leigh Morgan Matano, Heidi Gabrielle Morris, Anthony R Hesser, Sara E S Martin, Wonsik Lee, Tristan W Owens, Emaline Laney, Hidemasa Nakaminami, David Hooper, Timothy C Meredith, Suzanne Walker
Antibiotic-resistant strains of Staphylococcus aureus pose a major threat to human health and there is an ongoing need for new antibiotics to treat resistant infections. In a high throughput screen (HTS) of 230,000 small molecules designed to identify bioactive wall teichoic acid (WTA) inhibitors, we identified one hit, which was expanded through chemical synthesis into a small panel of potent compounds. We showed that these compounds target TarG, the transmembrane component of the two-component ATP-binding cassette (ABC) transporter TarGH, which exports WTA precursors to the cell surface for attachment to peptidoglycan...
July 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28726519/cancer-stem-cells-cd133-inhibition-and-cytotoxicity-of-certain-3-phenylthiazolo-3-2-a-benzimidazoles-design-direct-synthesis-crystal-study-and-in-vitro-biological-evaluation
#20
Ghada H Al-Ansary, Wagdy M Eldehna, Hazem A Ghabbour, Sara T A Al-Rashood, Khalid A Al-Rashood, Radwa A Eladwy, Abdullah Al-Dhfyan, Maha M Kabil, Hatem A Abdel-Aziz
Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
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