bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silico identified targeted inhibitors of P‐glycoprotein overcome multidrug resistance in human cancer cells in culture
Authors: Follit Courtney A. , Brewer Frances K. , Wise John G. , Vogel Pia D. 
Published: September 2015

AbstractFailure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P‐glycoprotein (P‐gp). P‐gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P‐gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P‐gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P‐gp inhibitors for use as co‐therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716–726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug‐like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P‐gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P‐gp‐mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naïve prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 μmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P‐gp inhibition are excellent leads for the development of co‐therapeutics for the treatment of multidrug resistances.
FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib‐mediated cytotoxicity
Authors: Ahmed Dilruba , de Verdier Petra J. , Ryk Charlotta , Lunqe Oscar , Stål Per , Flygare Jenny 
Published: September 2015

AbstractHepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin‐V and PI and 4′,6‐diamidino‐2‐phenylindole‐staining of nuclei. In addition, signs of both caspase‐dependent and – independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly‐ADP ribose polymerase‐cleavage as well as translocation of Apoptosis‐inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3‐II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC.
Randomized pharmacokinetic and drug–drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects
Authors: Das Shampa , Li Jianguo , Armstrong Jon , Learoyd Maria , Edeki Timi 
Published: September 2015

AbstractWe assessed pharmacokinetic and safety profiles of ceftazidime–avibactam administered ± metronidazole, and whether drug–drug interactions exist between ceftazidime and avibactam, or ceftazidime‐avibactam and metronidazole. The first study (NCT01430910) involved two cohorts of healthy subjects. Cohort 1 received ceftazidime–avibactam (2000–500 mg) as a single infusion or as multiple intravenous infusions over 11 days to evaluate ceftazidime–avibactam pharmacokinetics. Cohort 2 received ceftazidime, avibactam, or ceftazidime–avibactam over 4 days to assess drug–drug interaction between ceftazidime and avibactam. The second study (NCT01534247) assessed interaction between ceftazidime–avibactam and metronidazole in subjects receiving ceftazidime–avibactam (2000–500 mg), metronidazole (500 mg), or metronidazole followed by ceftazidime–avibactam over 4 days. In all studies, subjects received a single‐dose on the first and final days, and multiple‐doses every 8 h on intervening days. Concentration‐time profiles for ceftazidime and avibactam administered as single‐ or multiple‐doses separately or together with/without metronidazole were similar. There was no evidence of time‐dependent pharmacokinetics or accumulation. In both interaction studies, 90% confidence intervals for geometric least squares mean ratios of area under the curve and maximum plasma concentrations for each drug were within the predefined interval (80–125%) indicating no drug–drug interaction between ceftazidime and avibactam, or ceftazidime–avibactam and metronidazole. There were no safety concerns. In conclusion, pharmacokinetic parameters and safety of ceftazidime, avibactam, and metronidazole were similar after single and multiple doses with no observed drug–drug interaction between ceftazidime and avibactam, or ceftazidime–avibactam and metronidazole.
Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules
Authors: Harrell Andrew W. , Sychterz Caroline , Ho May Y. , Weber Andrew , Valko Klara , Negash Kitaw 
Published: September 2015

AbstractThe ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution.
Clearance of systemic hematologic tumors by venetoclax (Abt‐199) and navitoclax
Authors: Ackler Scott , Oleksijew Anatol , Chen Jun , Chyla Brenda J. , Clarin Jerry , Foster Kelly , McGonigal Thomas , Mishra Sasmita , Schlessinger Sally , Smith Morey L. , Tahir Stephen K. , Leverson Joel D. , Souers Andrew J. , Boghaert Erwin R. , Hickson Jonathan 
Published: September 2015

AbstractThe Bcl‐2 family inhibitors venetoclax and navitoclax demonstrated potent antitumor activity in chronic lymphocytic leukemia patients, notably in reducing marrow load and adenopathy. Subsequent trials with venetoclax have been initiated in non‐Hodgkin's lymphoma and multiple myeloma patients. Traditional preclinical models fall short either in faithfully recapitulating disease progression within such compartments or in allowing the direct longitudinal analysis of systemic disease. We show that intravenous inoculation of engineered RS4;11 (acute lymphoblastic leukemia) and Granta 519 (mantle cell lymphoma) bioluminescent reporter cell lines result in tumor engraftment of bone marrow, with additional invasion of the central nervous system in the case of Granta 519. Importantly, apoptosis induction and response of these systemically engrafted tumors to Bcl‐2 family inhibitors alone or in combination with standard‐of‐care agents could be monitored longitudinally with optical imaging, and was more accurately reflective of the observed clinical response.
Impact of neonicotinoid seed treatment of cotton on the cotton leafhopper,Amrasca devastans(Hemiptera: Cicadellidae), and its natural enemies
Authors: Saeed Rabia , Razaq Muhammad , Hardy Ian CW 
Published: September 2015

AbstractBACKGROUNDNeonicotinoid seed treatments suppress populations of pest insects efficiently and can enhance crop growth, but they may have negative effects on beneficial arthropods. We evaluated the effects of either imidacloprid or thiamethoxam on the abundances of a sucking pest, the cotton leafhopper (Amrasca devastans), and its arthropod predators under field conditions. We also evaluated the impact of seed treatment on transgenic cotton plant growth, with pests and natural enemies present or absent.RESULTSImidacloprid and thiamethoxam reduced pest abundance, with greater effects when dosages were higher. Treatment at recommended doses delayed the pest in reaching the economic damage threshold by around 10–15 days (thiamethoxam) and 20 days (imidacloprid). Recommended doses also enhanced plant growth under all tested conditions; growth is affected directly as well as via pest suppression. Neonicotinoid applications reduced abundance of beneficial arthropods, with lower populations after higher doses, but negative effects of imidacloprid were not apparent unless the manufacturer‐recommended dose was exceeded.CONCLUSIONImidacloprid applied at the recommended dose of 5 g kg−1seed is effective againstA. devastansand appears to be safer than thiamethoxam for natural enemies, and also enhances plant growth directly. We caution, however, that possible sublethal negative effects on individual beneficial arthropods were not evaluated. © 2015 Society of Chemical Industry
Concise Review: Exciting Cells: Modeling Genetic Epilepsies with Patient-Derived Induced Pluripotent Stem Cells
Authors: Tidball Andrew M. , Parent Jack M. 
Published: September 2015

Abstract
Human induced pluripotent stem cell (iPSC) models of epilepsy are becoming a revolutionary platform for mechanistic studies and drug discovery. The skyrocketing pace of epilepsy gene discovery is vastly outstripping the development of in vivo animal models. Currently, antiepileptic drug prescribing to patients with specific genetic epilepsies is based on small-scale clinical trials and empiricism; however, rapid production of patient-derived iPSC models will allow for precision therapy. We review iPSC-based studies that have already afforded novel discoveries in diseases with epileptic phenotypes, as well as challenges to using iPSC-based neurological disease models. We also discuss iPSC-derived cardiomyocyte studies of arrhythmia-inducing ion channelopathies that exemplify novel drug discovery and use of multielectrode array technology that can be translated to epilepsy research. Beyond initial studies of Rett, Timothy, Phelan-McDermid, and Dravet syndromes, the stage is set for groundbreaking iPSC-based mechanistic and therapeutic discoveries in genetic epilepsies with the potential to impact patient treatment and quality of life.
Contingent versus routine third‐trimester screening for late fetal growth restriction
Authors: Triunfo S. , Crovetto F. , Scazzocchio E. , Parra‐Saavedra M. , Gratacos E. , Figueras F. 
Published: September 2015

ABSTRACTObjectiveTo evaluate the use of third‐trimester ultrasound screening for late fetal growth restriction (FGR) on a contingent basis, according to risk accrued in the second trimester, in an unselected population.MethodsMaternal characteristics, fetal biometry and second‐trimester uterine artery (UtA) Doppler were included in logistic regression analysis to estimate risk for late FGR (birth weight < 3rd percentile, or 3rd–10th percentile plus abnormal cerebroplacental ratio or UtA Doppler, with delivery ≥ 34 weeks). Based on the second‐trimester risk, strategies for performing contingent third‐trimester ultrasound examinations in 10%, 25% or 50% of the cohort were tested against a strategy of routine ultrasound scanning in the entire population at 32 + 0 to 33 + 6 weeks.ResultsModels were constructed based on 1393 patients and validated in 1303 patients, including 73 (5.2%) and 82 late FGR (6.3%) cases, respectively. At the second‐trimester scan, the a‐posteriori second‐trimester risk (a‐posteriori first‐trimester risk (baseline a‐priori risk and mean arterial blood pressure) combined with second‐trimester abdominal circumference and UtA Doppler) yielded an area under the receiver–operating characteristics curve (AUC) of 0.81 (95% CI, 0.74–0.87) (detection rate (DR), 43.1% for a 10% false‐positive rate (FPR)). The combination of a‐posteriori second‐trimester risk plus third‐trimester estimated fetal weight (full model) yielded an AUC of 0.92 (95% CI, 0.88–0.96) (DR, 74% for a 10% FPR). Subjecting 10%, 25% or 50% of the study population to third‐trimester ultrasound, based on a‐posteriori second‐trimester risk, gave AUCs of 0.81 (95% CI, 0.75–0.88), 0.84 (95% CI, 0.78–0.91) and 0.89 (95% CI, 0.84–0.94), respectively. Only the 50% contingent model proved statistically equivalent to performing routine third‐trimester ultrasound scans (AUC, 0.92 (95% CI, 0.88–0.96), P = 0.11).ConclusionA strategy of selecting 50% of the study population to undergo third‐trimester ultrasound examination, based on accrued risk in the second trimester, proved equivalent to routine third‐trimester ultrasound scanning in predicting late FGR. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Use of a perineural coiled catheter at the sciatic nerve in dogs after tibial plateau levelling osteotomy – preliminary observations
Authors: Marolf Vincent , Luyet Cédric , Spadavecchia Claudia , Eichenberger Urs , Rytz Ulrich , Rohrbach Helene 
Published: September 2015

AbstractThe analgesic effects of peripheral nerve blocks can be prolonged with the placement of perineural catheters allowing repeated injections of local anaesthetics in humans. The objectives of this study were to evaluate the clinical suitability of a perineural coiled catheter (PCC) at the sciatic nerve and to evaluate pain during the early post‐operative period in dogs after tibial plateau levelling osteotomy. Pre‐operatively, a combined block of the sciatic and the femoral nerves was performed under sonographic guidance (ropivacaine 0.5%; 0.3 mL kg−1 per nerve). Thereafter, a PCC was placed near the sciatic nerve. Carprofen (4 mg kg−1 intravenously) was administered at the end of anaesthesia. After surgery, all dogs were randomly assigned to receive four injections of ropivacaine (group R; 0.25%, 0.3 mL kg−1) or NaCl 0.9% (group C; 0.3 mL kg−1) every 6 h through the PCC. Pain was assessed by use of a visual analogue scale (VAS) and a multi‐dimensional pain score (4Avet) before surgery (T‐1), for 390 min (T0, T30, T60, T120, T180, T240, T300, T360 and T390) as well as 1 day after surgery (Day 1). Methadone (0.1 mg kg−1) was administered each time the VAS was ≥40 mm or the 4Avet was ≥5. At T390 dogs received buprenorphine (0.02 mg kg−1). Data were compared using Mann–Whitney rank sum tests and repeated measures analysis of variance. Regardless of group allocation, 55% of dogs required methadone. VAS was significantly lower at T390 (P = 0.003), and at Day 1 (P = 0.002) and so was 4Avet at Day 1 (P = 0.012) in group R than in group C. Bleeding occurred in one dog at PCC placement and PCC dislodged six times of 47 PCCs placed. Minor complications occurred with PCC but allowed four repeated administrations of ropivacaine or saline over 24 h in 91.5% of the cases.
Expanding the Size of Catecholesters – Modified Ligands for the Hierarchical Assembly of Dinuclear Titanium(IV) Helicates
Authors: Van Craen David , de Groot Marita , Albrecht Markus , Pan Fanfang , Rissanen Kari 
Published: September 2015

AbstractFive 2,3‐dihydroxybenzoic acid derivatives 1 – 5 were used as starting materials to obtain the corresponding methyl and ethyl esters. Those were applied as ligands in the hierarchical self‐assembly of lithium‐bridged dinuclear titanium(IV) complexes 1a–4a, 1b–3b, and 5b. The equilibria between the mononuclear triscatecholate complexes (monomer) and the dinuclear helicates (dimer) were observed by 1H NMR spectroscopy in [D6]DMSO and [D4]MeOH at room temperature.
Self‐assembly of Dinuclear Double‐stranded Copper(II) Helicates with 3‐Ethoxy‐2‐hydroxyphenyl Substituted Diimines. Synthesis, Molecular Structure, and Host‐guest Recognition of H2O
Authors: Kelly Norman , Schulz Johanna , Gloe Kerstin , Doert Thomas , Gloe Karsten , Wenzel Marco , Acker Margret , Weigand Jan J. 
Published: September 2015

AbstractReaction of equimolar amounts of Cu(OAc)2·H2O and bis[4‐(3‐ethoxysalicylideneamino)phenyl]methane (H2L1) or bis[4‐(3‐ethoxysalicylideneamino)phenyl]sulfide (H2L2) in a 1:1 THF/MeOH mixture leads to the formation of structure‐analogous CuII helicates of the composition [{Cu2L2}(H2O)2}]·4H2O. The helicates form left‐ and right‐handed hydrogen bonded strands using the bound water molecules as glue. Finally, a compact 3D arrangement of the molecules is achieved by weak π···π and CH···π interactions. The CuII ions possess a strongly distorted tetrahedral arrangement with a N2O2 donor set of the involved diimines. In addition, the molecular structure of the ligand H2L2 was determined and solution studies of the complex formation using UV/Vis and ESI‐MS were performed.
Model checking CML: tool development and industrial applications
Authors: Mota A. , Farias A. , Woodcock J. , Larsen P. G. 
Published: September 2015

AbstractA model checker is an automatic tool that traverses a specific structure (normally a Kripke structure referred as the modelM) to check the satisfaction of some (temporal) logical propertyf. This is formally stated asM⊧f. For some formal notations, the modelMof a specificationS(written in a formal languageL) can be described as a labelled transition system (LTS). Specifically, it is not clear in general how usual tools such as SPIN, FDR, PAT, etc., create the LTS representation from a given process. Although one expects the coherence of the LTS generation with the semantics ofL, it is completely hidden inside the model checker itself. In this paper we show how to create a model checker forL, using a development approach based on its operational semantics. We use a systematic semantics embedding and the formal modeling using logic programming and analysis (FORMULA) framework to this end. We illustrate our strategy considering the formal language COMPASS modelling language (CML)—a new language that was based on CSP, VDM and the refinement calculus proposed for modelling and analysis of systems of systems. As FORMULA is based on satisfiability modulo theories solving, our model checker can handle communications and predicates involving data with infinite domains by building and manipulating a symbolic LTS. This goes beyond the capabilities of traditional CSP model checkers such as FDR and PAT. Moreover, we show how to reduce time and space complexities by simple semantic modifications in the embedding. This allows a more semantics-preserving tuning. Finally, we show a real implementation of our model checker in an integrated development platform for CML and its practical use on an industrial case study.
Sulfated Zirconium Catalyst for Synthesis of Dialkylated Diphenylether Disulfonate Gemini Surfactants
Authors: Jiao Tiliu , Liu Xiaochen , Wang Xiaoyu , Niu Jinping 
Published: September 2015

AbstractDialkylated diphenylether disulfonate with different alkyl chain lengths (Cn‐DADS, n = 8, 10 and 12) has been synthesized by Friedel‐Crafts alkylation of olefins (C8, C10 and C12) and diphenyl oxide, followed by sulfonation and neutralization with fuming sulfuric acid. Sulfated zirconia solid acids were prepared and used to catalyze the alkylation reaction. The structure of sulfated zirconia solid acids was identified by infrared spectroscopy. The title compounds were confirmed by infrared spectroscopy and electrospray ionization‐mass spectrometry. Equilibrium surface tension measurements show that the critical micelle concentration (CMC) decreases with an increase in chain length, and the surface tension at CMC (γcmc) of C8‐DADS is the lowest. The minimum area per molecule (Amin) values of Cn‐DADS increase, while the surface excess concentration (Γmax) values decrease with the increase of the alkyl chain length. C10‐DADS has the highest pC20 and CMC/C20 among Cn‐DADS.
Electron Transfer Pathways in Cholesterol Synthesis
Authors: Porter Todd D. 
Published: September 2015

AbstractCholesterol synthesis in the endoplasmic reticulum requires electron input at multiple steps and utilizes both NADH and NADPH as the electron source. Four enzymes catalyzing five steps in the pathway require electron input: squalene monooxygenase, lanosterol demethylase, sterol 4α‐methyl oxidase, and sterol C5‐desaturase. The electron‐donor proteins for these enzymes include cytochrome P450 reductase and the cytochrome b5 pathway. Here I review the evidence for electron donor protein requirements with these enzymes, the evidence for additional electron donor pathways, and the effect of deletion of these redox enzymes on cholesterol and lipid metabolism.
Measuring persistent and transient energy efficiency in the US
Authors: Filippini Massimo , Hunt Lester C. 
Published: September 2015

AbstractThe promotion of US energy efficiency policy is seen as a very important activity. Generally, the level of energy efficiency of a country or state is approximated by energy intensity, commonly calculated as the ratio of energy use to GDP. However, energy intensity is not an accurate proxy for energy efficiency given that changes in energy intensity are a function of changes in several factors including the structure of the economy, climate, efficiency in the use of resources, behaviour and technical change. The aim of this paper is to measure persistent and transient energy efficiency for the whole economy of 49 states in the US using a stochastic frontier energy demand approach. A total US energy demand frontier function is estimated using panel data for 49 states over the period 1995 to 2009 using two panel data models: the Mundlak version of the random effects model (which estimates the persistent part of the energy efficiency) and the true random effects model (which estimates the transient part of the energy efficiency). The analysis confirms that energy intensity is not a good indicator of energy efficiency, whereas, by controlling for a range of economic and other factors, the measures of energy efficiency obtained via the approach adopted here are. Moreover, the estimates show that although for some states energy intensity might give a reasonable indication of a state’s relative energy efficiency, this is not the case for all states.