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Drug screen

Ayako Shiba, Shigehiko Uchino, Tomoko Fujii, Masanori Takinami, Shoichi Uezono
BACKGROUND: Acute kidney injury (AKI) occurs in 6.1%-22.4% of patients undergoing major noncardiac surgery. Previous studies have shown no association between intraoperative urine output and postoperative acute renal failure. However, these studies used various definitions of acute renal failure. We therefore investigated the association between intraoperative oliguria and postoperative AKI defined by the serum creatinine criteria of the Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) classification...
June 20, 2018: Anesthesia and Analgesia
Elizabeth Stewart, Cathy Catroppa, Deepak Gill, Richard Webster, John Lawson, Anna Mandalis, Mark Sabaz, Belinda Barton, Suncica Lah
PURPOSE: This study aimed to examine Theory of Mind (ToM) and social competence in children and adolescents with genetic generalised epilepsy (GGE), and explore how they relate to neurocognitive and epilepsy variables. METHODS: Twenty-two children and adolescents with GGE (8-16 years old) and 22 typically developing controls completed two behavioural tasks (faux-pas, strange stories) assessing cognitive and affective ToM, and a battery of standardised neuropsychological tests...
June 18, 2018: Seizure: the Journal of the British Epilepsy Association
Seema Negi, Shashi Kala Singh, Sanjay Kumar, Subodh Kumar, Rakesh K Tyagi
Pregnane & Xenobiotic Receptor (PXR) is one of the 48 members of the ligand-modulated transcription factors belonging to nuclear receptor superfamily. Though PXR is now well-established as a 'xenosensor', regulating the central detoxification and drug metabolizing machinery, it has also emerged as a key player in several metabolic disorders. This makes PXR attractive to both, researchers and pharmaceutical industry since clinical success of small drug molecules can be pre-evaluated on PXR platform. At the early stages of drug discovery, cell-based assays are used for high-throughput screening of small molecules...
June 19, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Alberto Bresciani, Ottavia Cecchetti, Antonino Missineo, Pier Giorgio Pacifici, Licia Tomei, Steven Rodems
Glycosylation is a key posttranslational modification that tags protein to membranes, organelles, secretory pathways, and degradation. Aberrant protein glycosylation is present both in acquired diseases, such as cancer and neurodegeneration, and in congenital disorders of glycosylation (CDGs). Consequently, the ability to interrogate the activity of enzymes that can modify protein glycan moieties is key for drug discovery projects aimed at finding modulators of these enzymes. To date, low-throughput technologies such as SDS-PAGE and mass spectrometry have been used, which are not suitable for compound screening in drug discovery...
June 1, 2018: SLAS Discovery
Elodie Archer-Lahlou, Cathy Lan, R Thomas Jagoe
Standard in vitro myotube culture conditions are nonphysiological and there is increasing evidence that this may distort adaptations to both catabolic and anabolic stimuli and hamper preclinical research into mechanisms and treatments for muscle atrophy in cancer and other chronic diseases. We tested a new model of myotube culture which mimics more accurately the basal conditions for muscle tissue in patients with chronic disease, such as cancer. Myotubes derived from C2C12 myoblasts, cultured under the modified conditions were thinner, more numerous, with more uniform morphology and an increased proportion of mature myotubes...
June 2018: Physiological Reports
Ashley Suchomel, Helen Goeden, Julia Dady
Americans fill upward of four billion prescriptions for pharmaceuticals each year, and many of those pharmaceuticals eventually make their way into the environment. Hundreds of different active pharmaceutical ingredients (APIs) are detected in ambient waters and source water used for drinking water in the U.S. Very few of these drugs have health-based guidance values that suggest a safe level for individuals exposed in the ambient environment through drinking water. The Minnesota Department of Health (MDH) has developed a novel method to derive screening-level human health guidance values for APIs...
June 22, 2018: International Journal of Environmental Research and Public Health
Fernando Alonso, María Josefina Quezada, Gabriel Gola, Victoria Richmond, Gabriela Cabrera, Andrea Barquero, Javier Alberto Ramírez
Over the last decades, much effort has been devoted to the design of the "ideal" library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as they seek to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility...
June 21, 2018: ChemMedChem
John K Chan, Stephanie Chow, Subasish Bhowmik, Amandeep Mann, Daniel S Kapp, Robert L Coleman
Gynecologic cancers comprise of mostly uterine, ovarian, and cervical malignancies and are responsible for 95,000 new cases annually in the United States. Uterine cancer is the most common and the number of new cases and mortality has been increasing. Cervical cancer has decreased due to screening, early detection, and treatment of pre-invasive cancers. However, ovarian cancer remains the most lethal because of advanced stage at diagnosis and drug resistance. The metastatic spread pattern differs amongst these cancers, with uterine and cervical cancer found mostly in the primary organ and ovarian cancer disseminating throughout the peritoneum and upper abdomen at presentation...
June 21, 2018: Clinical & Experimental Metastasis
Jaleh Varshosaz, Ali Jahanian, Masoud Maktoobian
Background: Poly(methyl vinyl ether-maleic acid) (PMVEMA) is a water-soluble, biodegradable polymer used for drug delivery. The aim of the present study was to prepare nanofibers of this polymer as a fast-dissolving carrier for montelukast. Materials and Methods: Polymeric nanofibers were spun by electrospinning method using different ratios of biodegradable polymer of PMVEMA. The processing variables including voltage, distance of the needle to rotating screen, and flow rate of the solution were optimized based on the diameter of the nanofibers, drug content, and release efficiency by a Taguchi design...
2018: Advanced Biomedical Research
Wanyin Chen, Leonel Nguekeu Zebaze, Jihu Dong, Laëtitia Chézeau, Perrine Inquimbert, Sylvain Hugel, Songlin Niu, Fréderic Bihel, Emmanuel Boutant, Eléonore Réal, Pascal Villa, Marie-Pierre Junier, Hervé Chneiweiss, Marcel Hibert, Jacques Haiech, Marie-Claude Kilhoffer, Maria Zeniou
Glioblastoma is a highly heterogeneous brain tumor. The presence of cancer cells with stem-like and tumor initiation/propagation properties contributes to poor prognosis. Glioblastoma cancer stem-like cells (GSC) reside in hypoxic and acidic niches favoring cell quiescence and drug resistance. A high throughput screening recently identified the laxative Bisacodyl as a cytotoxic compound targeting quiescent GSC placed in acidic microenvironments. Bisacodyl activity requires its hydrolysis into DDPM, its pharmacologically active derivative...
June 5, 2018: Oncotarget
Helin Feng, Heather Tillman, Gang Wu, Andrew M Davidoff, Jun Yang
Osteosarcoma (OS) cell lines are widely used in understanding the biological functions of cancer, identification and validation of therapeutic targets, as well as in vitro or in vivo preclinical drug screening. Here we report there is a frequent loss-of-function of polycomb repressive complex 2 (PRC2) in OS cell lines but it is rare in tumor samples based on genomic sequencing data, western blotting and immunohistochemistry analysis of H3K27me3. U2OS and 143B cell lines have a complete loss of function of PRC2 and several others have partial loss...
June 5, 2018: Oncotarget
Jingya Sun, Xin Wang, Boyun Tang, Hongchun Liu, Minmin Zhang, Yueqin Wang, Fangfang Ping, Jian Ding, Aijun Shen, Meiyu Geng
Over the past decade, therapies targeting the VEGF/VEGFR and mTOR pathways have served as the standard of care for the clinical management of renal cell carcinoma (RCC) patients. Albeit promising, these targeted drugs have attained only modest clinical benefits with limited prolonged progression-free survival. Therefore, alternative reasonable and applicable therapeutic approaches should be introduced to improve the clinical outcome of RCC patients. Methods: FDA approved kinase inhibitors were screened to evaluate their abilities to suppress the proliferation of RCC cells...
2018: Theranostics
Gokhan Yildiz
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third-leading cause of malignancy-associated mortality worldwide. HCC cells are highly resistant to chemotherapeutic agents. Therefore, there are currently only two US Food and Drug Administration-approved drugs available for the treatment of HCC. The objective of the present study was to analyze the results of previously published high-throughput drug screening, and in vitro genomic and transcriptomic data from HCC cell lines, and to integrate the obtained results to define the underlying molecular mechanisms of drug sensitivity and resistance in HCC cells...
July 2018: Oncology Letters
Alessandro Grisa, Analia Veitz-Keenan
Data sourcesAn electronic search was performed in PubMed, Web of Science and the Cochrane Library and SciELO databases up to September 2016. References of included studies were also searched. English language restriction was applied.Study selectionClinical monitoring studies with at least six months of follow-up, including retrospective studies, prospective studies, and controlled and randomised clinical trials. Clinical case studies were excluded from the sample and only studies with a minimum of five patients were considered...
June 2018: Evidence-based Dentistry
Shmuel Benenson, Ran Nir-Paz, Mordechai Golomb, Carmela Schwartz, Sharon Amit, Allon E Moses, Matan J Cohen
Medical tourism has a potential of spreading multi-drug resistant bacteria (MDR). The Hadassah Medical Center serves as a referral center for global medical tourists and for Palestinian Authority residents. In order to assess whether patients of these groups are more likely to harbor MDR bacteria than local residents, we reviewed data from all patients admitted to our institution between 2009 and 2014. We compared MDR rates between countries of residency, controlling for gender, age, previous hospitalization and time from admission to MDR detection...
June 21, 2018: Scientific Reports
Natalia J Martinez, Rosita R Asawa, Matthew G Cyr, Alexey Zakharov, Daniel J Urban, Jacob S Roth, Eric Wallgren, Carleen Klumpp-Thomas, Nathan P Coussens, Ganesha Rai, Shyh-Ming Yang, Matthew D Hall, Juan J Marugan, Anton Simeonov, Mark J Henderson
Assessment of the interactions between a drug and its protein target in a physiologically relevant cellular environment constitutes a major challenge in the pre-clinical drug discovery space. The Cellular Thermal Shift Assay (CETSA) enables such an assessment by quantifying the changes in the thermal stability of proteins upon ligand binding in intact cells. Here, we present the development and validation of a homogeneous, standardized, target-independent, and high-throughput (384- and 1536-well formats) CETSA platform that uses a split Nano Luciferase approach (SplitLuc CETSA)...
June 21, 2018: Scientific Reports
Shasha Chong, Claire Dugast-Darzacq, Zhe Liu, Peng Dong, Gina M Dailey, Claudia Cattoglio, Alec Heckert, Sambashiva Banala, Luke Lavis, Xavier Darzacq, Robert Tjian
Many eukaryotic transcription factors (TFs) contain intrinsically disordered low-complexity domains (LCDs), but how they drive transactivation remains unclear. Here, live-cell single-molecule imaging reveals that TF-LCDs form local high-concentration interaction hubs at synthetic and endogenous genomic loci. TF-LCD hubs stabilize DNA binding, recruit RNA polymerase II (Pol II), and activate transcription. LCD-LCD interactions within hubs are highly dynamic, display selectivity with binding partners, and are differentially sensitive to disruption by hexanediols...
June 21, 2018: Science
Yoshiki Nakashima, Chika Miyagi-Shiohira, Hirofumi Noguchi, Takeshi Omasa
We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice...
June 19, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sumathi Sivapalasingam, Mohamed Kamal, Rabih Slim, Romana Hosain, Weiping Shao, Randall Stoltz, Joseph Yen, Laura G Pologe, Yuan Cao, Michael Partridge, Giane Sumner, Leah Lipsich
BACKGROUND: REGN3470-3471-3479 is a co-formulated cocktail of three human monoclonal antibodies targeting three non-overlapping epitopes on Ebola virus. We investigated safety, tolerability, pharmacokinetics, and anti-drug antibodies in healthy adults. METHODS: This randomised, double-blind, placebo-controlled, dose-escalation study was done at a phase 1 unit in the USA. Healthy adults, aged 18-60 years, with a body-mass index of 18·0-30·0 kg/m2 were randomly assigned (3:1) to receive a single intravenous dose of REGN3470-3471-3479 or placebo on day 1 (baseline) in one of the four sequential ascending intravenous dose cohorts (3 mg/kg, 15 mg/kg, 60 mg/kg, and 150 mg/kg)...
June 18, 2018: Lancet Infectious Diseases
Jiayin Diao, Can Xu, Huiting Zheng, Siyi He, Shumei Wang
Viticis Fructus is a traditional Chinese herbal drug processed by various methods to achieve different clinical purposes. Thermal treatment potentially alters chemical composition, which may impact on effectiveness and toxicity. In order to interpret the constituent discrepancies of raw versus processed (stir-fried) Viticis Fructus, a multivariate detection method (NIR, HPLC, and UPLC-MS) based on metabonomics and chemometrics was developed. Firstly, synergy interval partial least squares and partial least squares-discriminant analysis were employed to screen the distinctive wavebands (4319 - 5459 cm-1 ) based on preprocessed near-infrared spectra...
June 21, 2018: Planta Medica
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