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https://www.readbyqxmd.com/read/29236237/outcome-of-children-and-adolescents-with-central-nervous-system-tumors-in-phase-i-trials
#1
Fernando Carceller, Francisco Bautista, Irene Jiménez, Raquel Hladun-Álvaro, Cécile Giraud, Luca Bergamaschi, Madhumita Dandapani, Isabelle Aerts, François Doz, Didier Frappaz, Michela Casanova, Bruce Morland, Darren R Hargrave, Gilles Vassal, Andrew D J Pearson, Birgit Geoerger, Lucas Moreno, Lynley V Marshall
Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses...
December 13, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29236213/structural-probing-screening-and-structure-based-drug-repositioning-insights-into-the-identification-of-potential-cox-2-inhibitors-from-selective-coxibs
#2
Uma Devi Bommu, Kranthi Kumar Konidala, Rishika Pamanji, Suneetha Yeguvapalli
The rate-limiting enzyme cyclooxygenase-2 (COX-2) is considered as an insightful prognostic target for non-small cell lung cancer (NSCLC) therapy. Now, administration and prolonged utilization of selective COX-2 inhibitors (COXIBs) towards moderating the NSCLC has been associated with different side effects. In the present study, we focused on the structure-based drug repositioning approaches for predicting therapeutic potential de novo candidates for human COX-2. Due to discrepancies in the eminence of x-ray diffraction structures, creates a big barrier in drug discovery approach...
December 13, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/29235845/structure-based-identification-of-hiv-1-nucleocapsid-protein-inhibitors-active-against-wild-type-and-drug-resistant-hiv-1-strains
#3
Mattia Mori, Lesia Kovalenko, Savina Malancona, Francesco Saladini, Davide De Forni, Manuel Pires, Nicolas Humbert, Eleonore Real, Thomas Botzanowski, Sarah Cianférani, Alessia Giannini, Maria Chiara Dasso Lang, Giulia Cugia, Barbara Poddesu, Franco Lori, Maurizio Zazzi, Steven Harper, Vincenzo Summa, Yves Mély, Maurizio Botta
HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of HIV-1 life cycle are efficient in blocking viral replication, but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets. In this respect, pharmacological inhibition of the highly conserved and multifunctional nucleocapsid protein (NC) of HIV-1 is considered a promising alternative to current drugs, particularly to overcome DR...
December 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29235522/an-optogenetic-arrhythmia-model-to-study-catecholaminergic-polymorphic-ventricular-tachycardia-mutations
#4
Elisabeth Fischer, Alexander Gottschalk, Christina Schüler
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition of abnormal heart rhythm (arrhythmia), induced by physical activity or stress. Mutations in ryanodine receptor 2 (RyR2), a Ca2+ release channel located in the sarcoplasmic reticulum (SR), or calsequestrin 2 (CASQ2), a SR Ca2+ binding protein, are linked to CPVT. For specific drug development and to study distinct arrhythmias, simple models are required to implement and analyze such mutations. Here, we introduced CPVT inducing mutations into the pharynx of Caenorhabditis elegans, which we previously established as an optogenetically paced heart model...
December 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29235481/targeted-inhibition-of-stat-tet1-axis-as-a-therapeutic-strategy-for-acute-myeloid-leukemia
#5
Xi Jiang, Chao Hu, Kyle Ferchen, Ji Nie, Xiaolong Cui, Chih-Hong Chen, Liting Cheng, Zhixiang Zuo, William Seibel, Chunjiang He, Yixuan Tang, Jennifer R Skibbe, Mark Wunderlich, William C Reinhold, Lei Dong, Chao Shen, Stephen Arnovitz, Bryan Ulrich, Jiuwei Lu, Hengyou Weng, Rui Su, Huilin Huang, Yungui Wang, Chenying Li, Xi Qin, James Mulloy, Yi Zheng, Jiajie Diao, Jie Jin, Chong Li, Paul P Liu, Chuan He, Yuan Chen, Jianjun Chen
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML...
December 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29235363/phenotypic-screening-approaches-for-chagas-disease-drug-discovery
#6
Eric Chatelain, Jean-Robert Ioset
Introduction- Chagas disease, caused by the parasite Trypanosoma cruzi, is a global public health issue. Current treatments targeting the parasite are limited to two old nitroheterocyclic drugs with serious side effects. The need for new and safer drugs has prompted numerous drug discovery efforts to identify compounds suitable for parasitological cure in the last decade. Areas covered- Target-based drug discovery has been limited by the small number of well validated targets - the latest example being the failure of azoles, T...
December 13, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29234895/intestinal-stem-cells-to-advance-drug-development-precision-and-regenerative-medicine-a-paradigm-shift-in-translational-research
#7
Jonathan P Mochel, Albert E Jergens, Dawn Kingsbury, Hyun Jung Kim, Martín G Martín, Karin Allenspach
Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies...
December 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29234543/a-new-tool-for-self-evaluation-of-adherence-to-antimuscarinic-drugs-treatment-in-patients-with-urinary-incontinence
#8
Kirill V Kosilov, Sergay A Loparev, Irina G Kuzina, Olga V Shakirova, Yuliya I Gainullina, Liliya V Kosilova, Alexandra S Prokofyeva
Abstract objective: To evaluate the validity of the Medication Adherence Self-Report Inventory (MASRI) questionnaire in determining antimuscarinic drugs adherence in patients with urinary incontinence (UI). Patients and methods: In all, 629 patients [355 (56.4%) women and 274 (43.6%) men], aged 18-65 years, were included. All patients were prescribed antimuscarinic drugs and treatment adherence was tested at the start, and after 4, 8 and 12 weeks using the MASRI...
December 2017: Arab Journal of Urology
https://www.readbyqxmd.com/read/29234480/which-benefits-are-mentioned-most-often-in-drug-development-publications
#9
Vanessa Strüver
Objectives: The aim was to identify theoretically expected as well as actually reported benefits from drug development and the importance of individual patient benefits compared to the collective benefits to society in general. Background: Ethical guidelines require that clinical research involving humans offer the potential for benefit. A number of characteristics can be applied to define research benefit. Often benefit is categorized as being either direct or indirect...
2017: Current Therapeutic Research, Clinical and Experimental
https://www.readbyqxmd.com/read/29234137/ratiometric-mass-spectrometry-for-cell-identification-and-quantitation-using-intracellular-dual-biomarkers
#10
Xiaoming Chen, Fangjie Wo, Jiang Chen, Jie Tan, Tao Wang, Xiao Liang, Jianmin Wu
This study proposed an easy-to-use method for cell identification and quantitation by ratiometric matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Two pairs of MS peaks in the molecular fingerprint of cells were selected as intracellular dual-biomarkers due to the stability and specificity of their ratio values in different types of hepatocellular cancer (HCC) cell lines. Five types of HCC cells can be thereafter differentiated based on these two pairs of intracellular peptides/proteins...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29234073/identification-of-two-novel-genes-slc15a2-and-slco1b3-associated-with-maintenance-dose-variability-of-warfarin-in-a-chinese-population
#11
Liang-Liang Cai, Wen-Qing Huang, Zhi-Ying Su, Hui-Ming Ye, Lian-Sheng Wang, Yuan Wu, Zhong-Ying Zhang, Wei Zhang, Chi-Meng Tzeng
Warfarin is a commonly prescribed and effective oral anticoagulant. Genetic polymorphisms associated with warfarin metabolism and sensitivity have been implicated in the wide inter-individual dose variation that is observed. Several algorithms integrating patients' clinical characteristics and genetic polymorphism information have been explored to predict warfarin dose. However, most of these algorithms could explain only over half of the variation in a warfarin maintenance dose, suggesting that additional genetic factors may exist and need to be identified...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29233703/the-risk-of-osteonecrosis-on-alveolar-healing-after-tooth-extraction-and-systemic-administration-of-antiresorptive-drugs-in-rodents-a-systematic-review
#12
REVIEW
Victor Lousan do Nascimento Poubel, Carolina Amália Barcellos Silva, Luis André Mendonça Mezzomo, Graziela De Luca Canto, Elena Riet Correa Rivero
PURPOSE: There is much concern about the increasing number of patients with medication-related osteonecrosis of the jaw (MRONJ), and many studies have been published in an attempt to understand the pathophysiology of this condition. This study aimed to systematically review the literature on MRONJ arising in rodents under antiresorptive drug therapy after tooth extraction. METHODS: A search of electronic databases, including LILACS, PROQUEST, PubMed, SCOPUS, and the Web of Science...
November 20, 2017: Journal of Cranio-maxillo-facial Surgery
https://www.readbyqxmd.com/read/29233651/identification-of-bicyclic-hexafluoroisopropyl-alcohol-sulfonamides-as-retinoic-acid-receptor-related-orphan-receptor-gamma-ror%C3%AE-rorc-inverse-agonists-employing-structure-based-drug-design-to-improve-pregnane-x-receptor-pxr-selectivity
#13
Hua Gong, David S Weinstein, Zhonghui Lu, James J-W Duan, Sylwia Stachura, Lauren Haque, Ananta Karmakar, Hemalatha Hemagiri, Dhanya Kumar Raut, Arun Kumar Gupta, Javed Khan, Dan Camac, John S Sack, Andrew Pudzianowski, Dauh-Rurng Wu, Melissa Yarde, Ding-Ren Shen, Virna Borowski, Jenny H Xie, Huadong Sun, Celia D'Arienzo, Marta Dabros, Michael A Galella, Faye Wang, Carolyn A Weigelt, Qihong Zhao, William Foster, John E Somerville, Luisa M Salter-Cid, Joel C Barrish, Percy H Carter, T G Murali Dhar
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies...
December 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29233023/improving-the-efficacy-safety-balance-of-polypharmacology-in-multi-target-drug-discovery
#14
Balaguru Ravikumar, Tero Aittokallio
Polypharmacology has emerged as an essential paradigm for modern drug discovery process. Multiple lines of evidence suggest that agents capable of modulating multiple targets in a selective manner may offer also improved balance between therapeutic efficacy and safety compared to single-targeted agents. Areas covered: Herein, the authors review the recent progress made in experimental and computational strategies for addressing the critical challenges with rational discovery of selective multi-targeted agents within the context of polypharmacological modelling...
December 12, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29232638/engineering-a-self-sufficient-mycobacterium-tuberculosis-cyp130-by-gene-fusion-with-the-reductase-domain-of-cyp102a1-from-bacillus-megaterium
#15
Sandra Ortega Ugalde, Rosa A Luirink, Daan P Geerke, Nico P E Vermeulen, Wilbert Bitter, Jan N M Commandeur
CYP130 belongs to the subset of cytochrome P450s from Mycobacterium tuberculosis (Mtb) that have been structurally characterized. Despite several efforts for its functional characterization, CYP130 is still considered an orphan enzyme for which no endogenous or exogenous substrate has been identified. In addition, functional redox-partners for CYP130 have not been clearly established yet, hampering the elucidation of its physiological role. In the present study, a catalytically active fusion protein involving CYP130 and the NADPH reductase-domain of CYP102A1 from Bacillus megaterium was created...
December 7, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29232579/structure-based-identification-of-a-nedd8-activating-enzyme-inhibitor-via-drug-repurposing
#16
Ke-Jia Wu, Hai-Jing Zhong, Guodong Li, Chenfu Liu, Hui-Min David Wang, Dik-Lung Ma, Chung-Hang Leung
NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53...
December 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29232521/an-immunoglobulin-fc-fused-peptide-without-c-terminal-arg-or-lys-residue-augments-neuropilin-1-dependent-tumor-vascular-permeability
#17
Du-San Baek, Jeong-Ho Kim, Ye-Jin Kim, Yong-Sung Kim
Neuropilin-1 (NRP1), which functions as a co-receptor for vascular endothelial growth factor (VEGF) and is implicated in vascular permeability and tumorigenesis, has been targeted by peptides that specifically bind to the VEGF-binding region on NRP1. Like natural VEGF ligands, all known peptides with NRP1-binding activity bind only through a carboxy (C)-terminal R/K-x-x-R/K sequence motif (x stands for any amino acids); this strict requirement is called the C-end rule (CendR). Here, we report immunoglobulin Fc-fused NRP1-specific peptides deviating from CendR...
December 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29230918/poor-continuity-of-care-for-tb-diagnosis-and-treatment-in-zambian-prisons-a-situation-analysis
#18
S Hatwiinda, S M Topp, M Siyambango, J B Harris, K R Maggard, C Chileshe, N Kapata, S E Reid, G Henostroza
OBJECTIVES: Prisons act as infectious disease reservoirs. We aimed to explore the challenges of TB control and continuity of care in prisons in Zambia. METHODS: We evaluated treatment outcomes for a cohort of inmates diagnosed with TB during a TB REACH funded screening program initiated by the Zambia Prisons Service and the Centre for Infectious Disease Research in Zambia. RESULTS: Between October 2010 and September 2011, 6,282 inmates from six prisons were screened for TB, of whom 374 (6...
December 12, 2017: Tropical Medicine & International Health: TM & IH
https://www.readbyqxmd.com/read/29230877/neonatal-mouse-cortical-but-not-isogenic-human-astrocyte-feeder-layers-enhance-the-functional-maturation-of-induced-pluripotent-stem-cell-derived-neurons-in-culture
#19
Fritz W Lischka, Anastasia Efthymiou, Qiong Zhou, Michael D Nieves, Nikki M McCormack, Matthew D Wilkerson, Gauthaman Sukumar, Clifton L Dalgard, Martin L Doughty
Human induced pluripotent stem (iPS) cell-derived neurons and astrocytes are attractive cellular tools for nervous system disease modeling and drug screening. Optimal utilization of these tools requires differentiation protocols that efficiently generate functional cell phenotypes in vitro. As nervous system function is dependent on networked neuronal activity involving both neuronal and astrocytic synaptic functions, we examined astrocyte effects on the functional maturation of neurons from human iPS cell-derived neural stem cells (NSCs)...
December 12, 2017: Glia
https://www.readbyqxmd.com/read/29230865/glial-source-of-nitric-oxide-in-epileptogenesis-a-target-for-disease-modification-in-epilepsy
#20
REVIEW
Shaunik Sharma, Sreekanth Puttachary, Thimmasettappa Thippeswamy
Epileptogenesis is the process of developing an epileptic condition and/or its progression once it is established. The molecules that initiate, promote, and propagate remarkable changes in the brain during epileptogenesis are emerging as targets for prevention/treatment of epilepsy. Epileptogenesis is a continuous process that follows immediately after status epilepticus (SE) in animal models of acquired temporal lobe epilepsy (TLE). Both SE and epileptogenesis are potential therapeutic targets for the discovery of anticonvulsants and antiepileptogenic or disease-modifying agents...
December 12, 2017: Journal of Neuroscience Research
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