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non-targeted drug analysis

Janis C Weeks, William M Roberts, Kristin J Robinson, Melissa Keaney, Jon J Vermeire, Joseph F Urban, Shawn R Lockery, John M Hawdon
The screening of candidate compounds and natural products for anthelmintic activity is important for discovering new drugs against human and animal parasites. We previously validated in Caenorhabditis elegans a microfluidic device ('chip') that records non-invasively the tiny electrophysiological signals generated by rhythmic contraction (pumping) of the worm's pharynx. These electropharyngeograms (EPGs) are recorded simultaneously from multiple worms per chip, providing a medium-throughput readout of muscular and neural activity that is especially useful for compounds targeting neurotransmitter receptors and ion channels...
September 15, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Félix Hernández, Sara Castiglioni, Adrian Covaci, Pim de Voogt, Erik Emke, Barbara Kasprzyk-Hordern, Christoph Ort, Malcolm Reid, Juan V Sancho, Kevin V Thomas, Alexander L N van Nuijs, Ettore Zuccato, Lubertus Bijlsma
The analysis of illicit drugs in urban wastewater is the basis of wastewater-based epidemiology (WBE), and has received much scientific attention because the concentrations measured can be used as a new non-intrusive tool to provide evidence-based and real-time estimates of community-wide drug consumption. Moreover, WBE allows monitoring patterns and spatial and temporal trends of drug use. Although information and expertise from other disciplines is required to refine and effectively apply WBE, analytical chemistry is the fundamental driver in this field...
October 17, 2016: Mass Spectrometry Reviews
Björn Over, Pär Matsson, Christian Tyrchan, Per Artursson, Bradley C Doak, Michael A Foley, Constanze Hilgendorf, Stephen E Johnston, Maurice D Lee, Richard J Lewis, Patrick McCarren, Giovanni Muncipinto, Ulf Norinder, Matthew W D Perry, Jeremy R Duvall, Jan Kihlberg
Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability...
October 17, 2016: Nature Chemical Biology
Christoph Priesner, Ruth Esser, Sabine Tischer, Michael Marburger, Krasimira Aleksandrova, Britta Maecker-Kolhoff, Hans-Gert Heuft, Lilia Goudeva, Rainer Blasczyk, Lubomir Arseniev, Ulrike Köhl, Britta Eiz-Vesper, Stephan Klöß
BACKGROUND AND AIMS: The infusion of enriched CMV-specific donor T-cells appears to be a suitable alternative for the treatment of drug-resistant CMV reactivation or de novo infection after both solid organ and hematopoietic stem cell transplantation. Antiviral lymphocytes can be selected from apheresis products using the CliniMACS Cytokine-Capture-System(®) either with the well-established CliniMACS(®) Plus (Plus) device or with its more versatile successor CliniMACS Prodigy(®) (Prodigy)...
2016: Frontiers in Immunology
Imke H Bartelink, Arief Lalmohamed, Elisabeth M L van Reij, Christopher C Dvorak, Rada M Savic, Juliette Zwaveling, Robbert G M Bredius, Antoine C G Egberts, Marc Bierings, Morris Kletzel, Peter J Shaw, Christa E Nath, George Hempel, Marc Ansari, Maja Krajinovic, Yves Théorêt, Michel Duval, Ron J Keizer, Henrique Bittencourt, Moustapha Hassan, Tayfun Güngör, Robert F Wynn, Paul Veys, Geoff D E Cuvelier, Sarah Marktel, Robert Chiesa, Morton J Cowan, Mary A Slatter, Melisa K Stricherz, Cathryn Jennissen, Janel R Long-Boyle, Jaap Jan Boelens
BACKGROUND: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT...
October 13, 2016: Lancet Haematology
Andras Herner, Jasmina Marjanovic, Tracey Lewandowski, Violeta L Marin, Melanie J Patterson, Laura Miesbauer, Damien Ready, Jon Williams, Anil Vasudevan, Qing Lin
Photoaffinity labels are powerful tools for dissecting ligand-protein interactions, and have a broad utility in medicinal chemistry and drug discovery. Traditional photoaffinity labels work through non-specific C-H/X-H bond insertion reactions with the protein of interest by the highly reactive photo-generated intermediate. Herein, we report a new photo-affinity label, 2-aryl-5-carboxytetrazole (ACT) that interacts with the target protein via a unique mechanism in which the photo-generated carboxynitrile imine reacts with a proximal nucleophile near the target active site...
October 14, 2016: Journal of the American Chemical Society
Praveen K Bharti, Man M Shukla, Pascal Ringwald, Sri Krishna, Pushpendra P Singh, Ajay Yadav, Sweta Mishra, Usha Gahlot, Jai P Malaiya, Amit Kumar, Shambhu Prasad, Pradeep Baghel, Mohan Singh, Jaiprakash Vadadi, Mrigendra P Singh, Maria Dorina G Bustos, Leonard I Ortega, Eva-Maria Christophel, Sher S Kashyotia, Gagan S Sonal, Neeru Singh
BACKGROUND: Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states...
October 13, 2016: Malaria Journal
A Brédart, S Bodson, C Le Tourneau, C Flahault, F Bonnetain, A Beaudeau, E Coquan, S Dolbeault, X Paoletti
This qualitative study aimed to explore cancer patients' perceived tolerance of side effects in phase I drug trials. Patients with solid tumours receiving molecularly targeted agents with/without chemotherapy were eligible for inclusion. In-depth semi-structured interviews were carried out with 17 patients with a median [range] age of 63 [41-72] years. Treatment was discontinued in seven patients. Verbatim transcripts of the audio-taped interviews were analysed using a constructivist grounded theory approach...
October 12, 2016: European Journal of Cancer Care
Emiliano Calvo, Jean-Charles Soria, Wen Wee Ma, Tao Wang, Rastilav Bahleda, Anthony Tolcher, Diana Gernhardt, Joseph O'Connell, Robert Millham, Nagdeep Giri, Michael J Wick, Alex A Adjei, Manuel Hidalgo
PURPOSE: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib-figitumumab combination therapy in patients with advanced solid tumors. EXPERIMENTAL DESIGN: A standard 3+3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks (q3w) and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma (ACC)...
October 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qin Wang, Simone Sciabola, Gabriela Barreiro, Xinjun Hou, Guoyun Bai, Michael J Shapiro, Frank E Koehn, Anabella Villalobos, Matthew P Jacobson
Macrocycles pose challenges for computer-aided drug design due to their conformational complexity. One fundamental challenge is identifying all low-energy conformations of the macrocyclic ring, which is important for modeling target binding, passive membrane permeation, and other conformation-dependent properties. Macrocyclic polyketides are medically and biologically important natural products characterized by structural and functional diversity. Advances in synthetic biology and semi-synthetic methods may enable creation of an even more diverse set of non-natural product polyketides for drug discovery and other applications...
October 12, 2016: Journal of Chemical Information and Modeling
Giuseppina Musumeci, Giacomo Magnani, Isabella Bon, Serena Longo, Alessia Bertoldi, Anna Maria Degli Antoni, Maria Rita Rossi, Alessandro Ruggeri, Vittorio Sambri, Simona Semprini, Laura Sighinolfi, Maria Alessandra Ursitti, Alessandro Zerbini, Vincenzo Colangeli, Leonardo Calza, Alba Carola Finarelli, Erika Massimiliani, Maria Carla Re
It is crucial to establish the timing of infection and distinguish between early and long-lasting HIV-1 infections not only for partner notification and epidemiological surveillance, but also to offer early drug treatment and contain the spread of infection. This study analyzed serum and/or plasma samples with a first positive HIV antibody/antigen result coming from different Medical Centers in the Emilia Romagna Region, North East Italy, using the avidity assay, Western Blotting, RNA viral load, CD4 cell counts and genotyping assay...
September 13, 2016: New Microbiologica
John A Todd, Marina Evangelou, Antony J Cutler, Marcin L Pekalski, Neil M Walker, Helen E Stevens, Linsey Porter, Deborah J Smyth, Daniel B Rainbow, Ricardo C Ferreira, Laura Esposito, Kara M D Hunter, Kevin Loudon, Kathryn Irons, Jennie H Yang, Charles J M Bell, Helen Schuilenburg, James Heywood, Ben Challis, Sankalpa Neupane, Pamela Clarke, Gillian Coleman, Sarah Dawson, Donna Goymer, Katerina Anselmiova, Jane Kennet, Judy Brown, Sarah L Caddy, Jia Lu, Jane Greatorex, Ian Goodfellow, Chris Wallace, Tim I Tree, Mark Evans, Adrian P Mander, Simon Bond, Linda S Wicker, Frank Waldron-Lynch
BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs...
October 2016: PLoS Medicine
Margherita Siracusa, Fabio Petrelli
The aporia is obvious: food supplement, classified and regulated by food law, sometimes have the characteristics and the typical effects of medicines. In addition, these are produced by pharmaceutical companies and, through the scientific officer, are prescribed by doctors and dispensed by pharmacies. This study will attempt to retrace the winding, and sometimes overlapping, regulatory pathways of the legislation on food supplement, food and medicines. It will be important object the particular application of the precautionary principle behind the legislation on food supplement: application "in posterior", so the controls on the purity of the product and the possible effects resulting from the assumption is carried out ex post trade...
September 2016: Recenti Progressi in Medicina
B C Medeiros, A T Fathi, C D DiNardo, D A Pollyea, S M Chan, R Swords
Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation, and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (TCA, also called the 'citric acid' or Krebs) cycle...
October 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Maria Cristina Lo Giudice, Fabian Meder, Ester Polo, Steffi S Thomas, Kholoud Alnahdi, Sandra Lara, Kenneth A Dawson
Nanoparticles (NPs) functionalized with two active targeting ligands have been proposed in drug delivery for their promising capability to stimulate different pathways with one object. Due to the multivalency, the construction and analysis of the effective surface of such bifunctional nanoparticles, however, is significantly more complex than for nanoparticles bearing only one ligand. Here, we optimize construction and analysis of bifunctional NPs containing recognizable combinations of human serum albumin (HSA), transferrin (Tf), and epidermal growth factor (EGF) on fluorescent silica NPs grafted via common polyethylene glycol (PEG) linkers as a model system...
September 29, 2016: Nanoscale
Donatella Aiello, Francesca Casadonte, Rosa Terracciano, Rocco Damiano, Rocco Savino, Giovanni Sindona, Anna Napoli
Prostate cancer (PCa) is the sixth highest causes of cancer-related deaths in men. The molecular events underlying its behavior and evolution are not completely understood. Prostate-specific antigen (PSA) is the only approved Food and Drug Administration biomarker. A panel of ten stage-specific tumoral and adjacent non tumoral tissues from patients affected by PCa (Gleason score 6, 3+3; PSA 10 ÷19 ng/ml) was investigated by MS-based proteomics approach. The proposed method was based on identifying the base-soluble proteins from tissue, established an efficient study, which lead to a deeper molecular perspective understanding of the PCa...
2016: Oncoscience
Xiyu Ouyang, Jana M Weiss, Jacob de Boer, Marja H Lamoree, Pim E G Leonards
Household dust and laundry dryer lint are important indoor environmental matrices that may have notable health effects on humans due to chronic exposure. However, due to the sample complexity the studies conducted on these sample matrices until now were almost exclusively on the basis of target analysis. In this study, comprehensive two-dimensional liquid chromatography coupled with time-of-flight mass spectrometry (LC × LC-ToF MS) was applied, to enable non-target analysis of household dust as well as laundry dryer lint for the first time...
January 2017: Chemosphere
Yu Ouyang, Fei Zhong, Qiru Wang, Linlin Ding, Peipei Zhang, Lingling Chen, Yuchan Wang, Chun Cheng
DIX domain containing 1 (DIXDC1), is a human homolog of Ccd1, a DIX domain containing protein in zebrafish. The present study was undertaken to determine the expression and biologic function of DIXDC1 in Non-Hodgkin's lymphoma (NHL). Clinically, we detected that the expression of DIXDC1 was significantly lower in the indolent lymphomas compared with the progressive lymphomas by immunohistochemistry analysis. Functionally, we found that DIXDC1 could promote cell proliferation via modulating cell cycle progression and PI3K/AKT signaling pathway in NHLs...
September 8, 2016: Leukemia Research
Qingxiang Song, Huahua Song, Jianrong Xu, Jialin Huang, Meng Hu, Xiao Gu, Juan Chen, Gang Zheng, Hongzhuan Chen, Xiaoling Gao
Amyloid beta (Aβ) and its aggregation forms in the brain have been suggested as key targets for the therapy of Alzheimer's disease (AD). Therefore, the development of nanocarriers which possess both blood-brain barrier permeability and Aβ-targeting ability is of great importance for the intervention of AD. Here we constructed a biomimetic nanocarrier named apolipoprotein E (ApoE)-reconstituted high density lipoprotein nanocarrier (ANC) from recombinant ApoE and synthetic lipids to achieve the above goals...
October 4, 2016: Molecular Pharmaceutics
Guo-Hua Jin, Wei Xu, Yang Shi, Li-Bo Wang
Gastric cancer (GC) is a prevalent cancer, which remains incurable, and therefore requires an alternative treatment method. Celecoxib is a nonsteroidal anti-inflammatory drug that targets cyclooxygenase-2, and exhibits anticancer effects. The present study aimed to investigate the anti-GC mechanism of celecoxib using bioinformatics methods. Gene expression datasets GSE56807 (GC tissues and normal gastric tissues) and GSE54657 (celecoxib-treated and non-treated human GC epithelial AGS cells) were downloaded from the Gene Expression Omnibus database...
October 2016: Oncology Letters
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