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https://www.readbyqxmd.com/read/29156805/circulating-tumor-dna-shows-variable-clonal-response-of-breast-cancer-during-neoadjuvant-chemotherapy
#1
Ji-Yeon Kim, Donghyun Park, Dae-Soon Son, Seok Jin Nam, Seok Won Kim, Hae Hyun Jung, Yeon Jeong Kim, Gahee Park, Woong-Yang Park, Jeong Eon Lee, Yeon Hee Park
Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer (BC). In this study, we aimed to identify genetic alterations during the process of tumor clonal evolution and examine if ctDNA level well indicated clinical response to neoadjuvant chemotherapy (NAC) and BC recurrence. We performed targeted ultra-deep sequencing of plasma DNAs, matched germline DNAs and tumor DNAs from locally advanced BC patients. Serial plasma DNAs were collected at diagnosis, after the 1(st) cycle of NAC and after curative surgery...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156796/downregulation-of-dna-repair-proteins-and-increased-dna-damage-in-hypoxic-colon-cancer-cells-is-a-therapeutically-exploitable-vulnerability
#2
Jennifer M J Jongen, Lizet M van der Waals, Kari Trumpi, Jamila Laoukili, Niek A Peters, Susanne J Schenning-van Schelven, Klaas M Govaert, Inne H M Borel Rinkes, Onno Kranenburg
Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases. Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1α) and HIF-2α co-expression signatures...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156381/structure-based-methods-to-predict-mutational-resistance-to-diarylpyrimidine-non-nucleoside-reverse-transcriptase-inhibitors
#3
Syeda Maryam Azeem, Alecia N Muwonge, Nehaben Thakkar, Kristina W Lam, Kathleen M Frey
Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is a leading cause of HIV treatment failure. Often included in antiviral therapy, NNRTIs are chemically diverse compounds that bind an allosteric pocket of enzyme target reverse transcriptase (RT). Several new NNRTIs incorporate flexibility in order to compensate for lost interactions with amino acid conferring mutations in RT. Unfortunately, even successful inhibitors such as diarylpyrimidine (DAPY) inhibitor rilpivirine are affected by mutations in RT that confer resistance...
November 9, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29156132/the-pp1-tautomycetin-complex-reveals-a-path-towards-the-development-of-pp1-specific-inhibitors
#4
Meng S Choy, Mark Swingle, Brandon D'Arcy, Kevin Abney, Scott F Rusin, Arminja N Kettenbach, Rebecca Page, Richard E Honkanen, Wolfgang Peti
Selective inhibitors for each serine/threonine phosphatase (PPP) are essential to investigate the biological actions of PPPs and to guide drug development. Although multiple organisms (cyanobacteria, dinoflagellates, beetles, etc.) produce natural toxins that bind and inhibit the active sites of PPPs, they are largely non-selective, typically inhibiting one or more family members with equal potencies. Thus, the use of these toxins as chemical tools to study the relationship between individual PPPs and their biological substrates, and how disruptions in these relationships contributes to human disease, is severely limited...
November 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29155590/semisynthesis-and-biological-evaluation-of-xanthone-amphiphilics-as-selective-highly-potent-antifungal-agents-to-combat-fungal-resistance
#5
Shuimu Lin, Wan Ling Wendy Sin, Jun-Jie Koh, Fanghui Lim, Lin Wang, Derong Cao, Roger W Beuerman, Li Ren, Shouping Liu
New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangostin resulted in interesting antifungal agents with a novel mode of action. Two lead compounds (1 and 2) showed potent antifungal activity against a wide range of fungal pathogens, including drug-resistant C...
November 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29155589/the-reaction-mechanism-of-isopentenyl-phosphate-kinase-a-qm-mm-study
#6
James McClory, David J Timson, Warispreet Singh, Jian Zhang, Meilan Huang
Isopentenyl phosphate kinase (IPK) catalyzes the Mg2+-ATP dependent phosphorylation reactions to produce isopentenyl diphosphate, an important precursor in the synthesis of isopentenols. However, the position of the divalent metal ion in the crystal structures of IPK in complex with ATP and its native substrate IP has not been definitively resolved, and as a result ambiguity surrounds the catalytic mechanism of IP, limiting its exploitation as a biofuel and in drug design. Here we report the conformational change caused by substrate binding and the catalytically competent structure in complex with the metal ion Mg2+ using molecular dynamic simulations and density functional theory-based quantum mechanics/molecular mechanics calculations (B97d/AMBER99)...
November 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29155053/alpha-tocopherol-loaded-chitosan-oleate-nanoemulsions-for-wound-healing-evaluation-on-cell-lines-and-ex-vivo-human-biopsies-and-stabilization-in-spray-dried-trojan-microparticles
#7
M C Bonferoni, F Riva, A Invernizzi, E Dellera, G Sandri, S Rossi, G Marrubini, G Bruni, B Vigani, C Caramella, F Ferrari
An amphiphilic chitosan salt, chitosan oleate (CS-OA), was previously proposed for the physical stabilization of lemongrass antimicrobial nanoemulsions (NE) through a mild spontaneous emulsification process. As both chitosan and oleic acid are described in the literature for their positive effects in wound healing, in the present study CS-OA has been proposed to encapsulate alpha tocopherol (αTph) in NEs aimed to skin wounds. A NE formulation was developed showing about 220 nm dimensions, 36% drug loading, and αTph concentration up to 1 mg/ml...
November 15, 2017: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29154026/inhibitors-of-metallo-%C3%AE-lactamases
#8
REVIEW
Caitlyn M Rotondo, Gerard D Wright
The β-lactams are the most successful class of antibiotic drugs but they are vulnerable to inactivation by a growing cadre of β-lactamases that now number more than a thousand variants. β-Lactamases operate by one of two general chemical mechanisms either catalyzing β-lactam ring hydrolysis via a covalent enzyme intermediate through the aegis of an active site serine residue or through a noncovalent Zn-dependent mechanism. The Ser-β-lactamases are currently dominant in the clinic and consequently, there has been great effort to identify inhibitors and to co-formulate these with β-lactam antibiotics...
November 15, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/29153891/molecular-modeling-of-cationic-porphyrin-anthraquinone-hybrids-as-dna-topoisomerase-ii%C3%AE-inhibitors
#9
Muhammad Arba, Ruslin, Sunandar Ihsan, Setyanto Tri Wahyudi, Daryono H Tjahjono
Human DNA Topoisomerase II has been regarded as a promising target in anticancer drug discovery. In the present study, we designed six porphyrin-anthraquinone hybrids bearing pyrazole or pyridine group as meso substituents and evaluated their potentials as DNA Topoisomerase IIβ inhibitor. First, we investigated the binding orientation of porphyrin hybrids into DNA topoisomerase IIβ employing AutoDock 4.2 and then performed 20-ns molecular dynamics simulations to see the dynamic stability of each porphyrin-Topo IIβ complex using Amber 14...
October 5, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29153505/structural-basis-for-the-inhibitory-effects-of-ubistatins-in-the-ubiquitin-proteasome-pathway
#10
Mark A Nakasone, Timothy A Lewis, Olivier Walker, Anita Thakur, Wissam Mansour, Carlos A Castañeda, Jennifer L Goeckeler-Fried, Frank Parlati, Tsui-Fen Chou, Ortal Hayat, Daoning Zhang, Christina M Camara, Steven M Bonn, Urszula K Nowicka, Susan Krueger, Michael H Glickman, Jeffrey L Brodsky, Raymond J Deshaies, David Fushman
The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it...
November 15, 2017: Structure
https://www.readbyqxmd.com/read/29152321/impact-of-the-number-of-repeated-inhalations-and-patient-characteristics-on-the-residual-amount-of-inhaled-laninamivir-octanoate-hydrate-dry-powder-in-pediatric-patients-with-influenza
#11
Toshiki Murasaka, Kenji Ikemura, Tomoyuki Enokiya, Yuichi Muraki, Mayumi Ikemura, Koji Terada, Takuya Iwamoto, Masahiro Okuda
Background: A dry powder inhaled formulation is used for the anti-influenza drug laninamivir octanoate hydrate (laninamivir). Although two successive inhalations (puffs) are recommended to minimize residual amounts of active ingredients, previous reports suggest that pediatric patients with low peak inspiratory flow are unable to inhale the active ingredient adequately. In the present study, we prospectively investigated the appropriate number of repeated inhalations of laninamivir dry powder and factors influencing the residual amount of ingredients in pediatric patients with influenza...
2017: Journal of Pharmaceutical Health Care and Sciences
https://www.readbyqxmd.com/read/29151650/molecular-modeling-of-cloned-bacillus-subtilis-keratinase-and-its-insinuation-in-psoriasis-treatment-using-docking-studies
#12
Sonali Gupta, Parul Tewatia, Jyoti Misri, Rajni Singh
Present study demonstrated the expression of cloned Bacillus subtilis RSE163 keratinase gene and in silico binding affinities of deduced protein with psoriasis topical drugs for systemic absorption and permeation through skin. The ker gene expressed in E. coli showed significantly higher keratinase activity 450 ± 10.43 U representing 1342 bp nucleotides encoding 447 amino acids with molecular weight of 46 kDa. The modeled structure was validated using ramachandran's plot showing 305 residues (84.3%) in most favoured region...
December 2017: Indian Journal of Microbiology
https://www.readbyqxmd.com/read/29151416/-short-term-deep-sedation-strategy-in-patients-with-spontaneous-intracerebral-hemorrhage-a-randomized-controlled-trial
#13
Zhuheng Wang, Chunzhi Shi, Liping Sun, Qinghua Guo, Wei Qiao, Guanhua Zhou
OBJECTIVE: To evaluate the efficacy and safety of short-term deep sedation strategy in patients with spontaneous intracerebral hemorrhage (ICH) after surgery. METHODS: A perspective, randomized, parallel-group study was conducted. Adult patients with spontaneous ICH and undergoing craniotomy admitted to Daxing Teaching Hospital of Capital Medical University from December 2015 to November 2016 were enrolled. The patients who received surgery were randomly divided into a short-term deep sedation and a slight and middle sedation group...
November 2017: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
https://www.readbyqxmd.com/read/29151344/computation-of-hemagglutinin-free-energy-difference-by-the-confinement-method
#14
Sander Boonstra, Patrick R Onck, Erik Van der Giessen
Hemagglutinin (HA) mediates membrane fusion, a crucial step during influenza virus cell entry. How many HAs are needed for this process is still subject to debate. To aid in this discussion, the confinement free energy method was used to calculate the conformational free energy difference between the extended intermediate and postfusion state of HA. Special care was taken to comply with general guidelines for free energy calculations, thereby obtaining convergence and demonstrating reliability of the results...
November 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29150925/one-pot-synthesis-of-a-multi-template-molecularly-imprinted-polymer-for-the-extraction-of-six-sulfonamide-residues-from-milk-before-hplc-with-diode-array-detection
#15
Maria Kechagia, Victoria Samanidou, Abuzar Kabir, Kenneth G Furton
A highly selective molecularly imprinted polymer sorbent was synthesized and employed for the simultaneous determination of six sulfonamide antibiotic residues (sulfanilamide, sulfacetamide, sulfadiazine, sulfathiazole, sulfamerazine and sulfamethizole) in milk samples. Multi-analyte imprinted particles were used as sorbent in solid phase extraction. Sulfonamides were separated on a high-performance liquid chromatography column (Merck-Lichrospher RP18e, 5 μm 250 × 4 mm) and further identified and quantified by diode array detection...
November 18, 2017: Journal of Separation Science
https://www.readbyqxmd.com/read/29150397/fragment-based-design-synthesis-biological-evaluation-and-sar-of-1h-benzo-d-imidazol-2-yl-1h-indazol-derivatives-as-potent-pdk1-inhibitors
#16
Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L Warner, Sunil Sharma, David J Bearss, Hariprasad Vankayalapati
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively...
October 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29149813/structural-analysis-of-cd59-of-chinese-tree-shrew-a-new-reference-molecule-for-human-immune-system-specific-cd59-drug-discovery
#17
Subhamay Panda, Leena Kumari, Santamay Panda
BACKGROUND: Chinese tree shrews (Tupaia belangeri chinensis) bear several characteristics that are considered to be very crucial for utilizing in animal experimental models in biomedical research. Subsequent to the identification of key aspects and signaling pathways in nervous and immune systems, it is revealed that tree shrews acquires shared common as well as unique characteristics, and hence offers a genetic basis for employing this animal as a prospective model for biomedical research...
November 17, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/29148893/reduced-intensity-delayed-intensification-in-standard-risk-pediatric-acute-lymphoblastic-leukemia-defined-by-undetectable-minimal-residual-disease-results-of-an-international-randomized-trial-aieop-bfm-all-2000
#18
Martin Schrappe, Kirsten Bleckmann, Martin Zimmermann, Andrea Biondi, Anja Möricke, Franco Locatelli, Gunnar Cario, Carmelo Rizzari, Andishe Attarbaschi, Maria Grazia Valsecchi, Claus R Bartram, Elena Barisone, Felix Niggli, Charlotte Niemeyer, Anna Maria Testi, Georg Mann, Ottavio Ziino, Beat Schäfer, Renate Panzer-Grümayer, Rita Beier, Rosanna Parasole, Gudrun Göhring, Wolf-Dieter Ludwig, Fiorina Casale, Paul-Gerhardt Schlegel, Giuseppe Basso, Valentino Conter
Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II)...
November 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29148816/assessment-of-anti-piperacillin-igg-binding-to-structurally-related-drug-protein-adducts
#19
Mohammed Amali, Rosalind Jenkins, Xioali Meng, Lee Faulkner, Paul Whitaker, Daniel Peckham, B Kevin Park, Dean John Naisbitt
The risk of developing hypersensitivity to alternative antibiotics is a concern for penicillin hypersensitive patients and healthcare pro-viders. Herein we use piperacillin hypersensitivity as a model to explore the reactivity of drug-specific IgG against alternative β-lactam protein adducts. Mass spectrometry was used to show the drugs (amoxicillin, flucloxacillin, benzyl penicillin, aztreonam and pipera-cillin) bind to similar lysine residues on the protein carrier bovine serum albumin. However, the hapten-specific IgG antibodies found in piperacillin hypersensitive patient plasma did not bind to other β-lactam protein conjugates...
November 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/29147871/an-optimized-and-feasible-preparation-technique-for-the-industrial-production-of-hydrogel-patches
#20
Wei-Ze Li, Wen-Xia Han, Xu-Liang Hao, Ning Zhao, Xi-Feng Zhai, Li-Bin Yang, Shu-Miao He, Yu-Chuan Cheng, Han Zhang, Li-Na Fu, Yan Zhang, Ze Liang
For hydrogel patches, the laboratory tests could not fully reveal the existing problems of full scale of industrial production, and there are few studies about the preparation technique for the industrial manufacturing process of hydrogel patches. So, the purpose of this work was to elucidate the effects of mainly technological operation and its parameters on the performance of hydrogel patches at the industrial-scale production. The results revealed the following: (1) the aqueous phase was obtained by polyvinylpyrrolidone (PVP) along with tartaric acid dissolved in purified water, then feeding this into a vacuum mixer as a whole in one batch, thus extended the crosslinking reaction time of hydrogel paste (matrix) and allowed the operation of coating/cutting-off to be carried out easily, and there was no permeation of backing layer; (2) the gel strength of the hydrogel patches increased with the increase of working temperature, however, once the temperature exceeded 35 ± 2 °C, the hydrogel paste would lose water severely and the resultant physical crosslinking structure which has lower gel/cohesive strength would easily bring gelatinization/residues during application; (3) the relative humidity (RH) of the standing-workshop was dynamically controlled (namely at 35 ± 2 °C, keeping the RH at 55 ± 5% for 4 days, then 65 ± 5% for 2 days), which would make patches with satisfactory characteristics such as better flexibility, higher adhesive force, smooth flat matrix surface, and without gelatinization/residues and warped edge during the using process; (4) the aging of the packaged hydrogel patches was very sensitive to storage temperature, higher temperature, higher gel strength and lower adhesiveness...
November 16, 2017: AAPS PharmSciTech
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