Prediction of Phase Behavior of Spray-Dried Amorphous Solid Dispersions: Assessment of Thermodynamic Models, Standard Screening Methods and a Novel Atomization Screening Device with Regard to Prediction Accuracy

PubMed Central

Chavez, Pierre-François; Meeus, Joke; Robin, Florent; Schubert, Martin Alexander; Somville, Pascal

2018-01-01

The evaluation of drug–polymer miscibility in the early phase of drug development is essential to ensure successful amorphous solid dispersion (ASD) manufacturing. This work investigates the comparison of thermodynamic models, conventional experimental screening methods (solvent casting, quench cooling), and a novel atomization screening device based on their ability to predict drug–polymer miscibility, solid state properties (Tg value and width), and adequate polymer selection during the development of spray-dried amorphous solid dispersions (SDASDs). Binary ASDs of four drugs and seven polymers were produced at 20:80, 40:60, 60:40, and 80:20 (w/w). Samples were systematically analyzed using modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD). Principal component analysis (PCA) was used to qualitatively assess the predictability of screening methods with regards to SDASD development. Poor correlation was found between theoretical models and experimentally-obtained results. Additionally, the limited ability of usual screening methods to predict the miscibility of SDASDs did not guarantee the appropriate selection of lead excipient for the manufacturing of robust SDASDs. Contrary to standard approaches, our novel screening device allowed the selection of optimal polymer and drug loading and established insight into the final properties and performance of SDASDs at an early stage, therefore enabling the optimization of the scaled-up late-stage development. PMID:29518936

Validation of a school-based amblyopia screening protocol in a kindergarten population.

PubMed

Casas-Llera, Pilar; Ortega, Paula; Rubio, Inmaculada; Santos, Verónica; Prieto, María J; Alio, Jorge L

2016-08-04

To validate a school-based amblyopia screening program model by comparing its outcomes to those of a state-of-the-art conventional ophthalmic clinic examination in a kindergarten population of children between the ages of 4 and 5 years. An amblyopia screening protocol, which consisted of visual acuity measurement using Lea charts, ocular alignment test, ocular motility assessment, and stereoacuity with TNO random-dot test, was performed at school in a pediatric 4- to 5-year-old population by qualified healthcare professionals. The outcomes were validated in a selected group by a conventional ophthalmologic examination performed in a fully equipped ophthalmologic center. The ophthalmologic evaluation was used to confirm whether or not children were correctly classified by the screening protocol. The sensitivity and specificity of the test model to detect amblyopia were established. A total of 18,587 4- to 5-year-old children were subjected to the amblyopia screening program during the 2010-2011 school year. A population of 100 children were selected for the ophthalmologic validation screening. A sensitivity of 89.3%, specificity of 93.1%, positive predictive value of 83.3%, negative predictive value of 95.7%, positive likelihood ratio of 12.86, and negative likelihood ratio of 0.12 was obtained for the amblyopia screening validation model. The amblyopia screening protocol model tested in this investigation shows high sensitivity and specificity in detecting high-risk cases of amblyopia compared to the standard ophthalmologic examination. This screening program may be highly relevant for amblyopia screening at schools.

[Economic impact of lung cancer screening in France: A modeling study].

PubMed

Gendarme, S; Perrot, É; Reskot, F; Bhoowabul, V; Fourre, G; Souquet, P-J; Milleron, B; Couraud, S

2017-09-01

The National Lung Screening Trial found that, in a selected population with a high risk of lung cancer, an annual low-dose CT-scan decreased lung cancer mortality by 20% and overall mortality by 7% compared to annual chest X-Ray. In France, a work group stated that individual screening should be considered in this setting. However, the economic impact of an organized and generalized (to all eligible individuals) screening in France was never reported. This is a modeling study using French population demographic data and published data from randomized screening trials. We used the same selection criteria as NLST: 55-74-year-old smokers for at least 30 pack-years, current smoker or quit less than 15 years. We computed a second model including also 50-54-year-old individuals. Then, we used different participation rates: 65%, 45%, and 32%. According to the considered model, there would be 1,650,588 to 2,283,993 subjects eligible to screening in France. According to the model and participation rate, lung cancer screening would diagnose 3600 to 10,118 stages 1/2 lung cancer each year. There would be 5991 to 16,839 false-positives, of whom 1416 to 3981 would undergo unnecessary surgery. Screening policy would cost 105 to 215 € million per year. However, increasing the price of a cigarette pack by 0.05 to 0.10 € would fully cover the screening costs. Participation rate is a key point for screening impact. Screening could be easily funded by a small increase in cigarette prices. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

A Pre-Screening Questionnaire to Predict Non-24-Hour Sleep-Wake Rhythm Disorder (N24HSWD) among the Blind

PubMed Central

Flynn-Evans, Erin E.; Lockley, Steven W.

2016-01-01

Study Objectives: There is currently no questionnaire-based pre-screening tool available to detect non-24-hour sleep-wake rhythm disorder (N24HSWD) among blind patients. Our goal was to develop such a tool, derived from gold standard, objective hormonal measures of circadian entrainment status, for the detection of N24HSWD among those with visual impairment. Methods: We evaluated the contribution of 40 variables in their ability to predict N24HSWD among 127 blind women, classified using urinary 6-sulfatoxymelatonin period, an objective marker of circadian entrainment status in this population. We subjected the 40 candidate predictors to 1,000 bootstrapped iterations of a logistic regression forward selection model to predict N24HSWD, with model inclusion set at the p < 0.05 level. We removed any predictors that were not selected at least 1% of the time in the 1,000 bootstrapped models and applied a second round of 1,000 bootstrapped logistic regression forward selection models to the remaining 23 candidate predictors. We included all questions that were selected at least 10% of the time in the final model. We subjected the selected predictors to a final logistic regression model to predict N24SWD over 1,000 bootstrapped models to calculate the concordance statistic and adjusted optimism of the final model. We used this information to generate a predictive model and determined the sensitivity and specificity of the model. Finally, we applied the model to a cohort of 1,262 blind women who completed the survey, but did not collect urine samples. Results: The final model consisted of eight questions. The concordance statistic, adjusted for bootstrapping, was 0.85. The positive predictive value was 88%, the negative predictive value was 79%. Applying this model to our larger dataset of women, we found that 61% of those without light perception, and 27% with some degree of light perception, would be referred for further screening for N24HSWD. Conclusions: Our model has predictive utility sufficient to serve as a pre-screening questionnaire for N24HSWD among the blind. Citation: Flynn-Evans EE, Lockley SW. A pre-screening questionnaire to predict non-24-hour sleep-wake rhythm disorder (N24HSWD) among the blind. J Clin Sleep Med 2016;12(5):703–710. PMID:26951421

Efficient Modeling and Active Learning Discovery of Biological Responses

PubMed Central

Naik, Armaghan W.; Kangas, Joshua D.; Langmead, Christopher J.; Murphy, Robert F.

2013-01-01

High throughput and high content screening involve determination of the effect of many compounds on a given target. As currently practiced, screening for each new target typically makes little use of information from screens of prior targets. Further, choices of compounds to advance to drug development are made without significant screening against off-target effects. The overall drug development process could be made more effective, as well as less expensive and time consuming, if potential effects of all compounds on all possible targets could be considered, yet the cost of such full experimentation would be prohibitive. In this paper, we describe a potential solution: probabilistic models that can be used to predict results for unmeasured combinations, and active learning algorithms for efficiently selecting which experiments to perform in order to build those models and determining when to stop. Using simulated and experimental data, we show that our approaches can produce powerful predictive models without exhaustive experimentation and can learn them much faster than by selecting experiments at random. PMID:24358322

Identification of critical chemical features for Aurora kinase-B inhibitors using Hip-Hop, virtual screening and molecular docking

NASA Astrophysics Data System (ADS)

Sakkiah, Sugunadevi; Thangapandian, Sundarapandian; John, Shalini; Lee, Keun Woo

2011-01-01

This study was performed to find the selective chemical features for Aurora kinase-B inhibitors using the potent methods like Hip-Hop, virtual screening, homology modeling, molecular dynamics and docking. The best hypothesis, Hypo1 was validated toward a wide range of test set containing the selective inhibitors of Aurora kinase-B. Homology modeling and molecular dynamics studies were carried out to perform the molecular docking studies. The best hypothesis Hypo1 was used as a 3D query to screen the chemical databases. The screened molecules from the databases were sorted based on ADME and drug like properties. The selective hit compounds were docked and the hydrogen bond interactions with the critical amino acids present in Aurora kinase-B were compared with the chemical features present in the Hypo1. Finally, we suggest that the chemical features present in the Hypo1 are vital for a molecule to inhibit the Aurora kinase-B activity.

Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis.

PubMed

Wu, Olivia; Robertson, Lindsay; Twaddle, Sara; Lowe, Gordon; Clark, Peter; Walker, Isobel; Brenkel, Ivan; Greaves, Mike; Langhorne, Peter; Regan, Lesley; Greer, Ian

2005-10-01

Laboratory testing for the identification of heritable thrombophilia in high-risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost-effectiveness of universal and selective history-based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta-analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost-effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost-effective (ICER 6824 pounds). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER 202,402 pounds). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost-effective than universal screening in all the patient groups evaluated.

Construction of robust prognostic predictors by using projective adaptive resonance theory as a gene filtering method.

PubMed

Takahashi, Hiro; Kobayashi, Takeshi; Honda, Hiroyuki

2005-01-15

For establishing prognostic predictors of various diseases using DNA microarray analysis technology, it is desired to find selectively significant genes for constructing the prognostic model and it is also necessary to eliminate non-specific genes or genes with error before constructing the model. We applied projective adaptive resonance theory (PART) to gene screening for DNA microarray data. Genes selected by PART were subjected to our FNN-SWEEP modeling method for the construction of a cancer class prediction model. The model performance was evaluated through comparison with a conventional screening signal-to-noise (S2N) method or nearest shrunken centroids (NSC) method. The FNN-SWEEP predictor with PART screening could discriminate classes of acute leukemia in blinded data with 97.1% accuracy and classes of lung cancer with 90.0% accuracy, while the predictor with S2N was only 85.3 and 70.0% or the predictor with NSC was 88.2 and 90.0%, respectively. The results have proven that PART was superior for gene screening. The software is available upon request from the authors. honda@nubio.nagoya-u.ac.jp

A BENCHMARKING ANALYSIS FOR FIVE RADIONUCLIDE VADOSE ZONE MODELS (CHAIN, MULTIMED_DP, FECTUZ, HYDRUS, AND CHAIN 2D) IN SOIL SCREENING LEVEL CALCULATIONS

EPA Science Inventory

Five radionuclide vadose zone models with different degrees of complexity (CHAIN, MULTIMED_DP, FECTUZ, HYDRUS, and CHAIN 2D) were selected for use in soil screening level (SSL) calculations. A benchmarking analysis between the models was conducted for a radionuclide (99Tc) rele...

Mental health courts and their selection processes: modeling variation for consistency.

PubMed

Wolff, Nancy; Fabrikant, Nicole; Belenko, Steven

2011-10-01

Admission into mental health courts is based on a complicated and often variable decision-making process that involves multiple parties representing different expertise and interests. To the extent that eligibility criteria of mental health courts are more suggestive than deterministic, selection bias can be expected. Very little research has focused on the selection processes underpinning problem-solving courts even though such processes may dominate the performance of these interventions. This article describes a qualitative study designed to deconstruct the selection and admission processes of mental health courts. In this article, we describe a multi-stage, complex process for screening and admitting clients into mental health courts. The selection filtering model that is described has three eligibility screening stages: initial, assessment, and evaluation. The results of this study suggest that clients selected by mental health courts are shaped by the formal and informal selection criteria, as well as by the local treatment system.

Discovery of Novel HIV-1 Integrase Inhibitors Using QSAR-Based Virtual Screening of the NCI Open Database.

PubMed

Ko, Gene M; Garg, Rajni; Bailey, Barbara A; Kumar, Sunil

2016-01-01

Quantitative structure-activity relationship (QSAR) models can be used as a predictive tool for virtual screening of chemical libraries to identify novel drug candidates. The aims of this paper were to report the results of a study performed for descriptor selection, QSAR model development, and virtual screening for identifying novel HIV-1 integrase inhibitor drug candidates. First, three evolutionary algorithms were compared for descriptor selection: differential evolution-binary particle swarm optimization (DE-BPSO), binary particle swarm optimization, and genetic algorithms. Next, three QSAR models were developed from an ensemble of multiple linear regression, partial least squares, and extremely randomized trees models. A comparison of the performances of three evolutionary algorithms showed that DE-BPSO has a significant improvement over the other two algorithms. QSAR models developed in this study were used in consensus as a predictive tool for virtual screening of the NCI Open Database containing 265,242 compounds to identify potential novel HIV-1 integrase inhibitors. Six compounds were predicted to be highly active (plC50 > 6) by each of the three models. The use of a hybrid evolutionary algorithm (DE-BPSO) for descriptor selection and QSAR model development in drug design is a novel approach. Consensus modeling may provide better predictivity by taking into account a broader range of chemical properties within the data set conducive for inhibition that may be missed by an individual model. The six compounds identified provide novel drug candidate leads in the design of next generation HIV- 1 integrase inhibitors targeting drug resistant mutant viruses.

Novel Design Strategy for Checkpoint Kinase 2 Inhibitors Using Pharmacophore Modeling, Combinatorial Fusion, and Virtual Screening

PubMed Central

Wang, Yen-Ling

2014-01-01

Checkpoint kinase 2 (Chk2) has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. In this study, we will concentrate on Chk2 and the purpose is to find the potential inhibitors by the pharmacophore hypotheses (PhModels), combinatorial fusion, and virtual screening techniques. Applying combinatorial fusion into PhModels and virtual screening techniques is a novel design strategy for drug design. We used combinatorial fusion to analyze the prediction results and then obtained the best correlation coefficient of the testing set (r test) with the value 0.816 by combining the BesttrainBesttest and FasttrainFasttest prediction results. The potential inhibitors were selected from NCI database by screening according to BesttrainBesttest + FasttrainFasttest prediction results and molecular docking with CDOCKER docking program. Finally, the selected compounds have high interaction energy between a ligand and a receptor. Through these approaches, 23 potential inhibitors for Chk2 are retrieved for further study. PMID:24864236

Selection and Validation of Model Early Childhood Projects: Final Report.

ERIC Educational Resources Information Center

Stock, John R.; And Others

Presented is the final report of a research program to select and describe outstanding Handicapped Children's Early Education Program (HCEEP) projects. Projects were analyzed in terms of 14 components of an HCEEP program (such as screening, programing, and inservice training). A detailed discussion of model selection and validation is appendixed.)…

Protein pharmacophore selection using hydration-site analysis

PubMed Central

Hu, Bingjie; Lill, Markus A.

2012-01-01

Virtual screening using pharmacophore models is an efficient method to identify potential lead compounds for target proteins. Pharmacophore models based on protein structures are advantageous because a priori knowledge of active ligands is not required and the models are not biased by the chemical space of previously identified actives. However, in order to capture most potential interactions between all potentially binding ligands and the protein, the size of the pharmacophore model, i.e. number of pharmacophore elements, is typically quite large and therefore reduces the efficiency of pharmacophore based screening. We have developed a new method to select important pharmacophore elements using hydration-site information. The basic premise is that ligand functional groups that replace water molecules in the apo protein contribute strongly to the overall binding affinity of the ligand, due to the additional free energy gained from releasing the water molecule into the bulk solvent. We computed the free energy of water released from the binding site for each hydration site using thermodynamic analysis of molecular dynamics (MD) simulations. Pharmacophores which are co-localized with hydration sites with estimated favorable contributions to the free energy of binding are selected to generate a reduced pharmacophore model. We constructed reduced pharmacophore models for three protein systems and demonstrated good enrichment quality combined with high efficiency. The reduction in pharmacophore model size reduces the required screening time by a factor of 200–500 compared to using all protein pharmacophore elements. We also describe a training process using a small set of known actives to reliably select the optimal set of criteria for pharmacophore selection for each protein system. PMID:22397751

High-throughput screening and small animal models, where are we?

PubMed Central

Giacomotto, Jean; Ségalat, Laurent

2010-01-01

Current high-throughput screening methods for drug discovery rely on the existence of targets. Moreover, most of the hits generated during screenings turn out to be invalid after further testing in animal models. To by-pass these limitations, efforts are now being made to screen chemical libraries on whole animals. One of the most commonly used animal model in biology is the murine model Mus musculus. However, its cost limit its use in large-scale therapeutic screening. In contrast, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the fish Danio rerio are gaining momentum as screening tools. These organisms combine genetic amenability, low cost and culture conditions that are compatible with large-scale screens. Their main advantage is to allow high-throughput screening in a whole-animal context. Moreover, their use is not dependent on the prior identification of a target and permits the selection of compounds with an improved safety profile. This review surveys the versatility of these animal models for drug discovery and discuss the options available at this day. PMID:20423335

"Plate cherry picking": a novel semi-sequential screening paradigm for cheaper, faster, information-rich compound selection.

PubMed

Crisman, Thomas J; Jenkins, Jeremy L; Parker, Christian N; Hill, W Adam G; Bender, Andreas; Deng, Zhan; Nettles, James H; Davies, John W; Glick, Meir

2007-04-01

This work describes a novel semi-sequential technique for in silico enhancement of high-throughput screening (HTS) experiments now employed at Novartis. It is used in situations in which the size of the screen is limited by the readout (e.g., high-content screens) or the amount of reagents or tools (proteins or cells) available. By performing computational chemical diversity selection on a per plate basis (instead of a per compound basis), 25% of the 1,000,000-compound screening was optimized for general initial HTS. Statistical models are then generated from target-specific primary results (percentage inhibition data) to drive the cherry picking and testing from the entire collection. Using retrospective analysis of 11 HTS campaigns, the authors show that this method would have captured on average two thirds of the active compounds (IC(50) < 10 microM) and three fourths of the active Murcko scaffolds while decreasing screening expenditure by nearly 75%. This result is true for a wide variety of targets, including G-protein-coupled receptors, chemokine receptors, kinases, metalloproteinases, pathway screens, and protein-protein interactions. Unlike time-consuming "classic" sequential approaches that require multiple iterations of cherry picking, testing, and building statistical models, here individual compounds are cherry picked just once, based directly on primary screening data. Strikingly, the authors demonstrate that models built from primary data are as robust as models built from IC(50) data. This is true for all HTS campaigns analyzed, which represent a wide variety of target classes and assay types.

Pharmacophore modeling, docking, and principal component analysis based clustering: combined computer-assisted approaches to identify new inhibitors of the human rhinovirus coat protein.

PubMed

Steindl, Theodora M; Crump, Carolyn E; Hayden, Frederick G; Langer, Thierry

2005-10-06

The development and application of a sophisticated virtual screening and selection protocol to identify potential, novel inhibitors of the human rhinovirus coat protein employing various computer-assisted strategies are described. A large commercially available database of compounds was screened using a highly selective, structure-based pharmacophore model generated with the program Catalyst. A docking study and a principal component analysis were carried out within the software package Cerius and served to validate and further refine the obtained results. These combined efforts led to the selection of six candidate structures, for which in vitro anti-rhinoviral activity could be shown in a biological assay.

Improving virtual screening predictive accuracy of Human kallikrein 5 inhibitors using machine learning models.

PubMed

Fang, Xingang; Bagui, Sikha; Bagui, Subhash

2017-08-01

The readily available high throughput screening (HTS) data from the PubChem database provides an opportunity for mining of small molecules in a variety of biological systems using machine learning techniques. From the thousands of available molecular descriptors developed to encode useful chemical information representing the characteristics of molecules, descriptor selection is an essential step in building an optimal quantitative structural-activity relationship (QSAR) model. For the development of a systematic descriptor selection strategy, we need the understanding of the relationship between: (i) the descriptor selection; (ii) the choice of the machine learning model; and (iii) the characteristics of the target bio-molecule. In this work, we employed the Signature descriptor to generate a dataset on the Human kallikrein 5 (hK 5) inhibition confirmatory assay data and compared multiple classification models including logistic regression, support vector machine, random forest and k-nearest neighbor. Under optimal conditions, the logistic regression model provided extremely high overall accuracy (98%) and precision (90%), with good sensitivity (65%) in the cross validation test. In testing the primary HTS screening data with more than 200K molecular structures, the logistic regression model exhibited the capability of eliminating more than 99.9% of the inactive structures. As part of our exploration of the descriptor-model-target relationship, the excellent predictive performance of the combination of the Signature descriptor and the logistic regression model on the assay data of the Human kallikrein 5 (hK 5) target suggested a feasible descriptor/model selection strategy on similar targets. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of hepta-histidine as a candidate drug for Huntington’s disease by in silico-in vitro- in vivo-integrated screens of chemical libraries

NASA Astrophysics Data System (ADS)

Imamura, Tomomi; Fujita, Kyota; Tagawa, Kazuhiko; Ikura, Teikichi; Chen, Xigui; Homma, Hidenori; Tamura, Takuya; Mao, Ying; Taniguchi, Juliana Bosso; Motoki, Kazumi; Nakabayashi, Makoto; Ito, Nobutoshi; Yamada, Kazunori; Tomii, Kentaro; Okano, Hideyuki; Kaye, Julia; Finkbeiner, Steven; Okazawa, Hitoshi

2016-09-01

We identified drug seeds for treating Huntington’s disease (HD) by combining in vitro single molecule fluorescence spectroscopy, in silico molecular docking simulations, and in vivo fly and mouse HD models to screen for inhibitors of abnormal interactions between mutant Htt and physiological Ku70, an essential DNA damage repair protein in neurons whose function is known to be impaired by mutant Htt. From 19,468 and 3,010,321 chemicals in actual and virtual libraries, fifty-six chemicals were selected from combined in vitro-in silico screens; six of these were further confirmed to have an in vivo effect on lifespan in a fly HD model, and two chemicals exerted an in vivo effect on the lifespan, body weight and motor function in a mouse HD model. Two oligopeptides, hepta-histidine (7H) and Angiotensin III, rescued the morphological abnormalities of primary neurons differentiated from iPS cells of human HD patients. For these selected drug seeds, we proposed a possible common structure. Unexpectedly, the selected chemicals enhanced rather than inhibited Htt aggregation, as indicated by dynamic light scattering analysis. Taken together, these integrated screens revealed a new pathway for the molecular targeted therapy of HD.

Identification of hepta-histidine as a candidate drug for Huntington’s disease by in silico-in vitro- in vivo-integrated screens of chemical libraries

PubMed Central

Imamura, Tomomi; Fujita, Kyota; Tagawa, Kazuhiko; Ikura, Teikichi; Chen, Xigui; Homma, Hidenori; Tamura, Takuya; Mao, Ying; Taniguchi, Juliana Bosso; Motoki, Kazumi; Nakabayashi, Makoto; Ito, Nobutoshi; Yamada, Kazunori; Tomii, Kentaro; Okano, Hideyuki; Kaye, Julia; Finkbeiner, Steven; Okazawa, Hitoshi

2016-01-01

We identified drug seeds for treating Huntington’s disease (HD) by combining in vitro single molecule fluorescence spectroscopy, in silico molecular docking simulations, and in vivo fly and mouse HD models to screen for inhibitors of abnormal interactions between mutant Htt and physiological Ku70, an essential DNA damage repair protein in neurons whose function is known to be impaired by mutant Htt. From 19,468 and 3,010,321 chemicals in actual and virtual libraries, fifty-six chemicals were selected from combined in vitro-in silico screens; six of these were further confirmed to have an in vivo effect on lifespan in a fly HD model, and two chemicals exerted an in vivo effect on the lifespan, body weight and motor function in a mouse HD model. Two oligopeptides, hepta-histidine (7H) and Angiotensin III, rescued the morphological abnormalities of primary neurons differentiated from iPS cells of human HD patients. For these selected drug seeds, we proposed a possible common structure. Unexpectedly, the selected chemicals enhanced rather than inhibited Htt aggregation, as indicated by dynamic light scattering analysis. Taken together, these integrated screens revealed a new pathway for the molecular targeted therapy of HD. PMID:27653664

Multiple receptor-ligand based pharmacophore modeling and molecular docking to screen the selective inhibitors of matrix metalloproteinase-9 from natural products.

PubMed

Gao, Qi; Wang, Yijun; Hou, Jiaying; Yao, Qizheng; Zhang, Ji

2017-07-01

Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors. The reliability of pharmacophore model is validated based on the two different decoy sets and relevant experimental data. The virtual screening, combining pharmacophore model with molecular docking, is performed to identify the selective MMP-9 inhibitors from a database of natural products. The four novel MMP-9 inhibitors of natural products, NP-000686, NP-001752, NP-014331, and NP-015905, are found; one of them, NP-000686, is used to perform the experiment of in vitro bioassay inhibiting MMP-9, and the IC 50 value was estimated to be only 13.4 µM, showing the strongly inhibitory activity of NP-000686 against MMP-9, which suggests that our screening results should be reliable. The binding modes of screened inhibitors with MMP-9 active sites were discussed. In addition, the ADMET properties and physicochemical properties of screened four compounds were assessed. The found MMP-9 inhibitors of natural products could serve as the lead compounds for designing the new MMP-9 inhibitors by carrying out structural modifications in the future.

[Evaluation on a fast weight reduction model in vitro].

PubMed

Li, Songtao; Li, Ying; Wen, Ying; Sun, Changhao

2010-03-01

To establish a fast and effective model in vitro for screening weight-reducing drugs and taking preliminary evaluation of the model. Mature adipocytes of SD rat induced by oleic acid were used to establish a obesity model in vitro. Isoprel, genistein, caffeine were selected as positive agents and curcumine as negative agent to evaluate the obesity model. Lipolysis of adipocytes was stimulated significantly by isoprel, genistein and caffeine rather than curcumine. This model could be used efficiently for screening weight-losing drugs.

Simulation optimization of PSA-threshold based prostate cancer screening policies

PubMed Central

Zhang, Jingyu; Denton, Brian T.; Shah, Nilay D.; Inman, Brant A.

2013-01-01

We describe a simulation optimization method to design PSA screening policies based on expected quality adjusted life years (QALYs). Our method integrates a simulation model in a genetic algorithm which uses a probabilistic method for selection of the best policy. We present computational results about the efficiency of our algorithm. The best policy generated by our algorithm is compared to previously recommended screening policies. Using the policies determined by our model, we present evidence that patients should be screened more aggressively but for a shorter length of time than previously published guidelines recommend. PMID:22302420

A reliable computational workflow for the selection of optimal screening libraries.

PubMed

Gilad, Yocheved; Nadassy, Katalin; Senderowitz, Hanoch

2015-01-01

The experimental screening of compound collections is a common starting point in many drug discovery projects. Successes of such screening campaigns critically depend on the quality of the screened library. Many libraries are currently available from different vendors yet the selection of the optimal screening library for a specific project is challenging. We have devised a novel workflow for the rational selection of project-specific screening libraries. The workflow accepts as input a set of virtual candidate libraries and applies the following steps to each library: (1) data curation; (2) assessment of ADME/T profile; (3) assessment of the number of promiscuous binders/frequent HTS hitters; (4) assessment of internal diversity; (5) assessment of similarity to known active compound(s) (optional); (6) assessment of similarity to in-house or otherwise accessible compound collections (optional). For ADME/T profiling, Lipinski's and Veber's rule-based filters were implemented and a new blood brain barrier permeation model was developed and validated (85 and 74 % success rate for training set and test set, respectively). Diversity and similarity descriptors which demonstrated best performances in terms of their ability to select either diverse or focused sets of compounds from three databases (Drug Bank, CMC and CHEMBL) were identified and used for diversity and similarity assessments. The workflow was used to analyze nine common screening libraries available from six vendors. The results of this analysis are reported for each library providing an assessment of its quality. Furthermore, a consensus approach was developed to combine the results of these analyses into a single score for selecting the optimal library under different scenarios. We have devised and tested a new workflow for the rational selection of screening libraries under different scenarios. The current workflow was implemented using the Pipeline Pilot software yet due to the usage of generic components, it can be easily adapted and reproduced by computational groups interested in rational selection of screening libraries. Furthermore, the workflow could be readily modified to include additional components. This workflow has been routinely used in our laboratory for the selection of libraries in multiple projects and consistently selects libraries which are well balanced across multiple parameters.Graphical abstract.

An efficient route to selective bio-oxidation catalysts: an iterative approach comprising modeling, diversification, and screening, based on CYP102A1.

PubMed

Seifert, Alexander; Antonovici, Mihaela; Hauer, Bernhard; Pleiss, Jürgen

2011-06-14

Perillyl alcohol is the terminal hydroxylation product of the cheap and readily available terpene, limonene. It has high potential as an anti-tumor substance, but is of limited availability. In principle, cytochrome P450 monooxygenases, such as the self-sufficient CYP102A1, are promising catalysts for the oxidation of limonene or other inert hydrocarbons. The wild-type enzyme converts (4R)-limonene to four different oxidation products; however, terminal hydroxylation at the allylic C7 is not observed. Here we describe a generic strategy to engineer this widely used enzyme to hydroxylate exclusively the exposed, but chemically less reactive, primary C7 in the presence of other reactive positions. The approach presented here turns CYP102A1 into a highly selective catalyst with a shifted product spectra by successive rounds of modeling, the design of small focused libraries, and screening. In the first round a minimal CYP102A1 mutant library was rationally designed. It contained variants with improved or strongly shifted regio-, stereo- and chemoselectivity, compared to wild-type. From this library the variant with the highest perillyl alcohol ratio was fine-tuned by two additional rounds of molecular modeling, diversification, and screening. In total only 29 variants needed to be screened to identify the triple mutant A264V/A238V/L437F that converts (4R)-limonene to perillyl alcohol with a selectivity of 97 %. Focusing mutagenesis on a small number of relevant positions identified by computational approaches is the key for efficient screening for enzyme selectivity. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Risk prediction models for selection of lung cancer screening candidates: A retrospective validation study

PubMed Central

ten Haaf, Kevin; Tammemägi, Martin C.; Han, Summer S.; Kong, Chung Yin; Plevritis, Sylvia K.; de Koning, Harry J.; Steyerberg, Ewout W.

2017-01-01

Background Selection of candidates for lung cancer screening based on individual risk has been proposed as an alternative to criteria based on age and cumulative smoking exposure (pack-years). Nine previously established risk models were assessed for their ability to identify those most likely to develop or die from lung cancer. All models considered age and various aspects of smoking exposure (smoking status, smoking duration, cigarettes per day, pack-years smoked, time since smoking cessation) as risk predictors. In addition, some models considered factors such as gender, race, ethnicity, education, body mass index, chronic obstructive pulmonary disease, emphysema, personal history of cancer, personal history of pneumonia, and family history of lung cancer. Methods and findings Retrospective analyses were performed on 53,452 National Lung Screening Trial (NLST) participants (1,925 lung cancer cases and 884 lung cancer deaths) and 80,672 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) ever-smoking participants (1,463 lung cancer cases and 915 lung cancer deaths). Six-year lung cancer incidence and mortality risk predictions were assessed for (1) calibration (graphically) by comparing the agreement between the predicted and the observed risks, (2) discrimination (area under the receiver operating characteristic curve [AUC]) between individuals with and without lung cancer (death), and (3) clinical usefulness (net benefit in decision curve analysis) by identifying risk thresholds at which applying risk-based eligibility would improve lung cancer screening efficacy. To further assess performance, risk model sensitivities and specificities in the PLCO were compared to those based on the NLST eligibility criteria. Calibration was satisfactory, but discrimination ranged widely (AUCs from 0.61 to 0.81). The models outperformed the NLST eligibility criteria over a substantial range of risk thresholds in decision curve analysis, with a higher sensitivity for all models and a slightly higher specificity for some models. The PLCOm2012, Bach, and Two-Stage Clonal Expansion incidence models had the best overall performance, with AUCs >0.68 in the NLST and >0.77 in the PLCO. These three models had the highest sensitivity and specificity for predicting 6-y lung cancer incidence in the PLCO chest radiography arm, with sensitivities >79.8% and specificities >62.3%. In contrast, the NLST eligibility criteria yielded a sensitivity of 71.4% and a specificity of 62.2%. Limitations of this study include the lack of identification of optimal risk thresholds, as this requires additional information on the long-term benefits (e.g., life-years gained and mortality reduction) and harms (e.g., overdiagnosis) of risk-based screening strategies using these models. In addition, information on some predictor variables included in the risk prediction models was not available. Conclusions Selection of individuals for lung cancer screening using individual risk is superior to selection criteria based on age and pack-years alone. The benefits, harms, and feasibility of implementing lung cancer screening policies based on risk prediction models should be assessed and compared with those of current recommendations. PMID:28376113

Novel high-resolution computed tomography-based radiomic classifier for screen-identified pulmonary nodules in the National Lung Screening Trial.

PubMed

Peikert, Tobias; Duan, Fenghai; Rajagopalan, Srinivasan; Karwoski, Ronald A; Clay, Ryan; Robb, Richard A; Qin, Ziling; Sicks, JoRean; Bartholmai, Brian J; Maldonado, Fabien

2018-01-01

Optimization of the clinical management of screen-detected lung nodules is needed to avoid unnecessary diagnostic interventions. Herein we demonstrate the potential value of a novel radiomics-based approach for the classification of screen-detected indeterminate nodules. Independent quantitative variables assessing various radiologic nodule features such as sphericity, flatness, elongation, spiculation, lobulation and curvature were developed from the NLST dataset using 726 indeterminate nodules (all ≥ 7 mm, benign, n = 318 and malignant, n = 408). Multivariate analysis was performed using least absolute shrinkage and selection operator (LASSO) method for variable selection and regularization in order to enhance the prediction accuracy and interpretability of the multivariate model. The bootstrapping method was then applied for the internal validation and the optimism-corrected AUC was reported for the final model. Eight of the originally considered 57 quantitative radiologic features were selected by LASSO multivariate modeling. These 8 features include variables capturing Location: vertical location (Offset carina centroid z), Size: volume estimate (Minimum enclosing brick), Shape: flatness, Density: texture analysis (Score Indicative of Lesion/Lung Aggression/Abnormality (SILA) texture), and surface characteristics: surface complexity (Maximum shape index and Average shape index), and estimates of surface curvature (Average positive mean curvature and Minimum mean curvature), all with P<0.01. The optimism-corrected AUC for these 8 features is 0.939. Our novel radiomic LDCT-based approach for indeterminate screen-detected nodule characterization appears extremely promising however independent external validation is needed.

An efficient platform for genetic selection and screening of gene switches in Escherichia coli

PubMed Central

Muranaka, Norihito; Sharma, Vandana; Nomura, Yoko; Yokobayashi, Yohei

2009-01-01

Engineered gene switches and circuits that can sense various biochemical and physical signals, perform computation, and produce predictable outputs are expected to greatly advance our ability to program complex cellular behaviors. However, rational design of gene switches and circuits that function in living cells is challenging due to the complex intracellular milieu. Consequently, most successful designs of gene switches and circuits have relied, to some extent, on high-throughput screening and/or selection from combinatorial libraries of gene switch and circuit variants. In this study, we describe a generic and efficient platform for selection and screening of gene switches and circuits in Escherichia coli from large libraries. The single-gene dual selection marker tetA was translationally fused to green fluorescent protein (gfpuv) via a flexible peptide linker and used as a dual selection and screening marker for laboratory evolution of gene switches. Single-cycle (sequential positive and negative selections) enrichment efficiencies of >7000 were observed in mock selections of model libraries containing functional riboswitches in liquid culture. The technique was applied to optimize various parameters affecting the selection outcome, and to isolate novel thiamine pyrophosphate riboswitches from a complex library. Artificial riboswitches with excellent characteristics were isolated that exhibit up to 58-fold activation as measured by fluorescent reporter gene assay. PMID:19190095

Novel design strategy for checkpoint kinase 2 inhibitors using pharmacophore modeling, combinatorial fusion, and virtual screening.

PubMed

Lin, Chun-Yuan; Wang, Yen-Ling

2014-01-01

Checkpoint kinase 2 (Chk2) has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. In this study, we will concentrate on Chk2 and the purpose is to find the potential inhibitors by the pharmacophore hypotheses (PhModels), combinatorial fusion, and virtual screening techniques. Applying combinatorial fusion into PhModels and virtual screening techniques is a novel design strategy for drug design. We used combinatorial fusion to analyze the prediction results and then obtained the best correlation coefficient of the testing set (r test) with the value 0.816 by combining the Best(train)Best(test) and Fast(train)Fast(test) prediction results. The potential inhibitors were selected from NCI database by screening according to Best(train)Best(test) + Fast(train)Fast(test) prediction results and molecular docking with CDOCKER docking program. Finally, the selected compounds have high interaction energy between a ligand and a receptor. Through these approaches, 23 potential inhibitors for Chk2 are retrieved for further study.

Application of clustering analysis in the prediction of photovoltaic power generation based on neural network

NASA Astrophysics Data System (ADS)

Cheng, K.; Guo, L. M.; Wang, Y. K.; Zafar, M. T.

2017-11-01

In order to select effective samples in the large number of data of PV power generation years and improve the accuracy of PV power generation forecasting model, this paper studies the application of clustering analysis in this field and establishes forecasting model based on neural network. Based on three different types of weather on sunny, cloudy and rainy days, this research screens samples of historical data by the clustering analysis method. After screening, it establishes BP neural network prediction models using screened data as training data. Then, compare the six types of photovoltaic power generation prediction models before and after the data screening. Results show that the prediction model combining with clustering analysis and BP neural networks is an effective method to improve the precision of photovoltaic power generation.

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories.

PubMed

Dobi, Krisztina; Flachner, Beáta; Pukáncsik, Mária; Máthé, Enikő; Bognár, Melinda; Szaszkó, Mária; Magyar, Csaba; Hajdú, István; Lőrincz, Zsolt; Simon, István; Fülöp, Ferenc; Cseh, Sándor; Dormán, György

2015-10-01

Rapid in silico selection of target-focused libraries from commercial repositories is an attractive and cost-effective approach. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compound databases, but the generated library requires further focusing. We report here a combination of the 2D approach with pharmacophore matching which was used for selecting 5-HT6 antagonists. In the first screening round, 12 compounds showed >85% antagonist efficacy of the 91 screened. For the second-round (hit validation) screening phase, pharmacophore models were built, applied, and compared with the routine 2D similarity search. Three pharmacophore models were created based on the structure of the reference compounds and the first-round hit compounds. The pharmacophore search resulted in a high hit rate (40%) and led to novel chemotypes, while 2D similarity search had slightly better hit rate (51%), but lacking the novelty. To demonstrate the power of the virtual screening cascade, ligand efficiency indices were also calculated and their steady improvement was confirmed. © 2015 John Wiley & Sons A/S.

Independence screening for high dimensional nonlinear additive ODE models with applications to dynamic gene regulatory networks.

PubMed

Xue, Hongqi; Wu, Shuang; Wu, Yichao; Ramirez Idarraga, Juan C; Wu, Hulin

2018-05-02

Mechanism-driven low-dimensional ordinary differential equation (ODE) models are often used to model viral dynamics at cellular levels and epidemics of infectious diseases. However, low-dimensional mechanism-based ODE models are limited for modeling infectious diseases at molecular levels such as transcriptomic or proteomic levels, which is critical to understand pathogenesis of diseases. Although linear ODE models have been proposed for gene regulatory networks (GRNs), nonlinear regulations are common in GRNs. The reconstruction of large-scale nonlinear networks from time-course gene expression data remains an unresolved issue. Here, we use high-dimensional nonlinear additive ODEs to model GRNs and propose a 4-step procedure to efficiently perform variable selection for nonlinear ODEs. To tackle the challenge of high dimensionality, we couple the 2-stage smoothing-based estimation method for ODEs and a nonlinear independence screening method to perform variable selection for the nonlinear ODE models. We have shown that our method possesses the sure screening property and it can handle problems with non-polynomial dimensionality. Numerical performance of the proposed method is illustrated with simulated data and a real data example for identifying the dynamic GRN of Saccharomyces cerevisiae. Copyright © 2018 John Wiley & Sons, Ltd.

To Screen or Not to Screen? A Decision Analysis of the Utility of Screening for Developmental Dysplasia of the Hip

PubMed Central

Mahan, Susan T.; Katz, Jeffrey N.; Kim, Young-Jo

2009-01-01

Background: The United States Preventive Services Task Force recently determined that they could not recommend any screening strategies for developmental dysplasia of the hip. Disparate findings in the literature and treatment-related problems have led to confusion about whether or not to screen for this disorder. The purpose of the present study was to determine, with use of expected-value decision analysis, which of the following three strategies leads to the best chance of having a non-arthritic hip by the age of sixty years: (1) no screening for developmental dysplasia of the hip, (2) universal screening of newborns with both physical examination and ultrasonography, or (3) universal screening with physical examination but only selective use of ultrasonography for neonates considered to be at high risk. Methods: Developmental dysplasia of the hip, avascular necrosis, and the treatment algorithm were carefully defined. The outcome was determined as the probability of any neonate having a non-arthritic hip through the age of sixty years. A decision tree was then built with decision nodes as described above, and chance node probabilities were determined from a thorough review of the literature. Foldback analysis and sensitivity analyses were performed. Results: The expected value of a favorable hip outcome was 0.9590 for the strategy of screening all neonates with physical examination and selective use of ultrasonography, 0.9586 for screening all neonates with physical examination and ultrasonography, and 0.9578 for no screening. A lower expected value implies a greater risk for the development of osteoarthritis as a result of developmental dysplasia of the hip or avascular necrosis; thus, the optimum strategy was selective screening. This model was robust to sensitivity analysis, except when the rate of missed dysplasia rose as high as 4/1000 or the rate of treated hip subluxation/dislocation was the same; then, the optimum strategy was to screen all neonates with both physical examination and ultrasonography. Conclusions: Our decision analytic model indicated that the optimum strategy, associated with the highest probability of having a non-arthritic hip at the age of sixty years, was to screen all neonates for hip dysplasia with a physical examination and to use ultrasonography selectively for infants who are at high risk. Additional data on the costs and cost-effectiveness of these screening policies are needed to guide policy recommendations. Level of Evidence: Economic and decision analysis Level II. See Instructions to Authors for a complete description of levels of evidence. PMID:19571094

Homology modeling and virtual screening of inhibitors against TEM- and SHV-type-resistant mutants: A multilayer filtering approach.

PubMed

Baig, Mohammad H; Balaramnavar, Vishal M; Wadhwa, Gulshan; Khan, Asad U

2015-01-01

TEM and SHV are class-A-type β-lactamases commonly found in Escherichia coli and Klebsiella pneumoniae. Previous studies reported S130G and K234R mutations in SHVs to be 41- and 10-fold more resistant toward clavulanic acid than SHV-1, respectively, whereas TEM S130G and R244S also showed the same level of resistance. These selected mutants confer higher level of resistance against clavulanic acid. They also show little susceptibility against other commercially available β-lactamase inhibitors. In this study, we have used docking-based virtual screening approach in order to screen potential inhibitors against some of the major resistant mutants of SHV and TEM types β-lactamase. Two different inhibitor-resistant mutants from SHV and TEM were selected. Moreover, we have retained the active site water molecules within each enzyme. Active site water molecules were placed within modeled structure of the mutant whose structure was unavailable with protein databank. The novelty of this work lies in the use of multilayer virtual screening approach for the prediction of best and accurate results. We are reporting five inhibitors on the basis of their efficacy against all the selected resistant mutants. These inhibitors were selected on the basis of their binding efficacies and pharmacophore features. © 2015 International Union of Biochemistry and Molecular Biology, Inc.

Screening of metal-organic frameworks for carbon dioxide capture from flue gas using a combined experimental and modeling approach.

PubMed

Yazaydin, A Ozgür; Snurr, Randall Q; Park, Tae-Hong; Koh, Kyoungmoo; Liu, Jian; Levan, M Douglas; Benin, Annabelle I; Jakubczak, Paulina; Lanuza, Mary; Galloway, Douglas B; Low, John J; Willis, Richard R

2009-12-30

A diverse collection of 14 metal-organic frameworks (MOFs) was screened for CO(2) capture from flue gas using a combined experimental and modeling approach. Adsorption measurements are reported for the screened MOFs at room temperature up to 1 bar. These data are used to validate a generalized strategy for molecular modeling of CO(2) and other small molecules in MOFs. MOFs possessing a high density of open metal sites are found to adsorb significant amounts of CO(2) even at low pressure. An excellent correlation is found between the heat of adsorption and the amount of CO(2) adsorbed below 1 bar. Molecular modeling can aid in selection of adsorbents for CO(2) capture from flue gas by screening a large number of MOFs.

Φ-score: A cell-to-cell phenotypic scoring method for sensitive and selective hit discovery in cell-based assays.

PubMed

Guyon, Laurent; Lajaunie, Christian; Fer, Frédéric; Bhajun, Ricky; Sulpice, Eric; Pinna, Guillaume; Campalans, Anna; Radicella, J Pablo; Rouillier, Philippe; Mary, Mélissa; Combe, Stéphanie; Obeid, Patricia; Vert, Jean-Philippe; Gidrol, Xavier

2015-09-18

Phenotypic screening monitors phenotypic changes induced by perturbations, including those generated by drugs or RNA interference. Currently-used methods for scoring screen hits have proven to be problematic, particularly when applied to physiologically relevant conditions such as low cell numbers or inefficient transfection. Here, we describe the Φ-score, which is a novel scoring method for the identification of phenotypic modifiers or hits in cell-based screens. Φ-score performance was assessed with simulations, a validation experiment and its application to gene identification in a large-scale RNAi screen. Using robust statistics and a variance model, we demonstrated that the Φ-score showed better sensitivity, selectivity and reproducibility compared to classical approaches. The improved performance of the Φ-score paves the way for cell-based screening of primary cells, which are often difficult to obtain from patients in sufficient numbers. We also describe a dedicated merging procedure to pool scores from small interfering RNAs targeting the same gene so as to provide improved visualization and hit selection.

Φ-score: A cell-to-cell phenotypic scoring method for sensitive and selective hit discovery in cell-based assays

PubMed Central

Guyon, Laurent; Lajaunie, Christian; fer, Frédéric; bhajun, Ricky; sulpice, Eric; pinna, Guillaume; campalans, Anna; radicella, J. Pablo; rouillier, Philippe; mary, Mélissa; combe, Stéphanie; obeid, Patricia; vert, Jean-Philippe; gidrol, Xavier

2015-01-01

Phenotypic screening monitors phenotypic changes induced by perturbations, including those generated by drugs or RNA interference. Currently-used methods for scoring screen hits have proven to be problematic, particularly when applied to physiologically relevant conditions such as low cell numbers or inefficient transfection. Here, we describe the Φ-score, which is a novel scoring method for the identification of phenotypic modifiers or hits in cell-based screens. Φ-score performance was assessed with simulations, a validation experiment and its application to gene identification in a large-scale RNAi screen. Using robust statistics and a variance model, we demonstrated that the Φ-score showed better sensitivity, selectivity and reproducibility compared to classical approaches. The improved performance of the Φ-score paves the way for cell-based screening of primary cells, which are often difficult to obtain from patients in sufficient numbers. We also describe a dedicated merging procedure to pool scores from small interfering RNAs targeting the same gene so as to provide improved visualization and hit selection. PMID:26382112

Personalized Cancer Medicine: An Organoid Approach.

PubMed

Aboulkheyr Es, Hamidreza; Montazeri, Leila; Aref, Amir Reza; Vosough, Massoud; Baharvand, Hossein

2018-04-01

Personalized cancer therapy applies specific treatments to each patient. Using personalized tumor models with similar characteristics to the original tumors may result in more accurate predictions of drug responses in patients. Tumor organoid models have several advantages over pre-existing models, including conserving the molecular and cellular composition of the original tumor. These advantages highlight the tremendous potential of tumor organoids in personalized cancer therapy, particularly preclinical drug screening and predicting patient responses to selected treatment regimens. Here, we highlight the advantages, challenges, and translational potential of tumor organoids in personalized cancer therapy and focus on gene-drug associations, drug response prediction, and treatment selection. Finally, we discuss how microfluidic technology can contribute to immunotherapy drug screening in tumor organoids. Copyright © 2017 Elsevier Ltd. All rights reserved.

Modeling Individual Patient Preferences for Colorectal Cancer Screening Based on Their Tolerance for Complications Risk.

PubMed

Taksler, Glen B; Perzynski, Adam T; Kattan, Michael W

2017-04-01

Recommendations for colorectal cancer screening encourage patients to choose among various screening methods based on individual preferences for benefits, risks, screening frequency, and discomfort. We devised a model to illustrate how individuals with varying tolerance for screening complications risk might decide on their preferred screening strategy. We developed a discrete-time Markov mathematical model that allowed hypothetical individuals to maximize expected lifetime utility by selecting screening method, start age, stop age, and frequency. Individuals could choose from stool-based testing every 1 to 3 years, flexible sigmoidoscopy every 1 to 20 years with annual stool-based testing, colonoscopy every 1 to 20 years, or no screening. We compared the life expectancy gained from the chosen strategy with the life expectancy available from a benchmark strategy of decennial colonoscopy. For an individual at average risk of colorectal cancer who was risk neutral with respect to screening complications (and therefore was willing to undergo screening if it would actuarially increase life expectancy), the model predicted that he or she would choose colonoscopy every 10 years, from age 53 to 73 years, consistent with national guidelines. For a similar individual who was moderately averse to screening complications risk (and therefore required a greater increase in life expectancy to accept potential risks of colonoscopy), the model predicted that he or she would prefer flexible sigmoidoscopy every 12 years with annual stool-based testing, with 93% of the life expectancy benefit of decennial colonoscopy. For an individual with higher risk aversion, the model predicted that he or she would prefer 2 lifetime flexible sigmoidoscopies, 20 years apart, with 70% of the life expectancy benefit of decennial colonoscopy. Mathematical models may formalize how individuals with different risk attitudes choose between various guideline-recommended colorectal cancer screening strategies.

The mathematics of a successful deconvolution: a quantitative assessment of mixture-based combinatorial libraries screened against two formylpeptide receptors.

PubMed

Santos, Radleigh G; Appel, Jon R; Giulianotti, Marc A; Edwards, Bruce S; Sklar, Larry A; Houghten, Richard A; Pinilla, Clemencia

2013-05-30

In the past 20 years, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds for drug discovery and basic research. Mixture-based libraries and positional scanning deconvolution combine two approaches for the rapid identification of specific scaffolds and active ligands. Here we present a quantitative assessment of the screening of 32 positional scanning libraries in the identification of highly specific and selective ligands for two formylpeptide receptors. We also compare and contrast two mixture-based library approaches using a mathematical model to facilitate the selection of active scaffolds and libraries to be pursued for further evaluation. The flexibility demonstrated in the differently formatted mixture-based libraries allows for their screening in a wide range of assays.

Prediction of Chlamydia trachomatis infection to facilitate selective screening on population and individual level: a cross-sectional study of a population-based screening programme.

PubMed

van Klaveren, David; Götz, Hannelore M; Op de Coul, Eline Lm; Steyerberg, Ewout W; Vergouwe, Yvonne

2016-09-01

To develop prediction models for Chlamydia trachomatis (Ct) infection with different levels of detail in information, that is, from readily available data in registries and from additional questionnaires. All inhabitants of Rotterdam and Amsterdam aged 16-29 were invited yearly from 2008 until 2011 for home-based testing. Their registry data included gender, age, ethnicity and neighbourhood-level socioeconomic status (SES). Participants were asked to fill in a questionnaire on education, sexually transmitted infection history, symptoms, partner information and sexual behaviour. We developed prediction models for Ct infection using first-time participant data-including registry variables only and with additional questionnaire variables-by multilevel logistic regression analysis to account for clustering within neighbourhoods. We assessed the discriminative ability by the area under the receiver operating characteristic curve (AUC). Four per cent (3540/80 385) of the participants was infected. The strongest registry predictors for Ct infection were young age (especially for women) and Surinamese, Antillean or sub-Saharan African ethnicity. Neighbourhood-level SES was of minor importance. Strong questionnaire predictors were low to intermediate education level, ethnicity of the partner (non-Dutch) and having sex with casual partners. When using a prediction model including questionnaire risk factors (AUC 0.74, 95% CI 0.736 to 0.752) for selective screening, 48% of the participating population needed to be screened to find 80% (95% CI 78.4% to 81.0%) of Ct infections. The model with registry risk factors only (AUC 0.67, 95% CI 0.656 to 0.675) required 60% to be screened to find 78% (95% CI 76.6% to 79.4%) of Ct infections. A registry-based prediction model can facilitate selective Ct screening at population level, with further refinement at the individual level by including questionnaire risk factors. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Synergism of virtual screening and medicinal chemistry: identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1.

PubMed

Noeske, Tobias; Trifanova, Dina; Kauss, Valerjans; Renner, Steffen; Parsons, Christopher G; Schneider, Gisbert; Weil, Tanja

2009-08-01

We report the identification of novel potent and selective metabotropic glutamate receptor 1 (mGluR1) antagonists by virtual screening and subsequent hit optimization. For ligand-based virtual screening, molecules were represented by a topological pharmacophore descriptor (CATS-2D) and clustered by a self-organizing map (SOM). The most promising compounds were tested in mGluR1 functional and binding assays. We identified a potent chemotype exhibiting selective antagonistic activity at mGluR1 (functional IC(50)=0.74+/-0.29 microM). Hit optimization yielded lead structure 16 with an affinity of K(i)=0.024+/-0.001 microM and greater than 1000-fold selectivity for mGluR1 versus mGluR5. Homology-based receptor modelling suggests a binding site compatible with previously reported mutation studies. Our study demonstrates the usefulness of ligand-based virtual screening for scaffold-hopping and rapid lead structure identification in early drug discovery projects.

Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors.

PubMed

Kumar, B V S Suneel; Lakshmi, Narasu; Kumar, M Ravi; Rambabu, Gundla; Manjashetty, Thimmappa H; Arunasree, Kalle M; Sriram, Dharmarajan; Ramkumar, Kavya; Neamati, Nouri; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

Parameter screening: the use of a dummy parameter to identify non-influential parameters in a global sensitivity analysis

NASA Astrophysics Data System (ADS)

Khorashadi Zadeh, Farkhondeh; Nossent, Jiri; van Griensven, Ann; Bauwens, Willy

2017-04-01

Parameter estimation is a major concern in hydrological modeling, which may limit the use of complex simulators with a large number of parameters. To support the selection of parameters to include in or exclude from the calibration process, Global Sensitivity Analysis (GSA) is widely applied in modeling practices. Based on the results of GSA, the influential and the non-influential parameters are identified (i.e. parameters screening). Nevertheless, the choice of the screening threshold below which parameters are considered non-influential is a critical issue, which has recently received more attention in GSA literature. In theory, the sensitivity index of a non-influential parameter has a value of zero. However, since numerical approximations, rather than analytical solutions, are utilized in GSA methods to calculate the sensitivity indices, small but non-zero indices may be obtained for the indices of non-influential parameters. In order to assess the threshold that identifies non-influential parameters in GSA methods, we propose to calculate the sensitivity index of a "dummy parameter". This dummy parameter has no influence on the model output, but will have a non-zero sensitivity index, representing the error due to the numerical approximation. Hence, the parameters whose indices are above the sensitivity index of the dummy parameter can be classified as influential, whereas the parameters whose indices are below this index are within the range of the numerical error and should be considered as non-influential. To demonstrated the effectiveness of the proposed "dummy parameter approach", 26 parameters of a Soil and Water Assessment Tool (SWAT) model are selected to be analyzed and screened, using the variance-based Sobol' and moment-independent PAWN methods. The sensitivity index of the dummy parameter is calculated from sampled data, without changing the model equations. Moreover, the calculation does not even require additional model evaluations for the Sobol' method. A formal statistical test validates these parameter screening results. Based on the dummy parameter screening, 11 model parameters are identified as influential. Therefore, it can be denoted that the "dummy parameter approach" can facilitate the parameter screening process and provide guidance for GSA users to define a screening-threshold, with only limited additional resources. Key words: Parameter screening, Global sensitivity analysis, Dummy parameter, Variance-based method, Moment-independent method

Research on target information optics communications transmission characteristic and performance in multi-screens testing system

NASA Astrophysics Data System (ADS)

Li, Hanshan

2016-04-01

To enhance the stability and reliability of multi-screens testing system, this paper studies multi-screens target optical information transmission link properties and performance in long-distance, sets up the discrete multi-tone modulation transmission model based on geometric model of laser multi-screens testing system and visible light information communication principle; analyzes the electro-optic and photoelectric conversion function of sender and receiver in target optical information communication system; researches target information transmission performance and transfer function of the generalized visible-light communication channel; found optical information communication transmission link light intensity space distribution model and distribution function; derives the SNR model of information transmission communication system. Through the calculation and experiment analysis, the results show that the transmission error rate increases with the increment of transmission rate in a certain channel modulation depth; when selecting the appropriate transmission rate, the bit error rate reach 0.01.

Immobilized enzyme reactors in HPLC and its application in inhibitor screening: A review

PubMed Central

Fang, Si-Meng; Wang, Hai-Na; Zhao, Zhong-Xi; Wang, Wei-Hong

2011-01-01

This paper sets out to summarize the literatures based on immobilized enzyme bio-chromatography and its application in inhibitors screening in the last decade. In order to screen enzyme inhibitors from a mass of compounds in preliminary screening, multi-pore materials with good biocompatibility are used for the supports of immobilizing enzymes, and then the immobilized enzyme reactor applied as the immobilized enzyme stationary phase in HPLC. Therefore, a technology platform of high throughput screening is gradually established to screen the enzyme inhibitors as new anti-tumor drugs. Here, we briefly summarize the selective methods of supports, immobilization techniques, co-immobilized enzymes system and the screening model. PMID:29403726

Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2.

PubMed

Kaserer, Teresa; Temml, Veronika; Kutil, Zsofia; Vanek, Tomas; Landa, Premysl; Schuster, Daniela

2015-01-01

Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors. Copyright © 2015 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Quantification of mammographic masking risk with volumetric breast density maps: how to select women for supplemental screening

NASA Astrophysics Data System (ADS)

Holland, Katharina; van Gils, Carla H.; Wanders, Johanna OP; Mann, Ritse M.; Karssemeijer, Nico

2016-03-01

The sensitivity of mammograms is low for women with dense breasts, since cancers may be masked by dense tissue. In this study, we investigated methods to identify women with density patterns associated with a high masking risk. Risk measures are derived from volumetric breast density maps. We used the last negative screening mammograms of 93 women who subsequently presented with an interval cancer (IC), and, as controls, 930 randomly selected normal screening exams from women without cancer. Volumetric breast density maps were computed from the mammograms, which provide the dense tissue thickness at each location. These were used to compute absolute and percentage glandular tissue volume. We modeled the masking risk for each pixel location using the absolute and percentage dense tissue thickness and we investigated the effect of taking the cancer location probability distribution (CLPD) into account. For each method, we selected cases with the highest masking measure (by thresholding) and computed the fraction of ICs as a function of the fraction of controls selected. The latter can be interpreted as the negative supplemental screening rate (NSSR). Between the models, when incorporating CLPD, no significant differences were found. In general, the methods performed better when CLPD was included. At higher NSSRs some of the investigated masking measures had a significantly higher performance than volumetric breast density. These measures may therefore serve as an alternative to identify women with a high risk for a masked cancer.

Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches.

PubMed

Shinde, Ranajit Nivrutti; Kumar, G Siva; Eqbal, Shahbaz; Sobhia, M Elizabeth

2018-01-01

Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for Type 2 diabetes due to its specific role as a negative regulator of insulin signaling pathways. Discovery of active site directed PTP1B inhibitors is very challenging due to highly conserved nature of the active site and multiple charge requirements of the ligands, which makes them non-selective and non-permeable. Identification of the PTP1B allosteric site has opened up new avenues for discovering potent and selective ligands for therapeutic intervention. Interactions made by potent allosteric inhibitor in the presence of PTP1B were studied using Molecular Dynamics (MD). Computationally optimized models were used to build separate pharmacophore models of PTP1B and TCPTP, respectively. Based on the nature of interactions the target residues offered, a receptor based pharmacophore was developed. The pharmacophore considering conformational flexibility of the residues was used for the development of pharmacophore hypothesis to identify potentially active inhibitors by screening large compound databases. Two pharmacophore were successively used in the virtual screening protocol to identify potential selective and permeable inhibitors of PTP1B. Allosteric inhibition mechanism of these molecules was established using molecular docking and MD methods. The geometrical criteria values confirmed their ability to stabilize PTP1B in an open conformation. 23 molecules that were identified as potential inhibitors were screened for PTP1B inhibitory activity. After screening, 10 molecules which have good permeability values were identified as potential inhibitors of PTP1B. This study confirms that selective and permeable inhibitors can be identified by targeting allosteric site of PTP1B.

Development of a Climate Resilience Screening Index (CRSI): An Assessment of Resilience to Acute Meteorological Events and Selected Natural Hazards

EPA Science Inventory

We developed a conceptual model of climate resilience (CRSI – Climate Resilience Screening Index ) designed to be sensitive to changes in the natural environment, built environment, governance, and social structure and vulnerability or risk to climate events. CRSI has been used ...

The Mathematics of a Successful Deconvolution: A Quantitative Assessment of Mixture-Based Combinatorial Libraries Screened Against Two Formylpeptide Receptors

PubMed Central

Santos, Radleigh G.; Appel, Jon R.; Giulianotti, Marc A.; Edwards, Bruce S.; Sklar, Larry A.; Houghten, Richard A.; Pinilla, Clemencia

2014-01-01

In the past 20 years, synthetic combinatorial methods have fundamentally advanced the ability to synthesize and screen large numbers of compounds for drug discovery and basic research. Mixture-based libraries and positional scanning deconvolution combine two approaches for the rapid identification of specific scaffolds and active ligands. Here we present a quantitative assessment of the screening of 32 positional scanning libraries in the identification of highly specific and selective ligands for two formylpeptide receptors. We also compare and contrast two mixture-based library approaches using a mathematical model to facilitate the selection of active scaffolds and libraries to be pursued for further evaluation. The flexibility demonstrated in the differently formatted mixture-based libraries allows for their screening in a wide range of assays. PMID:23722730

Application of QSAR and shape pharmacophore modeling approaches for targeted chemical library design.

PubMed

Ebalunode, Jerry O; Zheng, Weifan; Tropsha, Alexander

2011-01-01

Optimization of chemical library composition affords more efficient identification of hits from biological screening experiments. The optimization could be achieved through rational selection of reagents used in combinatorial library synthesis. However, with a rapid advent of parallel synthesis methods and availability of millions of compounds synthesized by many vendors, it may be more efficient to design targeted libraries by means of virtual screening of commercial compound collections. This chapter reviews the application of advanced cheminformatics approaches such as quantitative structure-activity relationships (QSAR) and pharmacophore modeling (both ligand and structure based) for virtual screening. Both approaches rely on empirical SAR data to build models; thus, the emphasis is placed on achieving models of the highest rigor and external predictive power. We present several examples of successful applications of both approaches for virtual screening to illustrate their utility. We suggest that the expert use of both QSAR and pharmacophore models, either independently or in combination, enables users to achieve targeted libraries enriched with experimentally confirmed hit compounds.

Computationally inexpensive identification of noninformative model parameters by sequential screening

NASA Astrophysics Data System (ADS)

Cuntz, Matthias; Mai, Juliane; Zink, Matthias; Thober, Stephan; Kumar, Rohini; Schäfer, David; Schrön, Martin; Craven, John; Rakovec, Oldrich; Spieler, Diana; Prykhodko, Vladyslav; Dalmasso, Giovanni; Musuuza, Jude; Langenberg, Ben; Attinger, Sabine; Samaniego, Luis

2015-08-01

Environmental models tend to require increasing computational time and resources as physical process descriptions are improved or new descriptions are incorporated. Many-query applications such as sensitivity analysis or model calibration usually require a large number of model evaluations leading to high computational demand. This often limits the feasibility of rigorous analyses. Here we present a fully automated sequential screening method that selects only informative parameters for a given model output. The method requires a number of model evaluations that is approximately 10 times the number of model parameters. It was tested using the mesoscale hydrologic model mHM in three hydrologically unique European river catchments. It identified around 20 informative parameters out of 52, with different informative parameters in each catchment. The screening method was evaluated with subsequent analyses using all 52 as well as only the informative parameters. Subsequent Sobol's global sensitivity analysis led to almost identical results yet required 40% fewer model evaluations after screening. mHM was calibrated with all and with only informative parameters in the three catchments. Model performances for daily discharge were equally high in both cases with Nash-Sutcliffe efficiencies above 0.82. Calibration using only the informative parameters needed just one third of the number of model evaluations. The universality of the sequential screening method was demonstrated using several general test functions from the literature. We therefore recommend the use of the computationally inexpensive sequential screening method prior to rigorous analyses on complex environmental models.

Computationally inexpensive identification of noninformative model parameters by sequential screening

NASA Astrophysics Data System (ADS)

Mai, Juliane; Cuntz, Matthias; Zink, Matthias; Thober, Stephan; Kumar, Rohini; Schäfer, David; Schrön, Martin; Craven, John; Rakovec, Oldrich; Spieler, Diana; Prykhodko, Vladyslav; Dalmasso, Giovanni; Musuuza, Jude; Langenberg, Ben; Attinger, Sabine; Samaniego, Luis

2016-04-01

Environmental models tend to require increasing computational time and resources as physical process descriptions are improved or new descriptions are incorporated. Many-query applications such as sensitivity analysis or model calibration usually require a large number of model evaluations leading to high computational demand. This often limits the feasibility of rigorous analyses. Here we present a fully automated sequential screening method that selects only informative parameters for a given model output. The method requires a number of model evaluations that is approximately 10 times the number of model parameters. It was tested using the mesoscale hydrologic model mHM in three hydrologically unique European river catchments. It identified around 20 informative parameters out of 52, with different informative parameters in each catchment. The screening method was evaluated with subsequent analyses using all 52 as well as only the informative parameters. Subsequent Sobol's global sensitivity analysis led to almost identical results yet required 40% fewer model evaluations after screening. mHM was calibrated with all and with only informative parameters in the three catchments. Model performances for daily discharge were equally high in both cases with Nash-Sutcliffe efficiencies above 0.82. Calibration using only the informative parameters needed just one third of the number of model evaluations. The universality of the sequential screening method was demonstrated using several general test functions from the literature. We therefore recommend the use of the computationally inexpensive sequential screening method prior to rigorous analyses on complex environmental models.

Compound prioritization methods increase rates of chemical probe discovery in model organisms

PubMed Central

Wallace, Iain M; Urbanus, Malene L; Luciani, Genna M; Burns, Andrew R; Han, Mitchell KL; Wang, Hao; Arora, Kriti; Heisler, Lawrence E; Proctor, Michael; St. Onge, Robert P; Roemer, Terry; Roy, Peter J; Cummins, Carolyn L; Bader, Gary D; Nislow, Corey; Giaever, Guri

2011-01-01

SUMMARY Pre-selection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in S. cerevisiae and identified ~7,500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. This data was used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7,500 growth-inhibitory molecules has been made commercially available and the computational model and filter used are provided. PMID:22035796

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening

PubMed Central

Chatterjee, Arindam; Doerksen, Robert J.; Khan, Ikhlas A.

2014-01-01

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening work-flow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity. PMID:25438765

Breast cancer screening disparities among immigrant women by world region of origin: a population-based study in Ontario, Canada.

PubMed

Vahabi, Mandana; Lofters, Aisha; Kumar, Matthew; Glazier, Richard H

2016-07-01

Rates of mammography screening for breast cancer are disproportionately low in certain subgroups including low-income and immigrant women. The purpose of the study was to examine differences in rates of appropriate breast cancer screening (i.e., screening mammography every 2 years) among Ontario immigrant women by world region of origin and explore the association between appropriate breast cancer screening among these women groups and individual and structural factors. A cohort of 183,332 screening-eligible immigrant women living in Ontario between 2010 and 2012 was created from linked databases and classified into eight world regions of origin. Appropriate screening rates were calculated for each region by age group and selected sociodemographic, immigration, and healthcare-related characteristics. The association between appropriate screening across the eight regions of origin and selected sociodemographic, immigration, and health-related characteristics was explored using multivariate Poisson regression. Screening varied by region of origin, with South Asian women (48.5%) having the lowest and Caribbean and Latin American women (63.7%) the highest cancer screening rates. Factors significantly associated with lower screening across the world regions of origin included living in the lowest income neighborhoods, having a refugee status, being a new immigrant, not having a regular physical examination, not being enrolled in a primary care patient enrollment model, having a male physician, and having an internationally trained physician. Multiple interventions entailing cross-sector collaboration, promotion of patient enrollment models, community engagement, comprehensive and intensive outreach to women, and knowledge translation and transfer to physicians should be considered to address screening disparities among immigrant population. Consideration should be given to design and delivery of culturally appropriate and easily accessible cancer screening programs targeted at high- risk immigrant subgroups, such as women of South Asian origin, refugees, and new immigrants. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents.

PubMed

Patel, Preeti; Singh, Avineesh; Patel, Vijay K; Jain, Deepak K; Veerasamy, Ravichandran; Rajak, Harish

2016-01-01

Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.

PubMed

Sakai, Kenichi; Obata, Kouki; Yoshikawa, Mayumi; Takano, Ryusuke; Shibata, Masaki; Maeda, Hiroyuki; Mizutani, Akihiko; Terada, Katsuhide

2012-10-01

To design a high drug loading formulation of self-microemulsifying/micelle system. A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.

On various metrics used for validation of predictive QSAR models with applications in virtual screening and focused library design.

PubMed

Roy, Kunal; Mitra, Indrani

2011-07-01

Quantitative structure-activity relationships (QSARs) have important applications in drug discovery research, environmental fate modeling, property prediction, etc. Validation has been recognized as a very important step for QSAR model development. As one of the important objectives of QSAR modeling is to predict activity/property/toxicity of new chemicals falling within the domain of applicability of the developed models and QSARs are being used for regulatory decisions, checking reliability of the models and confidence of their predictions is a very important aspect, which can be judged during the validation process. One prime application of a statistically significant QSAR model is virtual screening for molecules with improved potency based on the pharmacophoric features and the descriptors appearing in the QSAR model. Validated QSAR models may also be utilized for design of focused libraries which may be subsequently screened for the selection of hits. The present review focuses on various metrics used for validation of predictive QSAR models together with an overview of the application of QSAR models in the fields of virtual screening and focused library design for diverse series of compounds with citation of some recent examples.

An actor-based model of social network influence on adolescent body size, screen time, and playing sports.

PubMed

Shoham, David A; Tong, Liping; Lamberson, Peter J; Auchincloss, Amy H; Zhang, Jun; Dugas, Lara; Kaufman, Jay S; Cooper, Richard S; Luke, Amy

2012-01-01

Recent studies suggest that obesity may be "contagious" between individuals in social networks. Social contagion (influence), however, may not be identifiable using traditional statistical approaches because they cannot distinguish contagion from homophily (the propensity for individuals to select friends who are similar to themselves) or from shared environmental influences. In this paper, we apply the stochastic actor-based model (SABM) framework developed by Snijders and colleagues to data on adolescent body mass index (BMI), screen time, and playing active sports. Our primary hypothesis was that social influences on adolescent body size and related behaviors are independent of friend selection. Employing the SABM, we simultaneously modeled network dynamics (friendship selection based on homophily and structural characteristics of the network) and social influence. We focused on the 2 largest schools in the National Longitudinal Study of Adolescent Health (Add Health) and held the school environment constant by examining the 2 school networks separately (N = 624 and 1151). Results show support in both schools for homophily on BMI, but also for social influence on BMI. There was no evidence of homophily on screen time in either school, while only one of the schools showed homophily on playing active sports. There was, however, evidence of social influence on screen time in one of the schools, and playing active sports in both schools. These results suggest that both homophily and social influence are important in understanding patterns of adolescent obesity. Intervention efforts should take into consideration peers' influence on one another, rather than treating "high risk" adolescents in isolation.

MODELS AND METHODS FOR PETROLEUM HYDROCARBON RISK ASSESSMENT: ONSITE, LUSTRISK, AND HSSM

EPA Science Inventory

U.S. EPA has developed three tiers of models for analysis of fuel releases from underground storage tank (UST) systems: 1) OnSite; 2) LUSTRisk, and 3) the Hydrocarbon Spill Screening Model (HSSM). The tiered approach to modeling allows users to select a model based upon the amoun...

The impact of overdiagnosis on the selection of efficient lung cancer screening strategies.

PubMed

Han, Summer S; Ten Haaf, Kevin; Hazelton, William D; Munshi, Vidit N; Jeon, Jihyoun; Erdogan, Saadet A; Johanson, Colden; McMahon, Pamela M; Meza, Rafael; Kong, Chung Yin; Feuer, Eric J; de Koning, Harry J; Plevritis, Sylvia K

2017-06-01

The U.S. Preventive Services Task Force (USPSTF) recently updated their national lung screening guidelines and recommended low-dose computed tomography (LDCT) for lung cancer (LC) screening through age 80. However, the risk of overdiagnosis among older populations is a concern. Using four comparative models from the Cancer Intervention and Surveillance Modeling Network, we evaluate the overdiagnosis of the screening program recommended by USPSTF in the U.S. 1950 birth cohort. We estimate the number of LC deaths averted by screening (D) per overdiagnosed case (O), yielding the ratio D/O, to quantify the trade-off between the harms and benefits of LDCT. We analyze 576 hypothetical screening strategies that vary by age, smoking, and screening frequency and evaluate efficient screening strategies that maximize the D/O ratio and other metrics including D and life-years gained (LYG) per overdiagnosed case. The estimated D/O ratio for the USPSTF screening program is 2.85 (model range: 1.5-4.5) in the 1950 birth cohort, implying LDCT can prevent ∼3 LC deaths per overdiagnosed case. This D/O ratio increases by 22% when the program stops screening at an earlier age 75 instead of 80. Efficiency frontier analysis shows that while the most efficient screening strategies that maximize the mortality reduction (D) irrespective of overdiagnosis screen through age 80, screening strategies that stop at age 75 versus 80 produce greater efficiency in increasing life-years gained per overdiagnosed case. Given the risk of overdiagnosis with LC screening, the stopping age of screening merits further consideration when balancing benefits and harms. © 2017 UICC.

Gastro-esophageal reflux disease symptoms and demographic factors as a pre-screening tool for Barrett's esophagus.

PubMed

Liu, Xinxue; Wong, Angela; Kadri, Sudarshan R; Corovic, Andrej; O'Donovan, Maria; Lao-Sirieix, Pierre; Lovat, Laurence B; Burnham, Rodney W; Fitzgerald, Rebecca C

2014-01-01

Barrett's esophagus (BE) occurs as consequence of reflux and is a risk factor for esophageal adenocarcinoma. The current "gold-standard" for diagnosing BE is endoscopy which remains prohibitively expensive and impractical as a population screening tool. We aimed to develop a pre-screening tool to aid decision making for diagnostic referrals. A prospective (training) cohort of 1603 patients attending for endoscopy was used for identification of risk factors to develop a risk prediction model. Factors associated with BE in the univariate analysis were selected to develop prediction models that were validated in an independent, external cohort of 477 non-BE patients referred for endoscopy with symptoms of reflux or dyspepsia. Two prediction models were developed separately for columnar lined epithelium (CLE) of any length and using a stricter definition of intestinal metaplasia (IM) with segments ≥ 2 cm with areas under the ROC curves (AUC) of 0.72 (95%CI: 0.67-0.77) and 0.81 (95%CI: 0.76-0.86), respectively. The two prediction models included demographics (age, sex), symptoms (heartburn, acid reflux, chest pain, abdominal pain) and medication for "stomach" symptoms. These two models were validated in the independent cohort with AUCs of 0.61 (95%CI: 0.54-0.68) and 0.64 (95%CI: 0.52-0.77) for CLE and IM ≥ 2 cm, respectively. We have identified and validated two prediction models for CLE and IM ≥ 2 cm. Both models have fair prediction accuracies and can select out around 20% of individuals unlikely to benefit from investigation for Barrett's esophagus. Such prediction models have the potential to generate useful cost-savings for BE screening among the symptomatic population.

Configuration evaluation and criteria plan. Volume 2: Evaluation critera plan (preliminary). Space Transportation Main Engine (STME) configuration study

NASA Technical Reports Server (NTRS)

Bair, E. K.

1986-01-01

The unbiased selection of the Space Transportation Main Engine (STME) configuration requires that the candidate engines be evaluated against a predetermined set of criteria which must be properly weighted to emphasize critical requirements defined prior to the actual evaluation. The evaluation and selection process involves the following functions: (1) determining if a configuration can satisfy basic STME requirements (yes/no); (2) defining the evaluation criteria; (3) selecting the criteria relative importance or weighting; (4) determining the weighting sensitivities; and (5) establishing a baseline for engine evaluation. The criteria weighting and sensitivities are cost related and are based on mission models and vehicle requirements. The evaluation process is used as a coarse screen to determine the candidate engines for the parametric studies and as a fine screen to determine concept(s) for conceptual design. The criteria used for the coarse and fine screen evaluation process is shown. The coarse screen process involves verifying that the candidate engines can meet the yes/no screening requirements and a semi-subjective quantitative evaluation. The fine screen engines have to meet all of the yes/no screening gates and are then subjected to a detailed evaluation or assessment using the quantitative cost evaluation processes. The option exists for re-cycling a concept through the quantitative portion of the screening and allows for some degree of optimization. The basic vehicle is a two stage LOX/HC, LOX/LH2 parallel burn vehicle capable of placing 150,000 lbs in low Earth orbit (LEO).

Lignin-degrading Peroxidases from Genome of Selective Ligninolytic Fungus Ceriporiopsis subverispora

Treesearch

Elena Fernandez-Fueyo; Francisco J. Ruiz-Duenas; Yuta Miki; Marta Jesus Martinez; Kenneth E. Hammel; Angel T. Martinez

2012-01-01

Background: The first genome of a selective lignin degrader is available. Results: Its screening shows 26 peroxidase genes, and 5 genes were heterologously expressed and the catalytic properties investigated. Conclusion: Two new peroxidases oxidize simple and dimeric lignin models and efficiently depolymerize lignin. Significance: Although lignin peroxidase and...

Radiologists' preferences for digital mammographic display. The International Digital Mammography Development Group.

PubMed

Pisano, E D; Cole, E B; Major, S; Zong, S; Hemminger, B M; Muller, K E; Johnston, R E; Walsh, R; Conant, E; Fajardo, L L; Feig, S A; Nishikawa, R M; Yaffe, M J; Williams, M B; Aylward, S R

2000-09-01

To determine the preferences of radiologists among eight different image processing algorithms applied to digital mammograms obtained for screening and diagnostic imaging tasks. Twenty-eight images representing histologically proved masses or calcifications were obtained by using three clinically available digital mammographic units. Images were processed and printed on film by using manual intensity windowing, histogram-based intensity windowing, mixture model intensity windowing, peripheral equalization, multiscale image contrast amplification (MUSICA), contrast-limited adaptive histogram equalization, Trex processing, and unsharp masking. Twelve radiologists compared the processed digital images with screen-film mammograms obtained in the same patient for breast cancer screening and breast lesion diagnosis. For the screening task, screen-film mammograms were preferred to all digital presentations, but the acceptability of images processed with Trex and MUSICA algorithms were not significantly different. All printed digital images were preferred to screen-film radiographs in the diagnosis of masses; mammograms processed with unsharp masking were significantly preferred. For the diagnosis of calcifications, no processed digital mammogram was preferred to screen-film mammograms. When digital mammograms were preferred to screen-film mammograms, radiologists selected different digital processing algorithms for each of three mammographic reading tasks and for different lesion types. Soft-copy display will eventually allow radiologists to select among these options more easily.

Molecular modeling on streptolysin-O of multidrug resistant Streptococcus pyogenes and computer aided screening and in vitro assay for novel herbal inhibitors.

PubMed

Skariyachan, Sinosh; Narayan, Naik Sowmyalaxmi; Aggimath, Tejaswini S; Nagaraj, Sushmitha; Reddy, Monika S; Narayanappa, Rajeswari

2014-03-01

Streptococcus pyogenes is a notorious pathogenic bacterium which causes various human diseases ranging from localized infections to life threatening invasive diseases. Streptolysin-O (SLO), pore-forming thiol-activated cytolysin, is the major virulent factor for streptococcal infections. Present therapies against streptococcal infections are limited as most of the strains have developed multi-drug resistance to present generation of drugs. Hence, there is a need for alternative therapeutic substances. Structure based virtual screening is a novel platform to select lead molecules with better pharmacokinetic properties. The 3D structure of SLO (not available in native form), essential for such studies, was computationally generated and this homology model was used as probable drug target. Based on literature survey, several phytoligands from 25 medicinal plants were selected. Out of these, leads from 11 plants showed better pharmacokinetic properties. The best lead molecules were screened based on computer aided drug likeness and pharmacokinetic predictions. The inhibitory properties of selected herbal leads against SLO were studied by molecular docking. An in vitro assay was further carried out and variations observed were found to be significant (p<0.05). Antibiotic sensitivity testing was also performed with the clinical strain of Streptococcus pyogenes with conventional drugs. The clinical strain showed multi-drug resistance to conventional drugs. Our study revealed that numerous phytoligands have better inhibitory properties towards the toxin. We noticed that incorporation of selected herbal extracts in blood agar medium showed significant reduction in hemolysis (MIC 300μl/plate), indicating inhibition of SLO. Furthermore, the butanol extracts of selected herbal preparation based on computer aided screening showed significant inhibitory properties at 250 mcg/disc concentration. We also noticed that selected herbal formulations have better antimicrobial properties at MIC range of 300- 400μl. Hence, our study suggests that these herbal extracts have better inhibitory properties against the toxin as well as drug resistant Streptococcus pyogenes.

Cost-Effectiveness of HBV and HCV Screening Strategies – A Systematic Review of Existing Modelling Techniques

PubMed Central

Geue, Claudia; Wu, Olivia; Xin, Yiqiao; Heggie, Robert; Hutchinson, Sharon; Martin, Natasha K.; Fenwick, Elisabeth; Goldberg, David

2015-01-01

Introduction Studies evaluating the cost-effectiveness of screening for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are generally heterogeneous in terms of risk groups, settings, screening intervention, outcomes and the economic modelling framework. It is therefore difficult to compare cost-effectiveness results between studies. This systematic review aims to summarise and critically assess existing economic models for HBV and HCV in order to identify the main methodological differences in modelling approaches. Methods A structured search strategy was developed and a systematic review carried out. A critical assessment of the decision-analytic models was carried out according to the guidelines and framework developed for assessment of decision-analytic models in Health Technology Assessment of health care interventions. Results The overall approach to analysing the cost-effectiveness of screening strategies was found to be broadly consistent for HBV and HCV. However, modelling parameters and related structure differed between models, producing different results. More recent publications performed better against a performance matrix, evaluating model components and methodology. Conclusion When assessing screening strategies for HBV and HCV infection, the focus should be on more recent studies, which applied the latest treatment regimes, test methods and had better and more complete data on which to base their models. In addition to parameter selection and associated assumptions, careful consideration of dynamic versus static modelling is recommended. Future research may want to focus on these methodological issues. In addition, the ability to evaluate screening strategies for multiple infectious diseases, (HCV and HIV at the same time) might prove important for decision makers. PMID:26689908

An infrastructure to mine molecular descriptors for ligand selection on virtual screening.

PubMed

Seus, Vinicius Rosa; Perazzo, Giovanni Xavier; Winck, Ana T; Werhli, Adriano V; Machado, Karina S

2014-01-01

The receptor-ligand interaction evaluation is one important step in rational drug design. The databases that provide the structures of the ligands are growing on a daily basis. This makes it impossible to test all the ligands for a target receptor. Hence, a ligand selection before testing the ligands is needed. One possible approach is to evaluate a set of molecular descriptors. With the aim of describing the characteristics of promising compounds for a specific receptor we introduce a data warehouse-based infrastructure to mine molecular descriptors for virtual screening (VS). We performed experiments that consider as target the receptor HIV-1 protease and different compounds for this protein. A set of 9 molecular descriptors are taken as the predictive attributes and the free energy of binding is taken as a target attribute. By applying the J48 algorithm over the data we obtain decision tree models that achieved up to 84% of accuracy. The models indicate which molecular descriptors and their respective values are relevant to influence good FEB results. Using their rules we performed ligand selection on ZINC database. Our results show important reduction in ligands selection to be applied in VS experiments; for instance, the best selection model picked only 0.21% of the total amount of drug-like ligands.

Validation of periodontitis screening model using sociodemographic, systemic, and molecular information in a Korean population.

PubMed

Kim, Hyun-Duck; Sukhbaatar, Munkhzaya; Shin, Myungseop; Ahn, Yoo-Been; Yoo, Wook-Sung

2014-12-01

This study aims to evaluate and validate a periodontitis screening model that includes sociodemographic, metabolic syndrome (MetS), and molecular information, including gingival crevicular fluid (GCF), matrix metalloproteinase (MMP), and blood cytokines. The authors selected 506 participants from the Shiwha-Banwol cohort: 322 participants from the 2005 cohort for deriving the screening model and 184 participants from the 2007 cohort for its validation. Periodontitis was assessed by dentists using the community periodontal index. Interleukin (IL)-6, IL-8, and tumor necrosis factor-α in blood and MMP-8, -9, and -13 in GCF were assayed using enzyme-linked immunosorbent assay. MetS was assessed by physicians using physical examination and blood laboratory data. Information about age, sex, income, smoking, and drinking was obtained by interview. Logistic regression analysis was applied to finalize the best-fitting model and validate the model using sensitivity, specificity, and c-statistics. The derived model for periodontitis screening had a sensitivity of 0.73, specificity of 0.85, and c-statistic of 0.86 (P <0.001); those of the validated model were 0.64, 0.91, and 0.83 (P <0.001), respectively. The model that included age, sex, income, smoking, drinking, and blood and GCF biomarkers could be useful in screening for periodontitis. A future prospective study is indicated for evaluating this model's ability to predict the occurrence of periodontitis.

Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors.

PubMed

Akram, Muhammad; Waratchareeyakul, Watcharee; Haupenthal, Joerg; Hartmann, Rolf W; Schuster, Daniela

2017-01-01

Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing's syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8 - 10 ), one selective CYP11B1 inhibitor (Compound 11 , IC 50 = 2.5 μM), and one selective CYP11B2 inhibitor (compound 12 , IC 50 = 1.1 μM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models.

A systematic approach to prioritize drug targets using machine learning, a molecular descriptor-based classification model, and high-throughput screening of plant derived molecules: a case study in oral cancer.

PubMed

Randhawa, Vinay; Kumar Singh, Anil; Acharya, Vishal

2015-12-01

Systems-biology inspired identification of drug targets and machine learning-based screening of small molecules which modulate their activity have the potential to revolutionize modern drug discovery by complementing conventional methods. To utilize the effectiveness of such pipelines, we first analyzed the dysregulated gene pairs between control and tumor samples and then implemented an ensemble-based feature selection approach to prioritize targets in oral squamous cell carcinoma (OSCC) for therapeutic exploration. Based on the structural information of known inhibitors of CXCR4-one of the best targets identified in this study-a feature selection was implemented for the identification of optimal structural features (molecular descriptor) based on which a classification model was generated. Furthermore, the CXCR4-centered descriptor-based classification model was finally utilized to screen a repository of plant derived small-molecules to obtain potential inhibitors. The application of our methodology may assist effective selection of the best targets which may have previously been overlooked, that in turn will lead to the development of new oral cancer medications. The small molecules identified in this study can be ideal candidates for trials as potential novel anti-oral cancer agents. Importantly, distinct steps of this whole study may provide reference for the analysis of other complex human diseases.

Pharmacophore modeling and in silico / in vitro screening for human cytochrome P450 11B1 & cytochrome P450 11B2 inhibitors

NASA Astrophysics Data System (ADS)

Akram, Muhammad; Waratchareeyakul, Watcharee; Haupenthal, Joerg; Hartmann, Rolf W.; Schuster, Daniela

2017-12-01

Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing’s syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8-10), one selective CYP11B1 inhibitor (Compound 11, IC50 = 2.5 µM), and one selective CYP11B2 inhibitor (compound 12, IC50 = 1.1 µM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models.

SIMULATING RADIONUCLIDE FATE AND TRANSPORT IN THE UNSATURATED ZONE: EVALUATION AND SENSITIVITY ANALYSES OF SELECT COMPUTER MODELS

EPA Science Inventory

Numerical, mathematical models of water and chemical movement in soils are used as decision aids for determining soil screening levels (SSLs) of radionuclides in the unsaturated zone. Many models require extensive input parameters which include uncertainty due to soil variabil...

Cost-effectiveness of early detection of breast cancer in Catalonia (Spain)

PubMed Central

2011-01-01

Background Breast cancer (BC) causes more deaths than any other cancer among women in Catalonia. Early detection has contributed to the observed decline in BC mortality. However, there is debate on the optimal screening strategy. We performed an economic evaluation of 20 screening strategies taking into account the cost over time of screening and subsequent medical costs, including diagnostic confirmation, initial treatment, follow-up and advanced care. Methods We used a probabilistic model to estimate the effect and costs over time of each scenario. The effect was measured as years of life (YL), quality-adjusted life years (QALY), and lives extended (LE). Costs of screening and treatment were obtained from the Early Detection Program and hospital databases of the IMAS-Hospital del Mar in Barcelona. The incremental cost-effectiveness ratio (ICER) was used to compare the relative costs and outcomes of different scenarios. Results Strategies that start at ages 40 or 45 and end at 69 predominate when the effect is measured as YL or QALYs. Biennial strategies 50-69, 45-69 or annual 45-69, 40-69 and 40-74 were selected as cost-effective for both effect measures (YL or QALYs). The ICER increases considerably when moving from biennial to annual scenarios. Moving from no screening to biennial 50-69 years represented an ICER of 4,469€ per QALY. Conclusions A reduced number of screening strategies have been selected for consideration by researchers, decision makers and policy planners. Mathematical models are useful to assess the impact and costs of BC screening in a specific geographical area. PMID:21605383

Development and test of selected model pedestrian safety regulations

DOT National Transportation Integrated Search

1981-04-01

Two model regulations to remove parking--one from suburban streets in daylight hours and one on the last 50 feet of the approach to crosswalks--were designed in previous work to prevent pedestrian dart and dash accidents by removing screening vehicle...

Supplement to MTI study on selective passenger screening in the mass transit rail environment.

DOT National Transportation Integrated Search

2010-01-01

This supplement updates and adds to MTIs 2007 report on Selective Screening of Rail Passengers (Jenkins and Butterworth MTI 06-07: Selective Screening of Rail Passengers). The report reviews current screening programs implemented (or planned) by n...

Screening of pollution control and clean-up materials for river chemical spills using the multiple case-based reasoning method with a difference-driven revision strategy.

PubMed

Liu, Rentao; Jiang, Jiping; Guo, Liang; Shi, Bin; Liu, Jie; Du, Zhaolin; Wang, Peng

2016-06-01

In-depth filtering of emergency disposal technology (EDT) and materials has been required in the process of environmental pollution emergency disposal. However, an urgent problem that must be solved is how to quickly and accurately select the most appropriate materials for treating a pollution event from the existing spill control and clean-up materials (SCCM). To meet this need, the following objectives were addressed in this study. First, the material base and a case base for environment pollution emergency disposal were established to build a foundation and provide material for SCCM screening. Second, the multiple case-based reasoning model method with a difference-driven revision strategy (DDRS-MCBR) was applied to improve the original dual case-based reasoning model method system, and screening and decision-making was performed for SCCM using this model. Third, an actual environmental pollution accident from 2012 was used as a case study to verify the material base, case base, and screening model. The results demonstrated that the DDRS-MCBR method was fast, efficient, and practical. The DDRS-MCBR method changes the passive situation in which the choice of SCCM screening depends only on the subjective experience of the decision maker and offers a new approach to screening SCCM.

Combining structure-based pharmacophore modeling, virtual screening, and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity

PubMed Central

Chen, Can; Wang, Ting; Wu, Fengbo; Huang, Wei; He, Gu; Ouyang, Liang; Xiang, Mingli; Peng, Cheng; Jiang, Qinglin

2014-01-01

Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2) to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS) production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important information for further research on novel PKM2 activators as antitumor agents. PMID:25214764

On the use of hidden Markov models for gaze pattern modeling

NASA Astrophysics Data System (ADS)

Mannaru, Pujitha; Balasingam, Balakumar; Pattipati, Krishna; Sibley, Ciara; Coyne, Joseph

2016-05-01

Some of the conventional metrics derived from gaze patterns (on computer screens) to study visual attention, engagement and fatigue are saccade counts, nearest neighbor index (NNI) and duration of dwells/fixations. Each of these metrics has drawbacks in modeling the behavior of gaze patterns; one such drawback comes from the fact that some portions on the screen are not as important as some other portions on the screen. This is addressed by computing the eye gaze metrics corresponding to important areas of interest (AOI) on the screen. There are some challenges in developing accurate AOI based metrics: firstly, the definition of AOI is always fuzzy; secondly, it is possible that the AOI may change adaptively over time. Hence, there is a need to introduce eye-gaze metrics that are aware of the AOI in the field of view; at the same time, the new metrics should be able to automatically select the AOI based on the nature of the gazes. In this paper, we propose a novel way of computing NNI based on continuous hidden Markov models (HMM) that model the gazes as 2D Gaussian observations (x-y coordinates of the gaze) with the mean at the center of the AOI and covariance that is related to the concentration of gazes. The proposed modeling allows us to accurately compute the NNI metric in the presence of multiple, undefined AOI on the screen in the presence of intermittent casual gazing that is modeled as random gazes on the screen.

The Influence of Intrinsic Framework Flexibility on Adsorption in Nanoporous Materials

DOE PAGES

Witman, Matthew; Ling, Sanliang; Jawahery, Sudi; ...

2017-03-30

For applications of metal–organic frameworks (MOFs) such as gas storage and separation, flexibility is often seen as a parameter that can tune material performance. In this work we aim to determine the optimal flexibility for the shape selective separation of similarly sized molecules (e.g., Xe/Kr mixtures). To obtain systematic insight into how the flexibility impacts this type of separation, we develop a simple analytical model that predicts a material’s Henry regime adsorption and selectivity as a function of flexibility. We elucidate the complex dependence of selectivity on a framework’s intrinsic flexibility whereby performance is either improved or reduced with increasingmore » flexibility, depending on the material’s pore size characteristics. However, the selectivity of a material with the pore size and chemistry that already maximizes selectivity in the rigid approximation is continuously diminished with increasing flexibility, demonstrating that the globally optimal separation exists within an entirely rigid pore. Molecular simulations show that our simple model predicts performance trends that are observed when screening the adsorption behavior of flexible MOFs. These flexible simulations provide better agreement with experimental adsorption data in a high-performance material that is not captured when modeling this framework as rigid, an approximation typically made in high-throughput screening studies. We conclude that, for shape selective adsorption applications, the globally optimal material will have the optimal pore size/chemistry and minimal intrinsic flexibility even though other nonoptimal materials’ selectivity can actually be improved by flexibility. In conclusion, equally important, we find that flexible simulations can be critical for correctly modeling adsorption in these types of systems.« less

The Influence of Intrinsic Framework Flexibility on Adsorption in Nanoporous Materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Witman, Matthew; Ling, Sanliang; Jawahery, Sudi

For applications of metal–organic frameworks (MOFs) such as gas storage and separation, flexibility is often seen as a parameter that can tune material performance. In this work we aim to determine the optimal flexibility for the shape selective separation of similarly sized molecules (e.g., Xe/Kr mixtures). To obtain systematic insight into how the flexibility impacts this type of separation, we develop a simple analytical model that predicts a material’s Henry regime adsorption and selectivity as a function of flexibility. We elucidate the complex dependence of selectivity on a framework’s intrinsic flexibility whereby performance is either improved or reduced with increasingmore » flexibility, depending on the material’s pore size characteristics. However, the selectivity of a material with the pore size and chemistry that already maximizes selectivity in the rigid approximation is continuously diminished with increasing flexibility, demonstrating that the globally optimal separation exists within an entirely rigid pore. Molecular simulations show that our simple model predicts performance trends that are observed when screening the adsorption behavior of flexible MOFs. These flexible simulations provide better agreement with experimental adsorption data in a high-performance material that is not captured when modeling this framework as rigid, an approximation typically made in high-throughput screening studies. We conclude that, for shape selective adsorption applications, the globally optimal material will have the optimal pore size/chemistry and minimal intrinsic flexibility even though other nonoptimal materials’ selectivity can actually be improved by flexibility. In conclusion, equally important, we find that flexible simulations can be critical for correctly modeling adsorption in these types of systems.« less

Screening of nanoparticulate delivery systems for the photodetection of cancer in a simple and cost-effective model.

PubMed

Zeisser-Labouèbe, Magali; Delie, Florence; Gurny, Robert; Lange, Norbert

2009-02-01

In urology, fluorescence-based imaging methods have been proven to significantly improve the detection of small, barely visible tumors and reduce the recurrence rate. Under ethical and economical pressure, new effective screening systems have to be developed to exploit and assess novel strategies for fluorescence photodetection in other areas. For this purpose, the chorioallantoic membrane (CAM) of the developing chick embryo is an attractive alternative model to the mammalian models. Hypericin encapsulated into nanoparticles for the photodetection of ovarian metastases was evaluated in the CAM model with respect to vascular extravazation and tumor targeting and compared with free drug following intravenous administration. To validate the CAM model as a valuable screening system for photodetection of cancer, we drew a comparison with results obtained on a conventional rodent model. Rodent and CAM models led to the same conclusion regarding the benefits of nanoencapsulation to improve selective accumulation of drug in ovarian micrometastases.

[Vis-NIR spectroscopic pattern recognition combined with SG smoothing applied to breed screening of transgenic sugarcane].

PubMed

Liu, Gui-Song; Guo, Hao-Song; Pan, Tao; Wang, Ji-Hua; Cao, Gan

2014-10-01

Based on Savitzky-Golay (SG) smoothing screening, principal component analysis (PCA) combined with separately supervised linear discriminant analysis (LDA) and unsupervised hierarchical clustering analysis (HCA) were used for non-destructive visible and near-infrared (Vis-NIR) detection for breed screening of transgenic sugarcane. A random and stability-dependent framework of calibration, prediction, and validation was proposed. A total of 456 samples of sugarcane leaves planting in the elongating stage were collected from the field, which was composed of 306 transgenic (positive) samples containing Bt and Bar gene and 150 non-transgenic (negative) samples. A total of 156 samples (negative 50 and positive 106) were randomly selected as the validation set; the remaining samples (negative 100 and positive 200, a total of 300 samples) were used as the modeling set, and then the modeling set was subdivided into calibration (negative 50 and positive 100, a total of 150 samples) and prediction sets (negative 50 and positive 100, a total of 150 samples) for 50 times. The number of SG smoothing points was ex- panded, while some modes of higher derivative were removed because of small absolute value, and a total of 264 smoothing modes were used for screening. The pairwise combinations of first three principal components were used, and then the optimal combination of principal components was selected according to the model effect. Based on all divisions of calibration and prediction sets and all SG smoothing modes, the SG-PCA-LDA and SG-PCA-HCA models were established, the model parameters were optimized based on the average prediction effect for all divisions to produce modeling stability. Finally, the model validation was performed by validation set. With SG smoothing, the modeling accuracy and stability of PCA-LDA, PCA-HCA were signif- icantly improved. For the optimal SG-PCA-LDA model, the recognition rate of positive and negative validation samples were 94.3%, 96.0%; and were 92.5%, 98.0% for the optimal SG-PCA-LDA model, respectively. Vis-NIR spectro- scopic pattern recognition combined with SG smoothing could be used for accurate recognition of transgenic sugarcane leaves, and provided a convenient screening method for transgenic sugarcane breeding.

Computer-aided system of evaluation for population-based all-in-one service screening (CASE-PASS): from study design to outcome analysis with bias adjustment.

PubMed

Chen, Li-Sheng; Yen, Amy Ming-Fang; Duffy, Stephen W; Tabar, Laszlo; Lin, Wen-Chou; Chen, Hsiu-Hsi

2010-10-01

Population-based routine service screening has gained popularity following an era of randomized controlled trials. The evaluation of these service screening programs is subject to study design, data availability, and the precise data analysis for adjusting bias. We developed a computer-aided system that allows the evaluation of population-based service screening to unify these aspects and facilitate and guide the program assessor to efficiently perform an evaluation. This system underpins two experimental designs: the posttest-only non-equivalent design and the one-group pretest-posttest design and demonstrates the type of data required at both the population and individual levels. Three major analyses were developed that included a cumulative mortality analysis, survival analysis with lead-time adjustment, and self-selection bias adjustment. We used SAS AF software to develop a graphic interface system with a pull-down menu style. We demonstrate the application of this system with data obtained from a Swedish population-based service screen and a population-based randomized controlled trial for the screening of breast, colorectal, and prostate cancer, and one service screening program for cervical cancer with Pap smears. The system provided automated descriptive results based on the various sources of available data and cumulative mortality curves corresponding to the study designs. The comparison of cumulative survival between clinically and screen-detected cases without a lead-time adjustment are also demonstrated. The intention-to-treat and noncompliance analysis with self-selection bias adjustments are also shown to assess the effectiveness of the population-based service screening program. Model validation was composed of a comparison between our adjusted self-selection bias estimates and the empirical results on effectiveness reported in the literature. We demonstrate a computer-aided system allowing the evaluation of population-based service screening programs with an adjustment for self-selection and lead-time bias. This is achieved by providing a tutorial guide from the study design to the data analysis, with bias adjustment. Copyright © 2010 Elsevier Inc. All rights reserved.

Pharmacophore Modelling and Synthesis of Quinoline-3-Carbohydrazide as Antioxidants

PubMed Central

El Bakkali, Mustapha; Ismaili, Lhassane; Tomassoli, Isabelle; Nicod, Laurence; Pudlo, Marc; Refouvelet, Bernard

2011-01-01

From well-known antioxidants agents, we developed a first pharmacophore model containing four common chemical features: one aromatic ring and three hydrogen bond acceptors. This model served as a template in virtual screening of Maybridge and NCI databases that resulted in selection of sixteen compounds. The selected compounds showed a good antioxidant activity measured by three chemical tests: DPPH radical, OH° radical, and superoxide radical scavenging. New synthetic compounds with a good correlation with the model were prepared, and some of them presented a good antioxidant activity. PMID:25954520

Discovery of Novel Hepatitis C Virus NS5B Polymerase Inhibitors by Combining Random Forest, Multiple e-Pharmacophore Modeling and Docking

PubMed Central

Wei, Yu; Li, Jinlong; Qing, Jie; Huang, Mingjie; Wu, Ming; Gao, Fenghua; Li, Dongmei; Hong, Zhangyong; Kong, Lingbao; Huang, Weiqiang; Lin, Jianping

2016-01-01

The NS5B polymerase is one of the most attractive targets for developing new drugs to block Hepatitis C virus (HCV) infection. We describe the discovery of novel potent HCV NS5B polymerase inhibitors by employing a virtual screening (VS) approach, which is based on random forest (RB-VS), e-pharmacophore (PB-VS), and docking (DB-VS) methods. In the RB-VS stage, after feature selection, a model with 16 descriptors was used. In the PB-VS stage, six energy-based pharmacophore (e-pharmacophore) models from different crystal structures of the NS5B polymerase with ligands binding at the palm I, thumb I and thumb II regions were used. In the DB-VS stage, the Glide SP and XP docking protocols with default parameters were employed. In the virtual screening approach, the RB-VS, PB-VS and DB-VS methods were applied in increasing order of complexity to screen the InterBioScreen database. From the final hits, we selected 5 compounds for further anti-HCV activity and cellular cytotoxicity assay. All 5 compounds were found to inhibit NS5B polymerase with IC50 values of 2.01–23.84 μM and displayed anti-HCV activities with EC50 values ranging from 1.61 to 21.88 μM, and all compounds displayed no cellular cytotoxicity (CC50 > 100 μM) except compound N2, which displayed weak cytotoxicity with a CC50 value of 51.3 μM. The hit compound N2 had the best antiviral activity against HCV, with a selective index of 32.1. The 5 hit compounds with new scaffolds could potentially serve as NS5B polymerase inhibitors through further optimization and development. PMID:26845440

Perceptions of Female and Male Superintendents for a Middle School Principalship as Moderated by Sex and National Origin of Applicants

ERIC Educational Resources Information Center

Young, Phillip; Young, Karen Holsey

2010-01-01

A 2 x 2 x 2 factorial design involving sex of superintendents, sex of applicants, and national origin of applicants (Hispanic vs. non-Hispanic) is used to assess screening decisions for a middle school principalship. Screening decisions are analyzed from a sequential model to capture selection as a process. Results indicate that biases surface…

Protein attributes contribute to halo-stability, bioinformatics approach

PubMed Central

2011-01-01

Halophile proteins can tolerate high salt concentrations. Understanding halophilicity features is the first step toward engineering halostable crops. To this end, we examined protein features contributing to the halo-toleration of halophilic organisms. We compared more than 850 features for halophilic and non-halophilic proteins with various screening, clustering, decision tree, and generalized rule induction models to search for patterns that code for halo-toleration. Up to 251 protein attributes selected by various attribute weighting algorithms as important features contribute to halo-stability; from them 14 attributes selected by 90% of models and the count of hydrogen gained the highest value (1.0) in 70% of attribute weighting models, showing the importance of this attribute in feature selection modeling. The other attributes mostly were the frequencies of di-peptides. No changes were found in the numbers of groups when K-Means and TwoStep clustering modeling were performed on datasets with or without feature selection filtering. Although the depths of induced trees were not high, the accuracies of trees were higher than 94% and the frequency of hydrophobic residues pointed as the most important feature to build trees. The performance evaluation of decision tree models had the same values and the best correctness percentage recorded with the Exhaustive CHAID and CHAID models. We did not find any significant difference in the percent of correctness, performance evaluation, and mean correctness of various decision tree models with or without feature selection. For the first time, we analyzed the performance of different screening, clustering, and decision tree algorithms for discriminating halophilic and non-halophilic proteins and the results showed that amino acid composition can be used to discriminate between halo-tolerant and halo-sensitive proteins. PMID:21592393

Weak cation exchange magnetic beads coupled with matrix-assisted laser desorption ionization-time of flight-mass spectrometry in screening serum protein markers in osteopenia.

PubMed

He, Wei-Tao; Liang, Bo-Cheng; Shi, Zhen-Yu; Li, Xu-Yun; Li, Chun-Wen; Shi, Xiao-Lin

2016-01-01

The present study aimed at investigating the weak cation magnetic separation technology and matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) in screening serum protein markers of osteopenia from ten postmenopausal women and ten postmenopausal women without osteopenia as control group, to find a new method for screening biomarkers and establishing a diagnostic model for primary type I osteoporosis. Serum samples were collected from postmenopausal women with osteopenia and postmenopausal women with normal bone mass. Proteins were extracted from serum samples by weak cation exchange magnetic beads technology, and mass spectra acquisition was done by MALDI-TOF-MS. The visualization and comparison of data sets, statistical peak evaluation, model recognition, and discovery of biomarker candidates were handled by the proteinchip data analysis system software(ZJU-PDAS). The diagnostic models were established using genetic arithmetic based support vector machine (SVM). The SVM result with the highest Youden Index was selected as the model. Combinatorial Peaks having the highest accuracy in distinguishing different samples were selected as potential biomarker. From the two group serum samples, a total of 133 differential features were selected. Ten features with significant intensity differences were screened. In the pair-wise comparisons, processing of MALDI-TOF spectra resulted in the identification of ten differential features between postmenopausal women with osteopenia and postmenopausal women with normal bone mass. The difference of features by Youden index showed that the highest features had a mass to charge ratio of 1699 and 3038 Da. A diagnosis model was established with these two peaks as the candidate marker, and the specificity of the model is 100 %, the sensitivity was 90 % by leave-one-out cross validation test. The two groups of specimens in SVM results on the scatter plot could be clearly distinguished. The peak with m/z 3038 in the SVM model was suggested as Secretin by TagIdent tool. To provide further validation, the secretin levels in serum were analyzed using enzyme-linked immunosorbent assays that is a competitive inhibition enzyme immunoassay technique for the in vitro quantitative measurement of secretin in human serum.

[A Method for Selecting Self-Adoptive Chromaticity of the Projected Markers].

PubMed

Zhao, Shou-bo; Zhang, Fu-min; Qu, Xing-hua; Zheng, Shi-wei; Chen, Zhe

2015-04-01

The authors designed a self-adaptive projection system which is composed of color camera, projector and PC. In detail, digital micro-mirror device (DMD) as a spatial light modulator for the projector was introduced in the optical path to modulate the illuminant spectrum based on red, green and blue light emitting diodes (LED). However, the color visibility of active markers is affected by the screen which has unknown reflective spectrum as well. Here active markers are projected spot array. And chromaticity feature of markers is sometimes submerged in similar spectral screen. In order to enhance the color visibility of active markers relative to screen, a method for selecting self-adaptive chromaticity of the projected markers in 3D scanning metrology is described. Color camera with 3 channels limits the accuracy of device characterization. For achieving interconversion of device-independent color space and device-dependent color space, high-dimensional linear model of reflective spectrum was built. Prior training samples provide additional constraints to yield high-dimensional linear model with more than three degrees of freedom. Meanwhile, spectral power distribution of ambient light was estimated. Subsequently, markers' chromaticity in CIE color spaces was selected via maximization principle of Euclidean distance. The setting values of RGB were easily estimated via inverse transform. Finally, we implemented a typical experiment to show the performance of the proposed approach. An 24 Munsell Color Checker was used as projective screen. Color difference in the chromaticity coordinates between the active marker and the color patch was utilized to evaluate the color visibility of active markers relative to the screen. The result comparison between self-adaptive projection system and traditional diode-laser light projector was listed and discussed to highlight advantage of our proposed method.

Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections.

PubMed

Don, Rob; Ioset, Jean-Robert

2014-01-01

The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation.

Cost-Effectiveness Analysis of Screening for and Managing Identified Hypertension for Cardiovascular Disease Prevention in Vietnam

PubMed Central

Nguyen, Thi-Phuong-Lan; Wright, E. Pamela; Nguyen, Thanh-Trung; Schuiling-Veninga, C. C. M.; Bijlsma, M. J.; Nguyen, Thi-Bach-Yen; Postma, M. J.

2016-01-01

Objective To inform development of guidelines for hypertension management in Vietnam, we evaluated the cost-effectiveness of different strategies on screening for hypertension in preventing cardiovascular disease (CVD). Methods A decision tree was combined with a Markov model to measure incremental cost-effectiveness of different approaches to hypertension screening. Values used as input parameters for the model were taken from different sources. Various screening intervals (one-off, annually, biannually) and starting ages to screen (35, 45 or 55 years) and coverage of treatment were analysed. We ran both a ten-year and a lifetime horizon. Input parameters for the models were extracted from local and regional data. Probabilistic sensitivity analysis was used to evaluate parameter uncertainty. A threshold of three times GDP per capita was applied. Results Cost per quality adjusted life year (QALY) gained varied in different screening scenarios. In a ten-year horizon, the cost-effectiveness of screening for hypertension ranged from cost saving to Int$ 758,695 per QALY gained. For screening of men starting at 55 years, all screening scenarios gave a high probability of being cost-effective. For screening of females starting at 55 years, the probability of favourable cost-effectiveness was 90% with one-off screening. In a lifetime horizon, cost per QALY gained was lower than the threshold of Int$ 15,883 in all screening scenarios among males. Similar results were found in females when starting screening at 55 years. Starting screening in females at 45 years had a high probability of being cost-effective if screening biannually was combined with increasing coverage of treatment by 20% or even if sole biannual screening was considered. Conclusion From a health economic perspective, integrating screening for hypertension into routine medical examination and related coverage by health insurance could be recommended. Screening for hypertension has a high probability of being cost-effective in preventing CVD. An adequate screening strategy can best be selected based on age, sex and screening interval. PMID:27192051

Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library.

PubMed

Huschmann, Franziska U; Linnik, Janina; Sparta, Karine; Ühlein, Monika; Wang, Xiaojie; Metz, Alexander; Schiebel, Johannes; Heine, Andreas; Klebe, Gerhard; Weiss, Manfred S; Mueller, Uwe

2016-05-01

Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein-ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds. When applied to the model protease endothiapepsin in a crystallographic screening experiment, a hit rate of nearly 10% was obtained. In comparison to other fragment libraries and considering that no pre-screening was performed, this hit rate is remarkably high. This demonstrates the general suitability of the selected compounds for an initial fragment-screening campaign. The library composition, experimental considerations and time requirements for a complete crystallographic fragment-screening campaign are discussed as well as the nine fully refined obtained endothiapepsin-fragment structures. While most of the fragments bind close to the catalytic centre of endothiapepsin in poses that have been observed previously, two fragments address new sites on the protein surface. ITC measurements show that the fragments bind to endothiapepsin with millimolar affinity.

Structures of endothiapepsin–fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library

PubMed Central

Huschmann, Franziska U.; Linnik, Janina; Sparta, Karine; Ühlein, Monika; Wang, Xiaojie; Metz, Alexander; Schiebel, Johannes; Heine, Andreas; Klebe, Gerhard; Weiss, Manfred S.; Mueller, Uwe

2016-01-01

Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein–ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds. When applied to the model protease endothiapepsin in a crystallographic screening experiment, a hit rate of nearly 10% was obtained. In comparison to other fragment libraries and considering that no pre-screening was performed, this hit rate is remarkably high. This demonstrates the general suitability of the selected compounds for an initial fragment-screening campaign. The library composition, experimental considerations and time requirements for a complete crystallographic fragment-screening campaign are discussed as well as the nine fully refined obtained endothiapepsin–fragment structures. While most of the fragments bind close to the catalytic centre of endothiapepsin in poses that have been observed previously, two fragments address new sites on the protein surface. ITC measurements show that the fragments bind to endothiapepsin with millimolar affinity. PMID:27139825

Simulation models in population breast cancer screening: A systematic review.

PubMed

Koleva-Kolarova, Rositsa G; Zhan, Zhuozhao; Greuter, Marcel J W; Feenstra, Talitha L; De Bock, Geertruida H

2015-08-01

The aim of this review was to critically evaluate published simulation models for breast cancer screening of the general population and provide a direction for future modeling. A systematic literature search was performed to identify simulation models with more than one application. A framework for qualitative assessment which incorporated model type; input parameters; modeling approach, transparency of input data sources/assumptions, sensitivity analyses and risk of bias; validation, and outcomes was developed. Predicted mortality reduction (MR) and cost-effectiveness (CE) were compared to estimates from meta-analyses of randomized control trials (RCTs) and acceptability thresholds. Seven original simulation models were distinguished, all sharing common input parameters. The modeling approach was based on tumor progression (except one model) with internal and cross validation of the resulting models, but without any external validation. Differences in lead times for invasive or non-invasive tumors, and the option for cancers not to progress were not explicitly modeled. The models tended to overestimate the MR (11-24%) due to screening as compared to optimal RCTs 10% (95% CI - 2-21%) MR. Only recently, potential harms due to regular breast cancer screening were reported. Most scenarios resulted in acceptable cost-effectiveness estimates given current thresholds. The selected models have been repeatedly applied in various settings to inform decision making and the critical analysis revealed high risk of bias in their outcomes. Given the importance of the models, there is a need for externally validated models which use systematical evidence for input data to allow for more critical evaluation of breast cancer screening. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Creation of a line of "depressed" mice from a selection of breeders exhibiting a behavioral helplessness].

PubMed

Vaugeois, J M; Costentin, J

1998-01-01

Antidepressants are used since 40 years. All presently used antidepressants have a slow onset of action and do not improve all patients; thus, there is an absolute need for new antidepressants. A variety of animal models, often based upon the monoaminergic theory of depressive disorders, has been used to screen the current antidepressants. In fact, the main focus of most of these animal models has been to predict the antidepressant potential i.e. to establish predictive validity. However, the evaluation of such animal models should also consider face validity, i.e. how closely the model resembles the human condition, and this should help to identify innovating medicines. Antidepressants, when taken by a healthy person, induce nothing more than side effects, unrelated to an action on mood, whereas they alleviate depressive symptomatology in depressed patients. We have speculated that genetically selected animal models would be closer to the human clinical situation than models based on standard laboratory strains. We have depicted here that marked differences exist between strains of mice in the amount of immobility i.e. "spontaneous helplessness" observed in the tail suspension test, a method used to screen potential antidepressants. We have studied the behavioural characteristics of mice selectively bred for spontaneous high or low immobility scores in the tail suspension test. Hopefully, these selectively bred lines will provide a novel approach to investigate behavioural, neurochemical and neuroendocrine correlates of antidepressant action.

Valuing Equal Protection in Aviation Security Screening.

PubMed

Nguyen, Kenneth D; Rosoff, Heather; John, Richard S

2017-12-01

The growing number of anti-terrorism policies has elevated public concerns about discrimination. Within the context of airport security screening, the current study examines how American travelers value the principle of equal protection by quantifying the "equity premium" that they are willing to sacrifice to avoid screening procedures that result in differential treatments. In addition, we applied the notion of procedural justice to explore the effect of alternative selective screening procedures on the value of equal protection. Two-hundred and twenty-two respondents were randomly assigned to one of three selective screening procedures: (1) randomly, (2) using behavioral indicators, or (3) based on demographic characteristics. They were asked to choose between airlines using either an equal or a discriminatory screening procedure. While the former requires all passengers to be screened in the same manner, the latter mandates all passengers undergo a quick primary screening and, in addition, some passengers are selected for a secondary screening based on a predetermined selection criterion. Equity premiums were quantified in terms of monetary cost, wait time, convenience, and safety compromise. Results show that equity premiums varied greatly across respondents, with many indicating little willingness to sacrifice to avoid inequitable screening, and a smaller minority willing to sacrifice anything to avoid the discriminatory screening. The selective screening manipulation was effective in that equity premiums were greater under selection by demographic characteristics compared to the other two procedures. © 2017 Society for Risk Analysis.

Development of Peritoneal Tumor-Targeting Vector by In Vivo Screening with a Random Peptide-Displaying Adenovirus Library

PubMed Central

Yoshida, Kimiko; Goto, Naoko; Ohnami, Shumpei; Aoki, Kazunori

2012-01-01

The targeting of gene transfer at the cell-entry level is one of the most attractive challenges in vector development. However, attempts to redirect adenovirus vectors to alternative receptors by engineering the capsid-coding region have shown limited success, because the proper targeting ligands on the cells of interest are generally unknown. To overcome this limitation, we have constructed a random peptide library displayed on the adenoviral fiber knob, and have successfully selected targeted vectors by screening the library on cancer cell lines in vitro. The infection of targeted vectors was considered to be mediated by specific receptors on target cells. However, the expression levels and kinds of cell surface receptors may be substantially different between in vitro culture and in vivo tumor tissue. Here, we screened the peptide display-adenovirus library in the peritoneal dissemination model of AsPC-1 pancreatic cancer cells. The vector displaying a selected peptide (PFWSGAV) showed higher infectivity in the AsPC-1 peritoneal tumors but not in organs and other peritoneal tumors as compared with a non-targeted vector. Furthermore, the infectivity of the PFWSGAV-displaying vector for AsPC-1 peritoneal tumors was significantly higher than that of a vector displaying a peptide selected by in vitro screening, indicating the usefulness of in vivo screening in exploring the targeting vectors. This vector-screening system can facilitate the development of targeted adenovirus vectors for a variety of applications in medicine. PMID:23029088

Protection motivation theory in predicting intention to receive cervical cancer screening in rural Chinese women.

PubMed

Bai, Yang; Liu, Qing; Chen, Xinguang; Gao, Yanduo; Gong, Huiyun; Tan, Xiaodong; Zhang, Min; Tuo, Jiyu; Zhang, Yuling; Xiang, Qunying; Deng, Fenghua; Liu, Guiling

2018-02-01

Despite the significance of cervical cancer screening, motivating more women to participate remains a challenge in resource-limited settings. In this study, we tested the protection motivation theory (PMT) in predicting screening intentions. Participants were women from Wufeng, a typical rural county in China. Participants (n = 3000) with no cervical cancer history were recruited from 10 randomly selected villages. As mediating variables, 6 PMT constructs (Perceived Risk, Fear Arousal, Perceived Severity, Response Efficacy, Response Cost, and Self-Efficacy) were measured using the standardized questionnaire. Structural equation modeling (SEM) method was employed to test PMT-based prediction models. Of the total sample, 57.77% believed that regular screening may reduce cervical cancer risk, and 45.26% agreed that women should be screened regularly. Our data fit the PMT model well (GFI = 0.95, AGFI = 0.93, CFI = 0.90, RMSEA = 0.06, SRMR = 0.04, Chi-square/df = 2.47). Knowledge of screening was directly and positively associated with screening intention. Age, annual income, and awareness of and prior experience with screening were significantly associated with screening intention by enhancing cervical cancer risk perception and by reducing response cost (P<0.05 for both). PMT can be used as guidance to investigate cervical cancer screening intentions among rural women in China with focus on cancer knowledge, some demographic factors, and awareness of and previous experience with screening. These findings, if verified with longitudinal data, can be used for intervention program development. Copyright © 2017 John Wiley & Sons, Ltd.

A Proposed Method to Predict Preterm Birth Using Clinical Data, Standard Maternal Serum Screening, and Cholesterol

PubMed Central

ALLEMAN, Brandon W.; SMITH, Amanda R.; BYERS, Heather M.; BEDELL, Bruce; RYCKMAN, Kelli K.; MURRAY, Jeffrey C.; BOROWSKI, Kristi S.

2013-01-01

Objective To create a predictive model for preterm birth (PTB) from available clinical data and serum analytes. Study Design Serum analytes, routine pregnancy screening plus cholesterol and corresponding health information were linked to birth certificate data for a cohort of 2699 Iowa women with serum sampled in the first and second trimester. Stepwise logistic regression was used to select the best predictive model for PTB. Results Serum screening markers remained significant predictors of PTB even after controlling for maternal characteristics. The best predictive model included maternal characteristics, first trimester total cholesterol (TC), TC change between trimesters and second trimester alpha-fetoprotein and inhibin A. The model showed better discriminatory ability than PTB history alone and performed similarly in subgroups of women without past PTB. Conclusions Using clinical and serum screening data a potentially useful predictor of PTB was constructed. Validation and replication in other populations, and incorporation of other measures that identify PTB risk, like cervical length, can be a step towards identifying additional women who may benefit from new or currently available interventions. PMID:23500456

Heritability and phenotypic variation of canine hip dysplasia radiographic traits in a cohort of Australian German shepherd dogs.

PubMed

Wilson, Bethany J; Nicholas, Frank W; James, John W; Wade, Claire M; Tammen, Imke; Raadsma, Herman W; Castle, Kao; Thomson, Peter C

2012-01-01

Canine Hip Dysplasia (CHD) is a common, painful and debilitating orthopaedic disorder of dogs with a partly genetic, multifactorial aetiology. Worldwide, potential breeding dogs are evaluated for CHD using radiographically based screening schemes such as the nine ordinally-scored British Veterinary Association Hip Traits (BVAHTs). The effectiveness of selective breeding based on screening results requires that a significant proportion of the phenotypic variation is caused by the presence of favourable alleles segregating in the population. This proportion, heritability, was measured in a cohort of 13,124 Australian German Shepherd Dogs born between 1976 and 2005, displaying phenotypic variation for BVAHTs, using ordinal, linear and binary mixed models fitted by a Restricted Maximum Likelihood method. Heritability estimates for the nine BVAHTs ranged from 0.14-0.24 (ordinal models), 0.14-0.25 (linear models) and 0.12-0.40 (binary models). Heritability for the summed BVAHT phenotype was 0.30 ± 0.02. The presence of heritable variation demonstrates that selection based on BVAHTs has the potential to improve BVAHT scores in the population. Assuming a genetic correlation between BVAHT scores and CHD-related pain and dysfunction, the welfare of Australian German Shepherds can be improved by continuing to consider BVAHT scores in the selection of breeding dogs, but that as heritability values are only moderate in magnitude the accuracy, and effectiveness, of selection could be improved by the use of Estimated Breeding Values in preference to solely phenotype based selection of breeding animals.

Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library.

PubMed

Männel, Barbara; Jaiteh, Mariama; Zeifman, Alexey; Randakova, Alena; Möller, Dorothee; Hübner, Harald; Gmeiner, Peter; Carlsson, Jens

2017-10-20

Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D 2 dopamine receptor (D 2 R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D 2 R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D 2 R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D 2 R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and β-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated β-arrestin recruitment (EC 50 = 320 nM, E max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.

Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study.

PubMed

Tammemagi, Martin C; Schmidt, Heidi; Martel, Simon; McWilliams, Annette; Goffin, John R; Johnston, Michael R; Nicholas, Garth; Tremblay, Alain; Bhatia, Rick; Liu, Geoffrey; Soghrati, Kam; Yasufuku, Kazuhiro; Hwang, David M; Laberge, Francis; Gingras, Michel; Pasian, Sergio; Couture, Christian; Mayo, John R; Nasute Fauerbach, Paola V; Atkar-Khattra, Sukhinder; Peacock, Stuart J; Cressman, Sonya; Ionescu, Diana; English, John C; Finley, Richard J; Yee, John; Puksa, Serge; Stewart, Lori; Tsai, Scott; Haider, Ehsan; Boylan, Colm; Cutz, Jean-Claude; Manos, Daria; Xu, Zhaolin; Goss, Glenwood D; Seely, Jean M; Amjadi, Kayvan; Sekhon, Harmanjatinder S; Burrowes, Paul; MacEachern, Paul; Urbanski, Stefan; Sin, Don D; Tan, Wan C; Leighl, Natasha B; Shepherd, Frances A; Evans, William K; Tsao, Ming-Sound; Lam, Stephen

2017-11-01

Results from retrospective studies indicate that selecting individuals for low-dose CT lung cancer screening on the basis of a highly predictive risk model is superior to using criteria similar to those used in the National Lung Screening Trial (NLST; age, pack-year, and smoking quit-time). We designed the Pan-Canadian Early Detection of Lung Cancer (PanCan) study to assess the efficacy of a risk prediction model to select candidates for lung cancer screening, with the aim of determining whether this approach could better detect patients with early, potentially curable, lung cancer. We did this single-arm, prospective study in eight centres across Canada. We recruited participants aged 50-75 years, who had smoked at some point in their life (ever-smokers), and who did not have a self-reported history of lung cancer. Participants had at least a 2% 6-year risk of lung cancer as estimated by the PanCan model, a precursor to the validated PLCOm2012 model. Risk variables in the model were age, smoking duration, pack-years, family history of lung cancer, education level, body-mass index, chest x-ray in the past 3 years, and history of chronic obstructive pulmonary disease. Individuals were screened with low-dose CT at baseline (T0), and at 1 (T1) and 4 (T4) years post-baseline. The primary outcome of the study was incidence of lung cancer. This study is registered with ClinicalTrials.gov, number NCT00751660. 7059 queries came into the study coordinating centre and were screened for PanCan risk. 15 were duplicates, so 7044 participants were considered for enrolment. Between Sept 24, 2008, and Dec 17, 2010, we recruited and enrolled 2537 eligible ever-smokers. After a median follow-up of 5·5 years (IQR 3·2-6·1), 172 lung cancers were diagnosed in 164 individuals (cumulative incidence 0·065 [95% CI 0·055-0·075], incidence rate 138·1 per 10 000 person-years [117·8-160·9]). There were ten interval lung cancers (6% of lung cancers and 6% of individuals with cancer): one diagnosed between T0 and T1, and nine between T1 and T4. Cumulative incidence was significantly higher than that observed in NLST (4·0%; p<0·0001). Compared with 593 (57%) of 1040 lung cancers observed in NLST, 133 (77%) of 172 lung cancers in the PanCan Study were early stage (I or II; p<0·0001). The PanCan model was effective in identifying individuals who were subsequently diagnosed with early, potentially curable, lung cancer. The incidence of cancers detected and the proportion of early stage cancers in the screened population was higher than observed in previous studies. This approach should be considered for adoption in lung cancer screening programmes. Terry Fox Research Institute and Canadian Partnership Against Cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Cost-Effectiveness of High-Risk Lung Cancer Screening and Drivers of Program Efficiency.

PubMed

Cressman, Sonya; Peacock, Stuart J; Tammemägi, Martin C; Evans, William K; Leighl, Natasha B; Goffin, John R; Tremblay, Alain; Liu, Geoffrey; Manos, Daria; MacEachern, Paul; Bhatia, Rick; Puksa, Serge; Nicholas, Garth; McWilliams, Annette; Mayo, John R; Yee, John; English, John C; Pataky, Reka; McPherson, Emily; Atkar-Khattra, Sukhinder; Johnston, Michael R; Schmidt, Heidi; Shepherd, Frances A; Soghrati, Kam; Amjadi, Kayvan; Burrowes, Paul; Couture, Christian; Sekhon, Harmanjatinder S; Yasufuku, Kazuhiro; Goss, Glenwood; Ionescu, Diana N; Hwang, David M; Martel, Simon; Sin, Don D; Tan, Wan C; Urbanski, Stefan; Xu, Zhaolin; Tsao, Ming-Sound; Lam, Stephen

2017-08-01

Lung cancer risk prediction models have the potential to make programs more affordable; however, the economic evidence is limited. Participants in the National Lung Cancer Screening Trial (NLST) were retrospectively identified with the risk prediction tool developed from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The high-risk subgroup was assessed for lung cancer incidence and demographic characteristics compared with those in the low-risk subgroup and the Pan-Canadian Early Detection of Lung Cancer Study (PanCan), which is an observational study that was high-risk-selected in Canada. A comparison of high-risk screening versus standard care was made with a decision-analytic model using data from the NLST with Canadian cost data from screening and treatment in the PanCan study. Probabilistic and deterministic sensitivity analyses were undertaken to assess uncertainty and identify drivers of program efficiency. Use of the risk prediction tool developed from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with a threshold set at 2% over 6 years would have reduced the number of individuals who needed to be screened in the NLST by 81%. High-risk screening participants in the NLST had more adverse demographic characteristics than their counterparts in the PanCan study. High-risk screening would cost $20,724 (in 2015 Canadian dollars) per quality-adjusted life-year gained and would be considered cost-effective at a willingness-to-pay threshold of $100,000 in Canadian dollars per quality-adjusted life-year gained with a probability of 0.62. Cost-effectiveness was driven primarily by non-lung cancer outcomes. Higher noncurative drug costs or current costs for immunotherapy and targeted therapies in the United States would render lung cancer screening a cost-saving intervention. Non-lung cancer outcomes drive screening efficiency in diverse, tobacco-exposed populations. Use of risk selection can reduce the budget impact, and screening may even offer cost savings if noncurative treatment costs continue to rise. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Zebrafish models in neuropsychopharmacology and CNS drug discovery.

PubMed

Khan, Kanza M; Collier, Adam D; Meshalkina, Darya A; Kysil, Elana V; Khatsko, Sergey L; Kolesnikova, Tatyana; Morzherin, Yury Yu; Warnick, Jason E; Kalueff, Allan V; Echevarria, David J

2017-07-01

Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug-induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets. © 2017 The British Pharmacological Society.

Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking.

PubMed

Chen, H F; Dong, X C; Zen, B S; Gao, K; Yuan, S G; Panaye, A; Doucet, J P; Fan, B T

2003-08-01

An efficient virtual and rational drug design method is presented. It combines virtual bioactive compound generation with 3D-QSAR model and docking. Using this method, it is possible to generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study of a set of anti-tumor drugs. With the constraints of pharmacophore obtained by DISCO implemented in SYBYL 6.8, 97 virtual bioactive compounds were generated, and their anti-tumor activities were predicted by CoMFA. Eight structures with high activity were selected and screened by the 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity. A comparative docking study with telomeric receptor was carried out, and the results showed that the generated structures could form more stable complexes with receptor than the reference compound selected from experimental data. This investigation showed that the proposed method was a feasible way for rational drug design with high screening efficiency.

Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries.

PubMed

Schuster, Daniela; Nashev, Lyubomir G; Kirchmair, Johannes; Laggner, Christian; Wolber, Gerhard; Langer, Thierry; Odermatt, Alex

2008-07-24

17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) plays a pivotal role in the local synthesis of the most potent estrogen estradiol. Its expression is a prognostic marker for the outcome of patients with breast cancer and inhibition of 17beta-HSD1 is currently under consideration for breast cancer prevention and treatment. We aimed to identify nonsteroidal 17beta-HSD1 inhibitor scaffolds by virtual screening with pharmacophore models built from crystal structures containing steroidal compounds. The most promising model was validated by comparing predicted and experimentally determined inhibitory activities of several flavonoids. Subsequently, a virtual library of nonsteroidal compounds was screened against the 3D pharmacophore. Analysis of 14 selected compounds yielded four that inhibited the activity of human 17beta-HSD1 (IC 50 below 50 microM). Specificity assessment of identified 17beta-HSD1 inhibitors emphasized the importance of including related short-chain dehydrogenase/reductase (SDR) members to analyze off-target effects. Compound 29 displayed at least 10-fold selectivity over the related SDR enzymes tested.

Fungal community structure under goat willows (Salix caprea L.) growing at metal polluted site: the potential of screening in a model phytostabilisation study

Treesearch

Marjana Regvar; Matevz Likar; Andrej Piltaver; Nives Kugonic; Jane E. Smith

2010-01-01

Goat willow (Salix caprea L.) was selected in a previous vegetation screening study as a potential candidate for the later-stage phytostabilisation efforts at a heavily metal polluted site in Slovenia. The aims of this study were to identify the fungi colonising roots of S. caprea along the gradient of vegetation succession and...

Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors

PubMed Central

Akram, Muhammad; Waratchareeyakul, Watcharee; Haupenthal, Joerg; Hartmann, Rolf W.; Schuster, Daniela

2017-01-01

Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing's syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8–10), one selective CYP11B1 inhibitor (Compound 11, IC50 = 2.5 μM), and one selective CYP11B2 inhibitor (compound 12, IC50 = 1.1 μM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models. PMID:29312923

Pharmacophore modeling for identification of anti-IGF-1R drugs and in-vitro validation of fulvestrant as a potential inhibitor

PubMed Central

Hanif, Rumeza; Jabeen, Ishrat; Mansoor, Qaisar; Ismail, Muhammad

2018-01-01

Insulin-like growth factor 1 receptor (IGF-1R) is an important therapeutic target for breast cancer treatment. The alteration in the IGF-1R associated signaling network due to various genetic and environmental factors leads the system towards metastasis. The pharmacophore modeling and logical approaches have been applied to analyze the behaviour of complex regulatory network involved in breast cancer. A total of 23 inhibitors were selected to generate ligand based pharmacophore using the tool, Molecular Operating Environment (MOE). The best model consisted of three pharmacophore features: aromatic hydrophobic (HyD/Aro), hydrophobic (HyD) and hydrogen bond acceptor (HBA). This model was validated against World drug bank (WDB) database screening to identify 189 hits with the required pharmacophore features and was further screened by using Lipinski positive compounds. Finally, the most effective drug, fulvestrant, was selected. Fulvestrant is a selective estrogen receptor down regulator (SERD). This inhibitor was further studied by using both in-silico and in-vitro approaches that showed the targeted effect of fulvestrant in ER+ MCF-7 cells. Results suggested that fulvestrant has selective cytotoxic effect and a dose dependent response on IRS-1, IGF-1R, PDZK1 and ER-α in MCF-7 cells. PDZK1 can be an important inhibitory target using fulvestrant because it directly regulates IGF-1R. PMID:29787591

Pharmacophore modeling for identification of anti-IGF-1R drugs and in-vitro validation of fulvestrant as a potential inhibitor.

PubMed

Khalid, Samra; Hanif, Rumeza; Jabeen, Ishrat; Mansoor, Qaisar; Ismail, Muhammad

2018-01-01

Insulin-like growth factor 1 receptor (IGF-1R) is an important therapeutic target for breast cancer treatment. The alteration in the IGF-1R associated signaling network due to various genetic and environmental factors leads the system towards metastasis. The pharmacophore modeling and logical approaches have been applied to analyze the behaviour of complex regulatory network involved in breast cancer. A total of 23 inhibitors were selected to generate ligand based pharmacophore using the tool, Molecular Operating Environment (MOE). The best model consisted of three pharmacophore features: aromatic hydrophobic (HyD/Aro), hydrophobic (HyD) and hydrogen bond acceptor (HBA). This model was validated against World drug bank (WDB) database screening to identify 189 hits with the required pharmacophore features and was further screened by using Lipinski positive compounds. Finally, the most effective drug, fulvestrant, was selected. Fulvestrant is a selective estrogen receptor down regulator (SERD). This inhibitor was further studied by using both in-silico and in-vitro approaches that showed the targeted effect of fulvestrant in ER+ MCF-7 cells. Results suggested that fulvestrant has selective cytotoxic effect and a dose dependent response on IRS-1, IGF-1R, PDZK1 and ER-α in MCF-7 cells. PDZK1 can be an important inhibitory target using fulvestrant because it directly regulates IGF-1R.

Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease.

PubMed

Shen, Sida; Benoy, Veronick; Bergman, Joel A; Kalin, Jay H; Frojuello, Mariana; Vistoli, Giulio; Haeck, Wanda; Van Den Bosch, Ludo; Kozikowski, Alan P

2016-02-17

Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.

The Variables Affecting the Success of Students

ERIC Educational Resources Information Center

Savas, Behsat; Gurel, Ramazan

2014-01-01

The aim of this study is to determine the variables affecting the success of students. This research, which was conducted through the relational screening model, has a sampling of students who were selected from a middle city in Turkey. The schools are classified into three as low, medium and high. A total of 3491 students are selected by using…

Classifying the Indication for Colonoscopy Procedures: A Comparison of NLP Approaches in a Diverse National Healthcare System.

PubMed

Patterson, Olga V; Forbush, Tyler B; Saini, Sameer D; Moser, Stephanie E; DuVall, Scott L

2015-01-01

In order to measure the level of utilization of colonoscopy procedures, identifying the primary indication for the procedure is required. Colonoscopies may be utilized not only for screening, but also for diagnostic or therapeutic purposes. To determine whether a colonoscopy was performed for screening, we created a natural language processing system to identify colonoscopy reports in the electronic medical record system and extract indications for the procedure. A rule-based model and three machine-learning models were created using 2,000 manually annotated clinical notes of patients cared for in the Department of Veterans Affairs. Performance of the models was measured and compared. Analysis of the models on a test set of 1,000 documents indicates that the rule-based system performance stays fairly constant as evaluated on training and testing sets. However, the machine learning model without feature selection showed significant decrease in performance. Therefore, rule-based classification system appears to be more robust than a machine-learning system in cases when no feature selection is performed.

Selected Tether Applications Cost Model

NASA Technical Reports Server (NTRS)

Keeley, Michael G.

1988-01-01

Diverse cost-estimating techniques and data combined into single program. Selected Tether Applications Cost Model (STACOM 1.0) is interactive accounting software tool providing means for combining several independent cost-estimating programs into fully-integrated mathematical model capable of assessing costs, analyzing benefits, providing file-handling utilities, and putting out information in text and graphical forms to screen, printer, or plotter. Program based on Lotus 1-2-3, version 2.0. Developed to provide clear, concise traceability and visibility into methodology and rationale for estimating costs and benefits of operations of Space Station tether deployer system.

Rates of Cervical Cancer Screening Among Women With Severe Mental Illness in the Public Health System.

PubMed

James, Monique; Thomas, Melanie; Frolov, Latoya; Riano, Nicholas S; Vittinghoff, Eric; Schillinger, Dean; Newcomer, John W; Mangurian, Christina

2017-08-01

This study aimed to determine cervical cancer screening rates among women with severe mental illness. California Medicaid administrative records (2010-2011) for 31,308 women with severe mental illness were examined. Participants received specialty mental health services and were not dually eligible for Medicare. Poisson models assessed association between selected predictors and cervical cancer screening. Overall, 20.2% of women with severe mental illness received cervical cancer screening during the one-year period. Compared with white women, Asian women (adjusted risk ratio [ARR]=1.23), black women (ARR=1.10), and Hispanic women (ARR=1.11) (p<.001) were more likely to have been screened. Women ages 28-37 were more likely than those ages 18-27 to have been screened (ARR=1.31, p<.001). Evidence of other health care use was the strongest predictor of screening (ARR=3.07, p<.001). Most women in the sample were not regularly screened for cervical cancer. Cervical cancer screening for this high-risk population should be prioritized.

From Omics to Drug Metabolism and High Content Screen of Natural Product in Zebrafish: A New Model for Discovery of Neuroactive Compound

PubMed Central

Hung, Ming Wai; Zhang, Zai Jun; Li, Shang; Lei, Benson; Yuan, Shuai; Cui, Guo Zhen; Man Hoi, Pui; Chan, Kelvin; Lee, Simon Ming Yuen

2012-01-01

The zebrafish (Danio rerio) has recently become a common model in the fields of genetics, environmental science, toxicology, and especially drug screening. Zebrafish has emerged as a biomedically relevant model for in vivo high content drug screening and the simultaneous determination of multiple efficacy parameters, including behaviour, selectivity, and toxicity in the content of the whole organism. A zebrafish behavioural assay has been demonstrated as a novel, rapid, and high-throughput approach to the discovery of neuroactive, psychoactive, and memory-modulating compounds. Recent studies found a functional similarity of drug metabolism systems in zebrafish and mammals, providing a clue with why some compounds are active in zebrafish in vivo but not in vitro, as well as providing grounds for the rationales supporting the use of a zebrafish screen to identify prodrugs. Here, we discuss the advantages of the zebrafish model for evaluating drug metabolism and the mode of pharmacological action with the emerging omics approaches. Why this model is suitable for identifying lead compounds from natural products for therapy of disorders with multifactorial etiopathogenesis and imbalance of angiogenesis, such as Parkinson's disease, epilepsy, cardiotoxicity, cerebral hemorrhage, dyslipidemia, and hyperlipidemia, is addressed. PMID:22919414

Screen or not to screen for peripheral arterial disease: guidance from a decision model.

PubMed

Vaidya, Anil; Joore, Manuela A; Ten Cate-Hoek, Arina J; Ten Cate, Hugo; Severens, Johan L

2014-01-29

Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling. A probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters. For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Years, 28,052 Euros), these results indicate that PAD screening and treatment is a dominant strategy. The cost effectiveness acceptability curves show 88% probability of PAD screening being cost effective at the Willingness To Pay (WTP) threshold of 40000 Euros. In a scenario analysis using clopidogrel as an alternative anti-platelet drug, PAD screening strategy remained dominant. This decision analysis suggests that targeted ABI screening and consequent secondary prevention of cardiovascular events using low dose aspirin or clopidogrel in the identified patients is a cost-effective strategy. Implementation of targeted PAD screening and subsequent treatment in primary care practices and in public health programs is likely to improve the societal health and to save health care costs by reducing catastrophic cardiovascular events.

Application of computer assisted combinatorial chemistry in antivirial, antimalarial and anticancer agents design

NASA Astrophysics Data System (ADS)

Burello, E.; Bologa, C.; Frecer, V.; Miertus, S.

Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anticancer drugs. These illustrate library focusing strategies.

Structure-based discovery of selective serotonin 5-HT(1B) receptor ligands.

PubMed

Rodríguez, David; Brea, José; Loza, María Isabel; Carlsson, Jens

2014-08-05

The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity to identify subtype selective ligands using structure-based methods. From docking screens of 1.3 million compounds, 22 molecules were predicted to be selective for the 5-HT1B receptor over the 5-HT2B subtype, a requirement for safe serotonergic drugs. Nine compounds were experimentally verified as 5-HT1B-selective ligands, with up to 300-fold higher affinities for this subtype. Three of the ligands were agonists of the G protein pathway. Analysis of state-of-the-art homology models of the two 5-HT receptors revealed that the crystal structures were critical for predicting selective ligands. Our results demonstrate that structure-based screening can guide the discovery of ligands with specific selectivity profiles. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors

PubMed Central

Gaurav, Anand; Gautam, Vertika

2017-01-01

Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. To achieve this goal, ligand based pharmacophore modeling approach is employed. Separate pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines, 2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created using the molecules as per the guidelines available for HypoGen program. Training set was used for hypothesis development while test set was used for validation purpose. Fisher validation was also used to test the significance of the developed hypothesis. The validated pharmacophore hypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zinc database of drug like molecules to identify selective PDE4B inhibitors. The hits were screened for their estimated activity and fit value. The top hit was subjected to docking into the active sites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to be evaluated further using in-vitro assays. PMID:29201082

Astronaut medical selection during the shuttle era: 1981-2011.

PubMed

Johnston, Smith L; Blue, Rebecca S; Jennings, Richard T; Tarver, William J; Gray, Gary W

2014-08-01

U.S. astronauts undergo extensive job-related screening and medical examinations prior to selection in order to identify candidates optimally suited for careers in spaceflight. Screening medical standards evolved over many years and after extensive spaceflight experience. These standards assess health-related risks for each astronaut candidate, minimizing the potential for medical impact on future mission success. This document discusses the evolution of the Shuttle-era medical selection standards and the most common reasons for medical dis-qualification of applicants. Data for astronaut candidate finalists were compiled from medical records and NASA archives from the period of 1978 to 2004 and were retrospectively reviewed for medically disqualifying conditions. During Shuttle selection cycles, a total of 372 applicants were disqualified due to 425 medical concerns. The most common disqualifying conditions included visual, cardiovascular, psychiatric, and behavioral disorders. During this time period, three major expert panel reviews resulted in refinements and alterations to selection standards for future cycles. Shuttle-era screening, testing, and specialist evaluations evolved through periodic expert reviews, evidence-based medicine, and astronaut medical care experience. The Shuttle medical program contributed to the development and implementation of NASA and international standards, longitudinal data collection, improved medical care, and occupational surveillance models. The lessons learned from the Shuttle program serve as the basis for medical selection for the ISS, exploration-class missions, and for those expected to participate in commercial spaceflight.

Data-Powered Participatory Decision Making: Leveraging Systems Thinking and Simulation to Guide Selection and Implementation of Evidence-Based Colorectal Cancer Screening Interventions.

PubMed

Wheeler, Stephanie B; Leeman, Jennifer; Hassmiller Lich, Kristen; Tangka, Florence K L; Davis, Melinda M; Richardson, Lisa C

A robust evidence base supports the effectiveness of timely colorectal cancer (CRC) screening, follow-up of abnormal results, and referral to care in reducing CRC morbidity and mortality. However, only two-thirds of the US population is current with recommended screening, and rates are much lower for those who are vulnerable because of their race/ethnicity, insurance status, or rural location. Multiple, multilevel factors contribute to observed disparities, and these factors vary across different populations and contexts. As highlighted by the Cancer Moonshot Blue Ribbon Panel working groups focused on Prevention and Early Detection and Implementation Science inadequate CRC screening and follow-up represent an enormous missed opportunity in cancer prevention and control. To measurably reduce CRC morbidity and mortality, the evidence base must be strengthened to guide the identification of (1) multilevel factors that influence screening across different populations and contexts, (2) multilevel interventions and implementation strategies that will be most effective at targeting those factors, and (3) combinations of strategies that interact synergistically to improve outcomes. Systems thinking and simulation modeling (systems science) provide a set of approaches and techniques to aid decision makers in using the best available data and research evidence to guide implementation planning in the context of such complexity. This commentary summarizes current challenges in CRC prevention and control, discusses the status of the evidence base to guide the selection and implementation of multilevel CRC screening interventions, and describes a multi-institution project to showcase how systems science can be leveraged to optimize selection and implementation of CRC screening interventions in diverse populations and contexts.

Iterative Focused Screening with Biological Fingerprints Identifies Selective Asc-1 Inhibitors Distinct from Traditional High Throughput Screening.

PubMed

Kutchukian, Peter S; Warren, Lee; Magliaro, Brian C; Amoss, Adam; Cassaday, Jason A; O'Donnell, Gregory; Squadroni, Brian; Zuck, Paul; Pascarella, Danette; Culberson, J Chris; Cooke, Andrew J; Hurzy, Danielle; Schlegel, Kelly-Ann Sondra; Thomson, Fiona; Johnson, Eric N; Uebele, Victor N; Hermes, Jeffrey D; Parmentier-Batteur, Sophie; Finley, Michael

2017-02-17

N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine-serine-cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs. To identify novel Asc-1 inhibitors, two different screening approaches were performed with whole-cell amino acid uptake in heterologous cells stably expressing human Asc-1: (1) a high-throughput screen (HTS) of 3 M compounds measuring 35 S l-cysteine uptake into cells attached to scintillation proximity assay beads in a 1536 well format and (2) an iterative focused screen (IFS) of a 45 000 compound diversity set using a 3 H d-serine uptake assay with a liquid scintillation plate reader in a 384 well format. Critically important for both screening approaches was the implementation of counter screens to remove nonspecific inhibitors of radioactive amino acid uptake. Furthermore, a 15 000 compound expansion step incorporating both on- and off-target data into chemical and biological fingerprint-based models for selection of additional hits enabled the identification of novel Asc-1-selective chemical matter from the IFS that was not identified in the full-collection HTS.

Application of multimedia models for screening assessment of long-range transport potential and overall persistence.

PubMed

Klasmeier, Jörg; Matthies, Michael; Macleod, Matthew; Fenner, Kathrin; Scheringer, Martin; Stroebe, Maximilian; Le Gall, Anne Christine; Mckone, Thomas; Van De Meent, Dik; Wania, Frank

2006-01-01

We propose a multimedia model-based methodology to evaluate whether a chemical substance qualifies as POP-like based on overall persistence (Pov) and potential for long-range transport (LRTP). It relies upon screening chemicals against the Pov and LRTP characteristics of selected reference chemicals with well-established environmental fates. Results indicate that chemicals of high and low concern in terms of persistence and long-range transport can be consistently identified by eight contemporary multimedia models using the proposed methodology. Model results for three hypothetical chemicals illustrate that the model-based classification of chemicals according to Pov and LRTP is not always consistent with the single-media half-life approach proposed by the UNEP Stockholm Convention and thatthe models provide additional insight into the likely long-term hazards associated with chemicals in the environment. We suggest this model-based classification method be adopted as a complement to screening against defined half-life criteria at the initial stages of tiered assessments designed to identify POP-like chemicals and to prioritize further environmental fate studies for new and existing chemicals.

Informing the Selection of Screening Hit Series with in Silico Absorption, Distribution, Metabolism, Excretion, and Toxicity Profiles.

PubMed

Sanders, John M; Beshore, Douglas C; Culberson, J Christopher; Fells, James I; Imbriglio, Jason E; Gunaydin, Hakan; Haidle, Andrew M; Labroli, Marc; Mattioni, Brian E; Sciammetta, Nunzio; Shipe, William D; Sheridan, Robert P; Suen, Linda M; Verras, Andreas; Walji, Abbas; Joshi, Elizabeth M; Bueters, Tjerk

2017-08-24

High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure-activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter. These profiles allow teams to quickly assess hit series for desirable ADMET properties or suspected liabilities that may require significant optimization. Accordingly, these in silico data can direct ADMET experimentation and profoundly impact the progression of hit series. Several prospective examples are presented to substantiate the value of this approach.

Identification of DNA primase inhibitors via a combined fragment-based and virtual screening

NASA Astrophysics Data System (ADS)

Ilic, Stefan; Akabayov, Sabine R.; Arthanari, Haribabu; Wagner, Gerhard; Richardson, Charles C.; Akabayov, Barak

2016-11-01

The structural differences between bacterial and human primases render the former an excellent target for drug design. Here we describe a technique for selecting small molecule inhibitors of the activity of T7 DNA primase, an ideal model for bacterial primases due to their common structural and functional features. Using NMR screening, fragment molecules that bind T7 primase were identified and then exploited in virtual filtration to select larger molecules from the ZINC database. The molecules were docked to the primase active site using the available primase crystal structure and ranked based on their predicted binding energies to identify the best candidates for functional and structural investigations. Biochemical assays revealed that some of the molecules inhibit T7 primase-dependent DNA replication. The binding mechanism was delineated via NMR spectroscopy. Our approach, which combines fragment based and virtual screening, is rapid and cost effective and can be applied to other targets.

Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi.

PubMed

Keenan, Martine; Alexander, Paul W; Chaplin, Jason H; Abbott, Michael J; Diao, Hugo; Wang, Zhisen; Best, Wayne M; Perez, Catherine J; Cornwall, Scott M J; Keatley, Sarah K; Thompson, R C Andrew; Charman, Susan A; White, Karen L; Ryan, Eileen; Chen, Gong; Ioset, Jean-Robert; von Geldern, Thomas W; Chatelain, Eric

2013-10-01

Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.

Screening and Characterization of Lactic Acid Bacteria Strains with Anti-inflammatory Activities through in vitro and Caenorhabditis elegans Model Testing

PubMed Central

Park, Mi Ri; Kim, Younghoon; Lee, Myung-Ki

2015-01-01

The present study was conducted to screen candidate probiotic strains for anti-inflammatory activity. Initially, a nitric oxide (NO) assay was used to test selected candidate probiotic strains for anti-inflammatory activity in cultures of the murine macrophage cell line, RAW 264.7. Then, the in vitro probiotic properties of the strains, including bile tolerance, acid resistance, and growth in skim milk media, were investigated. We also performed an in vitro hydrophobicity test and an intestinal adhesion assay using Caenorhabditis elegans as a surrogate in vivo model. From our screening, we obtained 4 probiotic candidate lactic acid bacteria (LAB) strains based on their anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 cell cultures and the results of the in vitro and in vivo probiotic property assessments. Molecular characterization using 16S rDNA sequencing analysis identified the 4 LAB strains as Lactobacillus plantarum. The selected L. plantarum strains (CAU1054, CAU1055, CAU1064, and CAU1106) were found to possess desirable in vitro and in vivo probiotic properties, and these strains are good candidates for further investigations in animal models and human clinical studies to elucidate the mechanisms underlying their anti-inflammatory activities. PMID:26761805

Optogenetic stimulation of multiwell MEA plates for neural and cardiac applications

NASA Astrophysics Data System (ADS)

Clements, Isaac P.; Millard, Daniel C.; Nicolini, Anthony M.; Preyer, Amanda J.; Grier, Robert; Heckerling, Andrew; Blum, Richard A.; Tyler, Phillip; McSweeney, K. M.; Lu, Yi-Fan; Hall, Diana; Ross, James D.

2016-03-01

Microelectrode array (MEA) technology enables advanced drug screening and "disease-in-a-dish" modeling by measuring the electrical activity of cultured networks of neural or cardiac cells. Recent developments in human stem cell technologies, advancements in genetic models, and regulatory initiatives for drug screening have increased the demand for MEA-based assays. In response, Axion Biosystems previously developed a multiwell MEA platform, providing up to 96 MEA culture wells arrayed into a standard microplate format. Multiwell MEA-based assays would be further enhanced by optogenetic stimulation, which enables selective excitation and inhibition of targeted cell types. This capability for selective control over cell culture states would allow finer pacing and probing of cell networks for more reliable and complete characterization of complex network dynamics. Here we describe a system for independent optogenetic stimulation of each well of a 48-well MEA plate. The system enables finely graded control of light delivery during simultaneous recording of network activity in each well. Using human induced pluripotent stem cell (hiPSC) derived cardiomyocytes and rodent primary neuronal cultures, we demonstrate high channel-count light-based excitation and suppression in several proof-of-concept experimental models. Our findings demonstrate advantages of combining multiwell optical stimulation and MEA recording for applications including cardiac safety screening, neural toxicity assessment, and advanced characterization of complex neuronal diseases.

Detector location selection based on VIP analysis in near-infrared detection of dural hematoma.

PubMed

Sun, Qiuming; Zhang, Yanjun; Ma, Jun; Tian, Feng; Wang, Huiquan; Liu, Dongyuan

2018-03-01

Detection of dural hematoma based on multi-channel near-infrared differential absorbance has the advantages of rapid and non-invasive detection. The location and number of detectors around the light source are critical for reducing the pathological characteristics of the prediction model on dural hematoma degree. Therefore, rational selection of detector numbers and their distances from the light source is very important. In this paper, a detector position screening method based on Variable Importance in the Projection (VIP) analysis is proposed. A preliminary modeling based on Partial Least Squares method (PLS) for the prediction of dural position μ a was established using light absorbance information from 30 detectors located 2.0-5.0 cm from the light source with a 0.1 cm interval. The mean relative error (MRE) of the dural position μ a prediction model was 4.08%. After VIP analysis, the number of detectors was reduced from 30 to 4 and the MRE of the dural position μ a prediction was reduced from 4.08% to 2.06% after the reduction in detector numbers. The prediction model after VIP detector screening still showed good prediction of the epidural position μ a . This study provided a new approach and important reference on the selection of detector location in near-infrared dural hematoma detection.

Modeling blur in various detector geometries for MeV radiography

NASA Astrophysics Data System (ADS)

Winch, Nicola M.; Watson, Scott A.; Hunter, James F.

2017-03-01

Monte Carlo transport codes have been used to model the detector blur and energy deposition in various detector geometries for applications in MeV radiography. Segmented scintillating detectors, where low Z scintillators combined with a high-Z metal matrix, can be designed in which the resolution increases with increasing metal fraction. The combination of various types of metal intensification screens and storage phosphor imaging plates has also been studied. A storage phosphor coated directly onto a metal intensification screen has superior performance over a commercial plate. Stacks of storage phosphor plates and tantalum intensification screens show an increase in energy deposited and detective quantum efficiency with increasing plate number, at the expense of resolution. Select detector geometries were tested by comparing simulation and experimental modulation transfer functions to validate the approach.

A novel approach to the discovery of anti-tumor pharmaceuticals: searching for activators of liponecrosis

PubMed Central

Arlia-Ciommo, Anthony; Svistkova, Veronika; Mohtashami, Sadaf; Titorenko, Vladimir I.

2016-01-01

A recently conducted chemical genetic screen for pharmaceuticals that can extend longevity of the yeast Saccharomyces cerevisiae has identified lithocholic acid as a potent anti-aging molecule. It was found that this hydrophobic bile acid is also a selective anti-tumor chemical compound; it kills different types of cultured cancer cells if used at concentrations that do not compromise the viability of non-cancerous cells. These studies have revealed that yeast can be successfully used as a model organism for high-throughput screens aimed at the discovery of selectively acting anti-tumor small molecules. Two metabolic traits of rapidly proliferating fermenting yeast, namely aerobic glycolysis and lipogenesis, are known to be similar to those of cancer cells. The mechanisms underlying these key metabolic features of cancer cells and fermenting yeast have been established; such mechanisms are discussed in this review. We also suggest how a yeast-based chemical genetic screen can be used for the high-throughput development of selective anti-tumor pharmaceuticals that kill only cancer cells. This screen consists of searching for chemical compounds capable of increasing the abundance of membrane lipids enriched in unsaturated fatty acids that would therefore be toxic only to rapidly proliferating cells, such as cancer cells and fermenting yeast. PMID:26636650

Superintendents' Perceptions about Social Distance, Succession, and "Sunset" Provisions for Asian, Latino, and Native American Candidates Seeking Building-Level Administrator Positions

ERIC Educational Resources Information Center

Young, I. Phillip; De La Torre, Guadalupe Xavier

2006-01-01

Research addressing the attraction and selection of individuals for administrator positions is encapsulated in a structural model that depicts different phases of the employee procurement process. Within the present study, attention is devoted to the prescreening stage of the selection process, and screening decisions of superintendents are…

Reference evapotranspiration forecasting based on local meteorological and global climate information screened by partial mutual information

NASA Astrophysics Data System (ADS)

Fang, Wei; Huang, Shengzhi; Huang, Qiang; Huang, Guohe; Meng, Erhao; Luan, Jinkai

2018-06-01

In this study, reference evapotranspiration (ET0) forecasting models are developed for the least economically developed regions subject to meteorological data scarcity. Firstly, the partial mutual information (PMI) capable of capturing the linear and nonlinear dependence is investigated regarding its utility to identify relevant predictors and exclude those that are redundant through the comparison with partial linear correlation. An efficient input selection technique is crucial for decreasing model data requirements. Then, the interconnection between global climate indices and regional ET0 is identified. Relevant climatic indices are introduced as additional predictors to comprise information regarding ET0, which ought to be provided by meteorological data unavailable. The case study in the Jing River and Beiluo River basins, China, reveals that PMI outperforms the partial linear correlation in excluding the redundant information, favouring the yield of smaller predictor sets. The teleconnection analysis identifies the correlation between Nino 1 + 2 and regional ET0, indicating influences of ENSO events on the evapotranspiration process in the study area. Furthermore, introducing Nino 1 + 2 as predictors helps to yield more accurate ET0 forecasts. A model performance comparison also shows that non-linear stochastic models (SVR or RF with input selection through PMI) do not always outperform linear models (MLR with inputs screen by linear correlation). However, the former can offer quite comparable performance depending on smaller predictor sets. Therefore, efforts such as screening model inputs through PMI and incorporating global climatic indices interconnected with ET0 can benefit the development of ET0 forecasting models suitable for data-scarce regions.

A multi-model approach to nucleic acid-based drug development.

PubMed

Gautherot, Isabelle; Sodoyer, Regís

2004-01-01

With the advent of functional genomics and the shift of interest towards sequence-based therapeutics, the past decades have witnessed intense research efforts on nucleic acid-mediated gene regulation technologies. Today, RNA interference is emerging as a groundbreaking discovery, holding promise for development of genetic modulators of unprecedented potency. Twenty-five years after the discovery of antisense RNA and ribozymes, gene control therapeutics are still facing developmental difficulties, with only one US FDA-approved antisense drug currently available in the clinic. Limited predictability of target site selection models is recognized as one major stumbling block that is shared by all of the so-called complementary technologies, slowing the progress towards a commercial product. Currently employed in vitro systems for target site selection include RNAse H-based mapping, antisense oligonucleotide microarrays, and functional screening approaches using libraries of catalysts with randomized target-binding arms to identify optimal ribozyme/DNAzyme cleavage sites. Individually, each strategy has its drawbacks from a drug development perspective. Utilization of message-modulating sequences as therapeutic agents requires that their action on a given target transcript meets criteria of potency and selectivity in the natural physiological environment. In addition to sequence-dependent characteristics, other factors will influence annealing reactions and duplex stability, as well as nucleic acid-mediated catalysis. Parallel consideration of physiological selection systems thus appears essential for screening for nucleic acid compounds proposed for therapeutic applications. Cellular message-targeting studies face issues relating to efficient nucleic acid delivery and appropriate analysis of response. For reliability and simplicity, prokaryotic systems can provide a rapid and cost-effective means of studying message targeting under pseudo-cellular conditions, but such approaches also have limitations. To streamline nucleic acid drug discovery, we propose a multi-model strategy integrating high-throughput-adapted bacterial screening, followed by reporter-based and/or natural cellular models and potentially also in vitro assays for characterization of the most promising candidate sequences, before final in vivo testing.

Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer.

PubMed

Zhang, Lu; Theodoropoulos, Panayotis C; Eskiocak, Ugur; Wang, Wentian; Moon, Young-Ah; Posner, Bruce; Williams, Noelle S; Wright, Woodring E; Kim, Sang Bum; Nijhawan, Deepak; De Brabander, Jef K; Shay, Jerry W

2016-10-19

Mutations in the adenomatous polyposis coli (APC) gene are common in colorectal cancer (CRC), and more than 90% of those mutations generate stable truncated gene products. We describe a chemical screen using normal human colonic epithelial cells (HCECs) and a series of oncogenically progressed HCECs containing a truncated APC protein. With this screen, we identified a small molecule, TASIN-1 (truncated APC selective inhibitor-1), that specifically kills cells with APC truncations but spares normal and cancer cells with wild-type APC. TASIN-1 exerts its cytotoxic effects through inhibition of cholesterol biosynthesis. In vivo administration of TASIN-1 inhibits tumor growth of CRC cells with truncated APC but not APC wild-type CRC cells in xenograft models and in a genetically engineered CRC mouse model with minimal toxicity. TASIN-1 represents a potential therapeutic strategy for prevention and intervention in CRC with mutant APC. Copyright © 2016, American Association for the Advancement of Science.

Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files.

PubMed

Bell, Andrew S; Bradley, Joseph; Everett, Jeremy R; Loesel, Jens; McLoughlin, David; Mills, James; Peakman, Marie-Claire; Sharp, Robert E; Williams, Christine; Zhu, Hongyao

2016-11-01

High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.

Evaluation of Empirical Data and Modeling Studies to Support Soil Vapor Intrusion Screening Criteria for Petroleum Hydrocarbon Compounds

EPA Science Inventory

This study is an evaluation of empirical data and select modeling studies of the behavior of petroleum hydrocarbon (PHC) vapors in subsurface soils and how they can affect subsurface-to-indoor air vapor intrusion (VI), henceforth referred to as petroleum vapor intrusion or “PVI” ...

Model for Participatory Governance for Community Colleges.

ERIC Educational Resources Information Center

Nichols, Suzanne

A model for participatory governance is developed as a means to better achieve the community college's broad goals and objectives. These are contrasted with those of 4-year institutions using student screening and selection devices, and high schools with their different educational emphasis. It presents the conflict faced by the community college:…

Biologically driven neural platform invoking parallel electrophoretic separation and urinary metabolite screening.

PubMed

Page, Tessa; Nguyen, Huong Thi Huynh; Hilts, Lindsey; Ramos, Lorena; Hanrahan, Grady

2012-06-01

This work reveals a computational framework for parallel electrophoretic separation of complex biological macromolecules and model urinary metabolites. More specifically, the implementation of a particle swarm optimization (PSO) algorithm on a neural network platform for multiparameter optimization of multiplexed 24-capillary electrophoresis technology with UV detection is highlighted. Two experimental systems were examined: (1) separation of purified rabbit metallothioneins and (2) separation of model toluene urinary metabolites and selected organic acids. Results proved superior to the use of neural networks employing standard back propagation when examining training error, fitting response, and predictive abilities. Simulation runs were obtained as a result of metaheuristic examination of the global search space with experimental responses in good agreement with predicted values. Full separation of selected analytes was realized after employing optimal model conditions. This framework provides guidance for the application of metaheuristic computational tools to aid in future studies involving parallel chemical separation and screening. Adaptable pseudo-code is provided to enable users of varied software packages and modeling framework to implement the PSO algorithm for their desired use.

Language and use of cancer screening services among border and non-border Hispanic Texas women.

PubMed

Fernández, Leticia E; Morales, Alfonso

2007-06-01

Compared to other groups, Mexican American women screen less frequently for cervical and breast cancer. The most significant barriers reported by previous researchers include not having a usual source of care, lacking health insurance and English-language difficulties. In this paper we document and examine the factors associated with disparities in cancer screening between border and non-border residents by language of interview (Spanish or English) among Texas Hispanic women. We hypothesize that, controlling for socioeconomic and demographic characteristics, border residents are more likely to utilize screening services than non-border residents because of the greater presence of bilingual services in border counties. We follow the framework of the Behavioral Model for Vulnerable Populations proposed by Gelberg et al. (Health Services Research, vol. 34, no. 6, pp. 1273-1302, 2000). This model conceptualizes use of health care as an outcome of the interplay of predisposing, enabling and need factors and recognizes that vulnerable groups face additional barriers to health care utilization. Data come from the 2000, 2002 and 2004 Texas Behavioral Risk Factor Surveillance surveys. Group differences in cancer screenings are explained largely by socioeconomic characteristics and structural barriers to access. The significance of language of interview and of border residence disappear after controlling for factors such as health insurance, income and a usual source of care. Women who selected to be interviewed in Spanish were less likely to report age-appropriate cancer examinations, health insurance and a regular health care provider than those who selected to be interviewed in English. Disparities in cancer screenings among vulnerable Hispanic populations could be reduced by promoting the establishment of a regular health care provider.

Development of a screening tool using electronic health records for undiagnosed Type 2 diabetes mellitus and impaired fasting glucose detection in the Slovenian population.

PubMed

Štiglic, G; Kocbek, P; Cilar, L; Fijačko, N; Stožer, A; Zaletel, J; Sheikh, A; Povalej Bržan, P

2018-05-01

To develop and validate a simplified screening test for undiagnosed Type 2 diabetes mellitus and impaired fasting glucose for the Slovenian population (SloRisk) to be used in the general population. Data on 11 391 people were collected from the electronic health records of comprehensive medical examinations in five Slovenian healthcare centres. Fasting plasma glucose as well as information related to the Finnish Diabetes Risk Score questionnaire, FINDRISC, were collected for 2073 people to build predictive models. Bootstrapping-based evaluation was used to estimate the area under the receiver-operating characteristic curve performance metric of two proposed logistic regression models as well as the Finnish Diabetes Risk Score model both at recommended and at alternative cut-off values. The final model contained five questions for undiagnosed Type 2 diabetes prediction and achieved an area under the receiver-operating characteristic curve of 0.851 (95% CI 0.850-0.853). The impaired fasting glucose prediction model included six questions and achieved an area under the receiver-operating characteristic curve of 0.840 (95% CI 0.839-0.840). There were four questions that were included in both models (age, sex, waist circumference and blood sugar history), with physical activity selected only for undiagnosed Type 2 diabetes and questions on family history and hypertension drug use selected only for the impaired fasting glucose prediction model. This study proposes two simplified models based on FINDRISC questions for screening of undiagnosed Type 2 diabetes and impaired fasting glucose in the Slovenian population. A significant improvement in performance was achieved compared with the original FINDRISC questionnaire. Both models include waist circumference instead of BMI. © 2018 Diabetes UK.

On determining specifications and selections of alternative technologies for airport checked-baggage security screening.

PubMed

Feng, Qianmei

2007-10-01

Federal law mandates that every checked bag at all commercial airports be screened by explosive detection systems (EDS), explosive trace detection systems (ETD), or alternative technologies. These technologies serve as critical components of airport security systems that strive to reduce security risks at both national and global levels. To improve the operational efficiency and airport security, emerging image-based technologies have been developed, such as dual-energy X-ray (DX), backscatter X-ray (BX), and multiview tomography (MVT). These technologies differ widely in purchasing cost, maintenance cost, operating cost, processing rate, and accuracy. Based on a mathematical framework that takes into account all these factors, this article investigates two critical issues for operating screening devices: setting specifications for continuous security responses by different technologies; and selecting technology or combination of technologies for efficient 100% baggage screening. For continuous security responses, specifications or thresholds are used for classifying threat items from nonthreat items. By investigating the setting of specifications on system security responses, this article assesses the risk and cost effectiveness of various technologies for both single-device and two-device systems. The findings provide the best selection of image-based technologies for both single-device and two-device systems. Our study suggests that two-device systems outperform single-device systems in terms of both cost effectiveness and accuracy. The model can be readily extended to evaluate risk and cost effectiveness of multiple-device systems for airport checked-baggage security screening.

3-Dimensional culture systems for anti-cancer compound profiling and high-throughput screening reveal increases in EGFR inhibitor-mediated cytotoxicity compared to monolayer culture systems.

PubMed

Howes, Amy L; Richardson, Robyn D; Finlay, Darren; Vuori, Kristiina

2014-01-01

3-dimensional (3D) culture models have the potential to bridge the gap between monolayer cell culture and in vivo studies. To benefit anti-cancer drug discovery from 3D models, new techniques are needed that enable their use in high-throughput (HT) screening amenable formats. We have established miniaturized 3D culture methods robust enough for automated HT screens. We have applied these methods to evaluate the sensitivity of normal and tumorigenic breast epithelial cell lines against a panel of oncology drugs when cultured as monolayers (2D) and spheroids (3D). We have identified two classes of compounds that exhibit preferential cytotoxicity against cancer cells over normal cells when cultured as 3D spheroids: microtubule-targeting agents and epidermal growth factor receptor (EGFR) inhibitors. Further improving upon our 3D model, superior differentiation of EC50 values in the proof-of-concept screens was obtained by co-culturing the breast cancer cells with normal human fibroblasts and endothelial cells. Further, the selective sensitivity of the cancer cells towards chemotherapeutics was observed in 3D co-culture conditions, rather than as 2D co-culture monolayers, highlighting the importance of 3D cultures. Finally, we examined the putative mechanisms that drive the differing potency displayed by EGFR inhibitors. In summary, our studies establish robust 3D culture models of human cells for HT assessment of tumor cell-selective agents. This methodology is anticipated to provide a useful tool for the study of biological differences within 2D and 3D culture conditions in HT format, and an important platform for novel anti-cancer drug discovery.

3-Dimensional Culture Systems for Anti-Cancer Compound Profiling and High-Throughput Screening Reveal Increases in EGFR Inhibitor-Mediated Cytotoxicity Compared to Monolayer Culture Systems

PubMed Central

Howes, Amy L.; Richardson, Robyn D.; Finlay, Darren; Vuori, Kristiina

2014-01-01

3-dimensional (3D) culture models have the potential to bridge the gap between monolayer cell culture and in vivo studies. To benefit anti-cancer drug discovery from 3D models, new techniques are needed that enable their use in high-throughput (HT) screening amenable formats. We have established miniaturized 3D culture methods robust enough for automated HT screens. We have applied these methods to evaluate the sensitivity of normal and tumorigenic breast epithelial cell lines against a panel of oncology drugs when cultured as monolayers (2D) and spheroids (3D). We have identified two classes of compounds that exhibit preferential cytotoxicity against cancer cells over normal cells when cultured as 3D spheroids: microtubule-targeting agents and epidermal growth factor receptor (EGFR) inhibitors. Further improving upon our 3D model, superior differentiation of EC50 values in the proof-of-concept screens was obtained by co-culturing the breast cancer cells with normal human fibroblasts and endothelial cells. Further, the selective sensitivity of the cancer cells towards chemotherapeutics was observed in 3D co-culture conditions, rather than as 2D co-culture monolayers, highlighting the importance of 3D cultures. Finally, we examined the putative mechanisms that drive the differing potency displayed by EGFR inhibitors. In summary, our studies establish robust 3D culture models of human cells for HT assessment of tumor cell-selective agents. This methodology is anticipated to provide a useful tool for the study of biological differences within 2D and 3D culture conditions in HT format, and an important platform for novel anti-cancer drug discovery. PMID:25247711

Economic evaluation of different screening alternatives for patients with clinically suspected acute deep vein thrombosis.

PubMed

Bogavac-Stanojević, Natasa; Dopsaj, Violeta; Jelić-Ivanović, Zorana; Lakić, Dragana; Vasić, Dragan; Petrova, Guenka

2013-01-01

We examined the cost-effectiveness of the three different D-dimer measurements in the screening of DVT in models with and without calculation of pre-test probability (PTP) score. Moreover, we calculated the minimal cost in DVT detection. In the group of 192 patients with clinically suspected acute DVT, we examined the three different D-dimer measurements (Innovance D-dimer, Hemosil D-dimer HS and Vidas D-dimer Exclusion II) in combination with and without PTP assessment. The diagnostic alternative employing Vidas D-dimer Exclusion II assay without and with PTP calculation gave lower incremental cost-effectiveness ratio (ICER) than the alternative employing Hemosil D-dimer HS assay (0.187 Euros vs. 0.998 Euros per one additional DVT positive patient selected for CUS in model without PTP assessment and 0.450 vs. 0.753 Euros per one DVT positive patient selected for CUS in model with PTP assessment). According to sensitivity analysis, the Hemosil D-dimer HS assay was the most cost effective alternative when one patient was admitted to the vascular ambulance per day. Vidas D-dimer Exclusion II assay was the most cost effective alternative when more than one patient were admitted to the vascular ambulance per day. Cost minimisation analysis indicated that selection of patients according to PTP score followed by D-dimer analysis decreases the cost of DVT diagnosis. ICER analysis enables laboratories to choose optimal laboratory tests according to number of patients admitted to laboratory. Results support the feasibility of using PTP scoring and D-dimer measurement before CUS examination in DVT screening.

[Selection of a melanine concentrating hormone receptor-1 (MCHR1) antagonists' focused library and its biological screening with AequoScreen].

PubMed

Flachner, Beáta; Hajdú, István; Dobi, Krisztina; Lorincz, Zsolt; Cseh, Sándor; Dormán, György

2013-01-01

Target focused libraries can be rapidly selected by 2D virtual screening methods from multimillion compounds' repositories if structures of active compounds are available. In the present study a multi-step virtual and in vitro screening cascade is reported to select Melanin Concentrating Hormone Receptor-1 (MCHR1) antagonists. The 2D similarity search combined with physicochemical parameter filtering is suitable for selecting candidates from multimillion compounds' repository. The seeds of the first round virtual screening were collected from the literature and commercial databases, while the seeds of the second round were the hits of the first round. In vitro screening underlined the efficiency of our approach, as in the second screening round the hit rate (8.6 %) significantly improved compared to the first round (1.9%), reaching the antagonist activity even below 10 nM.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.

PubMed

Ali, Yousuf O; Bradley, Gillian; Lu, Hui-Chen

2017-03-07

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer's, Huntington's, Parkinson's diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

PubMed Central

Ali, Yousuf O.; Bradley, Gillian; Lu, Hui-Chen

2017-01-01

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons. PMID:28266613

GPCRs from fusarium graminearum detection, modeling and virtual screening - the search for new routes to control head blight disease.

PubMed

Bresso, Emmanuel; Togawa, Roberto; Hammond-Kosack, Kim; Urban, Martin; Maigret, Bernard; Martins, Natalia Florencio

2016-12-15

Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an important issue to reduce cereal infection and economic impact. In the strategy for developing new fungicides, a critical step is the identification of new targets against which innovative chemicals weapons can be designed. As several G-protein coupled receptors (GPCRs) are implicated in signaling pathways critical for the fungi development and survival, such proteins could be valuable efficient targets to reduce Fusarium growth and therefore to prevent food contamination. In this study, GPCRs were predicted in the FG proteome using a manually curated pipeline dedicated to the identification of GPCRs. Based on several successive filters, the most appropriate GPCR candidate target for developing new fungicides was selected. Searching for new compounds blocking this particular target requires the knowledge of its 3D-structure. As no experimental X-Ray structure of the selected protein was available, a 3D model was built by homology modeling. The model quality and stability was checked by 100 ns of molecular dynamics simulations. Two stable conformations representative of the conformational families of the protein were extracted from the 100 ns simulation and were used for an ensemble docking campaign. The model quality and stability was checked by 100 ns of molecular dynamics simulations previously to the virtual screening step. The virtual screening step comprised the exploration of a chemical library with 11,000 compounds that were docked to the GPCR model. Among these compounds, we selected the ten top-ranked nontoxic molecules proposed to be experimentally tested to validate the in silico simulation. This study provides an integrated process merging genomics, structural bioinformatics and drug design for proposing innovative solutions to a world wide threat to grain producers and consumers.

Equal Employment Opportunity and ADA Implications of Screening and Selection.

ERIC Educational Resources Information Center

Norton, Steven D.; Hundley, John R.

1995-01-01

The process of screening and selecting new employees is viewed as one having discrete steps, each with implications concerning Equal Employment Opportunity and the Americans with Disabilities Act. Several screening and selection methods are examined, with questionnaire forms used by Indiana University, South Bend provided for illustration. Typical…

Screening and clustering of sparse regressions with finite non-Gaussian mixtures.

PubMed

Zhang, Jian

2017-06-01

This article proposes a method to address the problem that can arise when covariates in a regression setting are not Gaussian, which may give rise to approximately mixture-distributed errors, or when a true mixture of regressions produced the data. The method begins with non-Gaussian mixture-based marginal variable screening, followed by fitting a full but relatively smaller mixture regression model to the selected data with help of a new penalization scheme. Under certain regularity conditions, the new screening procedure is shown to possess a sure screening property even when the population is heterogeneous. We further prove that there exists an elbow point in the associated scree plot which results in a consistent estimator of the set of active covariates in the model. By simulations, we demonstrate that the new procedure can substantially improve the performance of the existing procedures in the content of variable screening and data clustering. By applying the proposed procedure to motif data analysis in molecular biology, we demonstrate that the new method holds promise in practice. © 2016, The International Biometric Society.

Cost effectiveness of screening immigrants for hepatitis B.

PubMed

Wong, William W L; Woo, Gloria; Jenny Heathcote, E; Krahn, Murray

2011-09-01

The prevalence of chronic hepatitis B (CHB) infection among the immigrants of North America ranges from 2 to 15%, among whom 40% develop advanced liver disease. Screening for hepatitis B surface antigen is not recommended for immigrants. The objective of this study is to estimate the health and economic effects of screening strategies for CHB among immigrants. We used the Markov model to examine the cost-effectiveness of three screening strategies: (i) 'No screening'; (ii) 'Screen and Treat' and (iii) 'Screen, Treat and Vaccinate' for 20-65 years old individuals who were born abroad but are currently living in Canada. Model data were obtained from the published literature. We measured predicted hepatitis B virus (HBV)-related deaths, costs (2008 Canadian Dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Our results show that screening all immigrants will prevent 59 HBV-related deaths per 10, 000 persons screened over the lifetime of the cohort. Screening was associated with an increase in quality-adjusted life expectancy (0.024 QALYs) and cost ($1665) per person with an ICER of $69, 209/QALY gained compared with 'No screening'. The 'Screen, Treat and Vaccinate' costs an additional $81, generates an additional 0.000022 QALYs per person, with an ICER of $3, 648,123/QALY compared with the 'Screen and Treat'. Sensitivity analyses suggested that the 'Screen and Treat' is likely to be moderately cost-effective. We show that a selective hepatitis B screening programme targeted at all immigrants in Canada is likely to be moderately cost-effective. Identification of silent CHB infection with the offer of treatment when appropriate can extend the lives of immigrants at reasonable cost. © 2011 John Wiley & Sons A/S.

Oncological screening for Bilateral Breast Reduction: a survey of practice variations in UK Breast and Plastics surgeons 2009.

PubMed

Hennedige, Anusha A; Kong, Tze Yean; Gandhi, Ashu

2011-07-01

Bilateral Breast Reduction (BBR) is a common procedure performed by Breast and Plastic surgeons in the UK. No consensus exists regarding preoperative screening for malignancy or for selective criteria for such screening. Preoperative BBR screening practices among UK Breast and Plastic surgeons are unknown. Ascertain the preoperative and postoperative BBR screening practices of UK Breast and Plastic surgeons. A questionnaire was posted to all 434 Breast and 335 Plastic surgeons in the UK. All results were analysed with relevant statistical methods. 64% of Breast surgeons and 72% of Plastic surgeons responded. 40% of Breast surgeons and 91% of Plastic surgeons perform BBR. Routine radiological screening: 92% Breast 41% Plastic (p < 0.05). Routine breast examination prior to BBR: 98% Breast 91% Plastic. Routine histology for BBR specimens: 96% Breast 90% Plastic. Selective screening of patients aged 30-40 years old: Breast 38% Plastic 10%. Selective screening of patients aged 40-50: Breast 78%, Plastic 53%. Selective screening of patients with strong family history of breast cancer: Breast 72%, Plastic 91%. Selective screening of patients with previous breast cancer: Breast 77%, Plastic 93%. There are significant differences in practice between UK Breast surgeons and Plastic surgeons in preoperative oncological screening for BBR. The large discrepancy in preoperative radiological screening, reflects a ubiquitous pro-screening ideology among Breast surgeons not prevalent among Plastic surgeons. These results will provoke debate towards the direction of consensus to ultimately reflect best practice. Copyright © 2010. Published by Elsevier Ltd.

Ligand-Based Pharmacophore Modeling and Virtual Screening for the Discovery of Novel 17β-Hydroxysteroid Dehydrogenase 2 Inhibitors

PubMed Central

2014-01-01

17β-Hydroxysteroid dehydrogenase 2 (17β-HSD2) catalyzes the inactivation of estradiol into estrone. This enzyme is expressed only in a few tissues, and therefore its inhibition is considered as a treatment option for osteoporosis to ameliorate estrogen deficiency. In this study, ligand-based pharmacophore models for 17β-HSD2 inhibitors were constructed and employed for virtual screening. From the virtual screening hits, 29 substances were evaluated in vitro for 17β-HSD2 inhibition. Seven compounds inhibited 17β-HSD2 with low micromolar IC50 values. To investigate structure–activity relationships (SAR), 30 more derivatives of the original hits were tested. The three most potent hits, 12, 22, and 15, had IC50 values of 240 nM, 1 μM, and 1.5 μM, respectively. All but 1 of the 13 identified inhibitors were selective over 17β-HSD1, the enzyme catalyzing conversion of estrone into estradiol. Three of the new, small, synthetic 17β-HSD2 inhibitors showed acceptable selectivity over other related HSDs, and six of them did not affect other HSDs. PMID:24960438

[HTRF-based high-throughput PGE2 release prohibition model and application in discovering traditional Chinese medicine active ingredients].

PubMed

Bai, Zhi-Ru; Fei, Hong-Qiang; Li, Na; Cao, Liang; Zhang, Chen-Feng; Wang, Tuan-Jie; Ding, Gang; Wang, Zhen-Zhong; Xiao, Wei

2016-02-01

Prostaglandin (PG) E2 is an active substance in pathological and physiological mechanisms, such as inflammation and pain. The in vitro high-throughput assay for screening the inhibitors of reducing PEG2 production is a useful method for finding out antiphlogistic and analgesic candidates. The assay was based on LPS-induced PGE2 production model using a homogeneous time-resolved fluorescence(HTRF) PGE2 testing kit combined with liquid handling automation and detection instruments. The critical steps, including the cell density optimization and IC50 values determination of a positive compound, were taken to verify the stability and sensibility of the assay. Low intra-plate, inter-plate and day-to-day variability were observed in this 384-well, high-throughput format assay. Totally 5 121 samples were selected from the company's traditional Chinese medicine(TCM) material base library and used to screen PGE2 inhibitors. In this model, the cell plating density was 2 000 cells for each well; the average IC₅₀ value for positive compounds was (7.3±0.1) μmol; the Z' factor for test plates was more than 0.5 and averaged at 0.7. Among the 5 121 samples, 228 components exhibited a PGE2 production prohibition rate of more than 50%, and 23 components exhibited more than 80%. This model reached the expected standards in data stability and accuracy, indicating the reliability and authenticity of the screening results. The automated screening system was introduced to make the model fast and efficient, with a average daily screening amount exceeding 14 000 data points and provide a new model for discovering new anti-inflammatory and analgesic drug and quickly screening effective constituents of TCM in the early stage. Copyright© by the Chinese Pharmaceutical Association.

Selection of Rear Projection Screens for Learning Carrels.

ERIC Educational Resources Information Center

Smith, Edgar A.

The selection of a rear projection screen for a learning carrel should take into account the viewing angle involved. In some carrels, the viewer can be seated in front of the screen (i.e., on the normal axis) since the screen is used primarily to present information. In these cases, where the screen will be viewed only from a restricted range, a…

Vertical profiles of selected mean and turbulent characteristics of the boundary layer within and above a large banana screenhouse

NASA Astrophysics Data System (ADS)

Tanny, Josef; Lukyanov, Victor; Neiman, Michael; Cohen, Shabtai; Teitel, Meir

2017-04-01

The area of agricultural crops covered by screens is constantly increasing worldwide. While irrigation requirements for open canopies are well documented, corresponding information for covered crops is scarce. Therefore much effort in recent years has focused on measuring and modeling evapotranspiration of screen-covered crops. One model that can be utilized for such estimations is the mixing length model. As a first step towards future application of this model, selected mean and turbulent properties of the boundary layer above and below a shading screen were measured and analyzed. Experiments were carried out in a large banana plantation, covered by a light-weight horizontal shading screen deployed 5.5 m high. During the measurement period, plant height increased from 2.5 to 4.1 m. A 3D ultrasonic anemometer and temperature and humidity sensors were mounted on a lifting tower with a manual crank that could measure between 2.8 and 10.2 m height, i.e., both below and above the screen. In each profile, the sensors measured at different heights during consecutive time intervals of about 15 min each. Vertical profiles were measured around noon when external meteorological conditions were relatively stable. An additional stationary tower installed within the screenhouse about 20 m to the north of the lifting tower, continuously measured corresponding reference values at 4.5 m height. Footprint analysis shows that out of the 62 measured time intervals, only in 4 cases the 90% flux contribution originated from outside the screenhouse. Both horizontal air velocity, Uh, and normalized horizontal air velocity increased with height. Air temperature generally decreased with height, indicating that the boundary layer was statically unstable. Specific humidity decreased with height, as is typical for a well irrigated crop. Friction velocity, u∗, was higher above than below the screen, illustrating the role of the screen as a momentum sink. The mean ratio between friction velocity below and above the screen was 0.55. Vertical profiles of the surface drag coefficientCd = (u∗/U h)2 showed a consistent decease of √Cd-with height, mainly above the screen. This result is expected since, with a constant flux layer, the surface drag is bound to decrease with height. The energy spectrum of each velocity component, both below and above the screen, was calculated separately and their sum, the 3D spectrum (Tennekes and Lumely, 1972), was plotted as a function of frequency. Slopes of linear fits to the spectra ranged between -1.42 and -1.68, with a mean value of -1.59±0.04. These slopes are close to -5/3 (-1.67), the value typical of the inertial subrange in steady state turbulent boundary layers (Stull, 1988).

Inhibition of decay fungi using cotton cellulose hydrolysis as a model for wood decay

Treesearch

Frederick Green

2000-01-01

Environmental pressures to replace chromium and arsenic in fixed waterborne preservatives have been increasing. Potential inhibitors of brown-, white- and soft-rot fungi need to be evaluated as alternative preservatives by screening and testing in, in vitro model systems. This paper reports the inhibition of cellulose depolymerization and weight loss of selected decay...

A Prototype Model for Automating Nursing Diagnosis, Nurse Care Planning and Patient Classification.

DTIC Science & Technology

1986-03-01

Each diagnosis has an assessment level. Assessment levels are defining characteristics observed by the nurse or subjectively stated by the patient... characteristics of this order line. Select IV Order (Figure 4.l.1.le] is the first screen of a series of three. Select IV Order has up to 10 selections...For I F Upatient orders. Input Files Used: IVC.Scr and Procfile.Prg * Output Files Used: None Calling Routine: IUB.Prg * Routine Called: None

Development of a risk assessment tool for projecting individualized probabilities of developing breast cancer for Chinese women.

PubMed

Wang, Yuan; Gao, Ying; Battsend, Munkhzul; Chen, Kexin; Lu, Wenli; Wang, Yaogang

2014-11-01

The optimal approach regarding breast cancer screening for Chinese women is unclear due to the relative low incidence rate. A risk assessment tool may be useful for selection of high-risk subsets of population for mammography screening in low-incidence and resource-limited developing country. The odd ratios for six main risk factors of breast cancer were pooled by review manager after a systematic research of literature. Health risk appraisal (HRA) model was developed to predict an individual's risk of developing breast cancer in the next 5 years from current age. The performance of this HRA model was assessed based on a first-round screening database. Estimated risk of breast cancer increased with age. Increases in the 5-year risk of developing breast cancer were found with the existence of any of included risk factors. When individuals who had risk above median risk (3.3‰) were selected from the validation database, the sensitivity is 60.0% and the specificity is 47.8%. The unweighted area under the curve (AUC) was 0.64 (95% CI = 0.50-0.78). The risk-prediction model reported in this article is based on a combination of risk factors and shows good overall predictive power, but it is still weak at predicting which particular women will develop the disease. It would be very helpful for the improvement of a current model if more population-based prospective follow-up studies were used for the validation.

Cost-effectiveness of screening for asymptomatic carotid atherosclerotic disease.

PubMed

Derdeyn, C P; Powers, W J

1996-11-01

The value of screening for asymptomatic carotid stenosis has become an important issue with the recently reported beneficial effect of endarterectomy. The purpose of this study is to evaluate the cost-effectiveness of using Doppler ultrasound as a screening tool to select subjects for arteriography and subsequent surgery. A computer model was developed to simulate the cost-effectiveness of screening a cohort of 1000 men during a 20-year period. The primary outcome measure was incremental present-value dollar expenditures for screening and treatment per incremental present-value quality-adjusted life-year (QALY) saved. Estimates of disease prevalence and arteriographic and surgical complication rates were obtained from the literature. Probabilities of stroke and death with surgical and medical treatment were obtained from published clinical trials. Doppler ultrasound sensitivity and specificity were obtained through review of local experience. Estimates of costs were obtained from local Medicare reimbursement data. A one-time screening program of a population with a high prevalence (20%) of > or = 60% stenosis cost $35130 per incremental QALY gained. Decreased surgical benefit or increased annual discount rate was detrimental, resulting in lost QALYs. Annual screening cost $457773 per incremental QALY gained. In a low-prevalence (4%) population, one-time screening cost $52588 per QALY gained, while annual screening was detrimental. The cost-effectiveness of a one-time screening program for an asymptomatic population with a high prevalence of carotid stenosis may be cost-effective. Annual screening is detrimental. The most sensitive variables in this simulation model were long-term stroke risk reduction after surgery and annual discount rate for accumulated costs and QALYs.

Estimating the harms and benefits of prostate cancer screening as used in common practice versus recommended good practice: A microsimulation screening analysis.

PubMed

Carlsson, Sigrid V; de Carvalho, Tiago M; Roobol, Monique J; Hugosson, Jonas; Auvinen, Anssi; Kwiatkowski, Maciej; Villers, Arnauld; Zappa, Marco; Nelen, Vera; Páez, Alvaro; Eastham, James A; Lilja, Hans; de Koning, Harry J; Vickers, Andrew J; Heijnsdijk, Eveline A M

2016-11-15

Prostate-specific antigen (PSA) screening and concomitant treatment can be implemented in several ways. The authors investigated how the net benefit of PSA screening varies between common practice versus "good practice." Microsimulation screening analysis (MISCAN) was used to evaluate the effect on quality-adjusted life-years (QALYs) if 4 recommendations were followed: limited screening in older men, selective biopsy in men with elevated PSA, active surveillance for low-risk tumors, and treatment preferentially delivered at high-volume centers. Outcomes were compared with a base model in which annual screening started at ages 55 to 69 years and were simulated using data from the European Randomized Study of Screening for Prostate Cancer. In terms of QALYs gained compared with no screening, for 1000 screened men who were followed over their lifetime, recommended good practice led to 73 life-years (LYs) and 74 QALYs gained compared with 73 LYs and 56 QALYs for the base model. In contrast, common practice led to 78 LYs gained but only 19 QALYs gained, for a greater than 75% relative reduction in QALYs gained from unadjusted LYs gained. The poor outcomes for common practice were influenced predominantly by the use of aggressive treatment for men with low-risk disease, and PSA testing in older men also strongly reduced potential QALY gains. Commonly used PSA screening and treatment practices are associated with little net benefit. Following a few straightforward clinical recommendations, particularly greater use of active surveillance for low-risk disease and reducing screening in older men, would lead to an almost 4-fold increase in the net benefit of prostate cancer screening. Cancer 2016;122:3386-3393. © 2016 American Cancer Society. © 2016 American Cancer Society.

Vasa previa screening strategies: a decision and cost-effectiveness analysis.

PubMed

Sinkey, R G; Odibo, A O

2018-05-22

The aim of this study is to perform a decision and cost-effectiveness analysis comparing four screening strategies for the antenatal diagnosis of vasa previa among singleton pregnancies. A decision-analytic model was constructed comparing vasa previa screening strategies. Published probabilities and costs were applied to four transvaginal screening scenarios which occurred at the time of mid-trimester ultrasound: no screening, ultrasound-indicated screening, screening pregnancies conceived by in vitro fertilization (IVF), and universal screening. Ultrasound-indicated screening was defined as performing a transvaginal ultrasound at the time of routine anatomy ultrasound in response to one of the following sonographic findings associated with an increased risk of vasa previa: low-lying placenta, marginal or velamentous cord insertion, or bilobed or succenturiate lobed placenta. The primary outcome was cost per quality adjusted life years (QALY) in U.S. dollars. The analysis was from a healthcare system perspective with a willingness to pay (WTP) threshold of $100,000 per QALY selected. One-way and multivariate sensitivity analyses (Monte-Carlo simulation) were performed. This decision-analytic model demonstrated that screening pregnancies conceived by IVF was the most cost-effective strategy with an incremental cost effectiveness ratio (ICER) of $29,186.50 / QALY. Ultrasound-indicated screening was the second most cost-effective with an ICER of $56,096.77 / QALY. These data were robust to all one-way and multivariate sensitivity analyses performed. Within our baseline assumptions, transvaginal ultrasound screening for vasa previa appears to be most cost-effective when performed among IVF pregnancies. However, both IVF and ultrasound-indicated screening strategies fall within contemporary willingness-to-pay thresholds, suggesting that both strategies may be appropriate to apply in clinical practice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Incorporating Virtual Reactions into a Logic-based Ligand-based Virtual Screening Method to Discover New Leads

PubMed Central

Reynolds, Christopher R; Muggleton, Stephen H; Sternberg, Michael J E

2015-01-01

The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21×1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs. PMID:26583052

Disappointing performance of literature-derived selective screening criteria for asymptomatic Chlamydia trachomatis infection in an inner-city population.

PubMed

van Valkengoed, I G; Boeke, A J; Morré, S A; van den Brule, A J; Meijer, C J; Devillé, W; Bouter, L M

2000-10-01

In an inner-city population with a low prevalence of Chlamydia trachomatis infection, selective screening may be indicated to increase the efficiency of screening. To evaluate the performance of sets of selective screening criteria for asymptomatic Chlamydia trachomatis infection in an inner-city population. The criteria were derived from reports of studies carried out in various settings. A total of 5714 women age 15 to 40 years living in Amsterdam were invited for a screening based on home-obtained urine specimens. Criteria identified from the literature were applied to the screening population. A calculated area under the receiver-operator characteristic curve (AUC) of greater than 0.75 was considered a good measure of diagnostic accuracy. Of the four sets of criteria, selection based on the following determinants showed the highest diagnostic accuracy: younger than 25 years, being unmarried, number of partners during the previous 6 months, Surinam or Antillean origin (black), and vaginal douching (AUC, 0.67; 95% CI, 0.65-0.69). Selection based on age alone showed an AUC of 0.57 (95% CI, 0.55-0.69). The performance of selective screening criteria for asymptomatic C trachomatis infection in an inner-city population in Amsterdam was insufficient to recommend its implementation in practice.

Web-based newborn screening system for metabolic diseases: machine learning versus clinicians.

PubMed

Chen, Wei-Hsin; Hsieh, Sheau-Ling; Hsu, Kai-Ping; Chen, Han-Ping; Su, Xing-Yu; Tseng, Yi-Ju; Chien, Yin-Hsiu; Hwu, Wuh-Liang; Lai, Feipei

2013-05-23

A hospital information system (HIS) that integrates screening data and interpretation of the data is routinely requested by hospitals and parents. However, the accuracy of disease classification may be low because of the disease characteristics and the analytes used for classification. The objective of this study is to describe a system that enhanced the neonatal screening system of the Newborn Screening Center at the National Taiwan University Hospital. The system was designed and deployed according to a service-oriented architecture (SOA) framework under the Web services .NET environment. The system consists of sample collection, testing, diagnosis, evaluation, treatment, and follow-up services among collaborating hospitals. To improve the accuracy of newborn screening, machine learning and optimal feature selection mechanisms were investigated for screening newborns for inborn errors of metabolism. The framework of the Newborn Screening Hospital Information System (NSHIS) used the embedded Health Level Seven (HL7) standards for data exchanges among heterogeneous platforms integrated by Web services in the C# language. In this study, machine learning classification was used to predict phenylketonuria (PKU), hypermethioninemia, and 3-methylcrotonyl-CoA-carboxylase (3-MCC) deficiency. The classification methods used 347,312 newborn dried blood samples collected at the Center between 2006 and 2011. Of these, 220 newborns had values over the diagnostic cutoffs (positive cases) and 1557 had values that were over the screening cutoffs but did not meet the diagnostic cutoffs (suspected cases). The original 35 analytes and the manifested features were ranked based on F score, then combinations of the top 20 ranked features were selected as input features to support vector machine (SVM) classifiers to obtain optimal feature sets. These feature sets were tested using 5-fold cross-validation and optimal models were generated. The datasets collected in year 2011 were used as predicting cases. The feature selection strategies were implemented and the optimal markers for PKU, hypermethioninemia, and 3-MCC deficiency were obtained. The results of the machine learning approach were compared with the cutoff scheme. The number of the false positive cases were reduced from 21 to 2 for PKU, from 30 to 10 for hypermethioninemia, and 209 to 46 for 3-MCC deficiency. This SOA Web service-based newborn screening system can accelerate screening procedures effectively and efficiently. An SVM learning methodology for PKU, hypermethioninemia, and 3-MCC deficiency metabolic diseases classification, including optimal feature selection strategies, is presented. By adopting the results of this study, the number of suspected cases could be reduced dramatically.

Web-Based Newborn Screening System for Metabolic Diseases: Machine Learning Versus Clinicians

PubMed Central

Chen, Wei-Hsin; Hsu, Kai-Ping; Chen, Han-Ping; Su, Xing-Yu; Tseng, Yi-Ju; Chien, Yin-Hsiu; Hwu, Wuh-Liang; Lai, Feipei

2013-01-01

Background A hospital information system (HIS) that integrates screening data and interpretation of the data is routinely requested by hospitals and parents. However, the accuracy of disease classification may be low because of the disease characteristics and the analytes used for classification. Objective The objective of this study is to describe a system that enhanced the neonatal screening system of the Newborn Screening Center at the National Taiwan University Hospital. The system was designed and deployed according to a service-oriented architecture (SOA) framework under the Web services .NET environment. The system consists of sample collection, testing, diagnosis, evaluation, treatment, and follow-up services among collaborating hospitals. To improve the accuracy of newborn screening, machine learning and optimal feature selection mechanisms were investigated for screening newborns for inborn errors of metabolism. Methods The framework of the Newborn Screening Hospital Information System (NSHIS) used the embedded Health Level Seven (HL7) standards for data exchanges among heterogeneous platforms integrated by Web services in the C# language. In this study, machine learning classification was used to predict phenylketonuria (PKU), hypermethioninemia, and 3-methylcrotonyl-CoA-carboxylase (3-MCC) deficiency. The classification methods used 347,312 newborn dried blood samples collected at the Center between 2006 and 2011. Of these, 220 newborns had values over the diagnostic cutoffs (positive cases) and 1557 had values that were over the screening cutoffs but did not meet the diagnostic cutoffs (suspected cases). The original 35 analytes and the manifested features were ranked based on F score, then combinations of the top 20 ranked features were selected as input features to support vector machine (SVM) classifiers to obtain optimal feature sets. These feature sets were tested using 5-fold cross-validation and optimal models were generated. The datasets collected in year 2011 were used as predicting cases. Results The feature selection strategies were implemented and the optimal markers for PKU, hypermethioninemia, and 3-MCC deficiency were obtained. The results of the machine learning approach were compared with the cutoff scheme. The number of the false positive cases were reduced from 21 to 2 for PKU, from 30 to 10 for hypermethioninemia, and 209 to 46 for 3-MCC deficiency. Conclusions This SOA Web service–based newborn screening system can accelerate screening procedures effectively and efficiently. An SVM learning methodology for PKU, hypermethioninemia, and 3-MCC deficiency metabolic diseases classification, including optimal feature selection strategies, is presented. By adopting the results of this study, the number of suspected cases could be reduced dramatically. PMID:23702487

A Validated Clinical Risk Prediction Model for Lung Cancer in Smokers of All Ages and Exposure Types: A HUNT Study.

PubMed

Markaki, Maria; Tsamardinos, Ioannis; Langhammer, Arnulf; Lagani, Vincenzo; Hveem, Kristian; Røe, Oluf Dimitri

2018-05-01

Lung cancer causes >1·6 million deaths annually, with early diagnosis being paramount to effective treatment. Here we present a validated risk assessment model for lung cancer screening. The prospective HUNT2 population study in Norway examined 65,237 people aged >20years in 1995-97. After a median of 15·2years, 583 lung cancer cases had been diagnosed; 552 (94·7%) ever-smokers and 31 (5·3%) never-smokers. We performed multivariable analyses of 36 candidate risk predictors, using multiple imputation of missing data and backwards feature selection with Cox regression. The resulting model was validated in an independent Norwegian prospective dataset of 45,341 ever-smokers, in which 675 lung cancers had been diagnosed after a median follow-up of 11·6years. Our final HUNT Lung Cancer Model included age, pack-years, smoking intensity, years since smoking cessation, body mass index, daily cough, and hours of daily indoors exposure to smoke. External validation showed a 0·879 concordance index (95% CI [0·866-0·891]) with an area under the curve of 0·87 (95% CI [0·85-0·89]) within 6years. Only 22% of ever-smokers would need screening to identify 81·85% of all lung cancers within 6years. Our model of seven variables is simple, accurate, and useful for screening selection. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Ligand-binding pocket shape differences between S1P1 and S1P3 determine efficiency of chemical probe identification by uHTS

PubMed Central

Schürer, Stephan C.; Brown, Steven J.; Cabrera, Pedro Gonzales; Schaeffer, Marie-Therese; Chapman, Jacqueline; Jo, Euijung; Chase, Peter; Spicer, Tim; Hodder, Peter; Rosen, Hugh

2008-01-01

We have studied the Sphingosine 1-phosphate (S1P) receptor system to better understand why certain molecular targets within a closely related family are much more tractable when identifying compelling chemical leads. Five medically important G protein-coupled receptors for S1P regulate heart rate, coronary artery caliber, endothelial barrier integrity, and lymphocyte trafficking. Selective S1P receptor agonist probes would be of great utility to study receptor subtype-specific function. Through systematic screening of the same libraries, we identified novel selective agonists chemotypes for each of the S1P1 and S1P3 receptors. uHTS for S1P1 was more effective than for S1P3, with many selective, low nanomolar hits of proven mechanism emerging for. Receptor structure modeling and ligand docking reveal differences between the receptor binding pockets, which are the basis for sub-type selectivity. Novel selective agonists interact primarily in the hydrophobic pocket of the receptor in the absence of head-group interactions. Chemistry-space and shape-based analysis of the screening libraries in combination with the binding models explain the observed differential hit rates and enhanced efficiency for lead discovery for S1P1 vs. S1P3 in this closely related receptor family. PMID:18590333

A SCREENING-LEVEL MODEL EVALUATION OF ATRAZINE IN THE LAKE MICHIGAN BASIN

EPA Science Inventory

Atrazine, a widely used herbicide in the agricultural regions of the Lake Michigan basin, was selected as a priority toxic chemical study in the United States Environmental Protection Agency (U.S. EPA) - sponsored Lake Michigan Mass Balance Project.

Guidelines for Microplate Selection in High Content Imaging.

PubMed

Trask, Oscar J

2018-01-01

Since the inception of commercialized automated high content screening (HCS) imaging devices in the mid to late 1990s, the adoption of media vessels typically used to house and contain biological specimens for interrogation has transitioned from microscope slides and petri dishes into multi-well microtiter plates called microplates. The early 96- and 384-well microplates commonly used in other high-throughput screening (HTS) technology applications were often not designed for optical imaging. Since then, modifications and the use of next-generation materials with improved optical clarity have enhanced the quality of captured images, reduced autofocusing failures, and empowered the use of higher power magnification objectives to resolve fine detailed measurements at the subcellular pixel level. The plethora of microplates and their applications requires practitioners of high content imaging (HCI) to be especially diligent in the selection and adoption of the best plates for running longitudinal studies or larger screening campaigns. While the highest priority in experimental design is the selection of the biological model, the choice of microplate can alter the biological response and ultimately may change the experimental outcome. This chapter will provide readers with background, troubleshooting guidelines, and considerations for choosing an appropriate microplate.

Simple animal models for amyotrophic lateral sclerosis drug discovery.

PubMed

Patten, Shunmoogum A; Parker, J Alex; Wen, Xiao-Yan; Drapeau, Pierre

2016-08-01

Simple animal models have enabled great progress in uncovering the disease mechanisms of amyotrophic lateral sclerosis (ALS) and are helping in the selection of therapeutic compounds through chemical genetic approaches. Within this article, the authors provide a concise overview of simple model organisms, C. elegans, Drosophila and zebrafish, which have been employed to study ALS and discuss their value to ALS drug discovery. In particular, the authors focus on innovative chemical screens that have established simple organisms as important models for ALS drug discovery. There are several advantages of using simple animal model organisms to accelerate drug discovery for ALS. It is the authors' particular belief that the amenability of simple animal models to various genetic manipulations, the availability of a wide range of transgenic strains for labelling motoneurons and other cell types, combined with live imaging and chemical screens should allow for new detailed studies elucidating early pathological processes in ALS and subsequent drug and target discovery.

Parent Experience With False-Positive Newborn Screening Results for Cystic Fibrosis.

PubMed

Hayeems, Robin Z; Miller, Fiona A; Barg, Carolyn J; Bombard, Yvonne; Kerr, Elizabeth; Tam, Karen; Carroll, June C; Potter, Beth K; Chakraborty, Pranesh; Davies, Christine; Milburn, Jennifer; Patton, Sarah; Bytautas, Jessica P; Taylor, Louise; Price, April; Gonska, Tanja; Keenan, Katherine; Ratjen, Felix; Guttmann, Astrid

2016-09-01

The risk of psychosocial harm in families of infants with false-positive (FP) newborn bloodspot screening (NBS) results for cystic fibrosis (CF) is a longstanding concern. Whether well designed retrieval and confirmatory testing systems can mitigate risks remains unknown. Using a mixed-methods cohort design, we obtained prospective self-report data from mothers of infants with FP CF NBS results 2 to 3 months after confirmatory testing at Ontario's largest follow-up center, and from a randomly selected control sample of mothers of screen negative infants from the same region. Mothers completed a questionnaire assessing experience and psychosocial response. A sample of mothers of FP infants completed qualitative interviews. One hundred thirty-four mothers of FP infants (response rate, 55%) and 411 controls (response rate, 47%) completed questionnaires; 54 mothers of FP infants were interviewed. Selected psychosocial response measures did not detect psychosocial distress in newborns or 1 year later (P > .05). Mothers recalled distress during notification of the positive result and in the follow-up testing period related to fear of chronic illness, but valued the screening system of care in mitigating concerns. Although immediate distress was reported among mothers of FP infants, selected psychometric tools did not detect these concerns. The NBS center from which mothers were recruited minimizes delay between notification and confirmatory testing and ensures trained professionals are communicating results and facilitating follow-up. These factors may explain the presence of minimal psychosocial burden. The screening system reflected herein may be a model for NBS programs working to minimize FP-related psychosocial harm. Copyright © 2016 by the American Academy of Pediatrics.

Generalized Linear Mixed Model Analysis of Urban-Rural Differences in Social and Behavioral Factors for Colorectal Cancer Screening

PubMed Central

Wang, Ke-Sheng; Liu, Xuefeng; Ategbole, Muyiwa; Xie, Xin; Liu, Ying; Xu, Chun; Xie, Changchun; Sha, Zhanxin

2017-01-01

Objective: Screening for colorectal cancer (CRC) can reduce disease incidence, morbidity, and mortality. However, few studies have investigated the urban-rural differences in social and behavioral factors influencing CRC screening. The objective of the study was to investigate the potential factors across urban-rural groups on the usage of CRC screening. Methods: A total of 38,505 adults (aged ≥40 years) were selected from the 2009 California Health Interview Survey (CHIS) data - the latest CHIS data on CRC screening. The weighted generalized linear mixed-model (WGLIMM) was used to deal with this hierarchical structure data. Weighted simple and multiple mixed logistic regression analyses in SAS ver. 9.4 were used to obtain the odds ratios (ORs) and their 95% confidence intervals (CIs). Results: The overall prevalence of CRC screening was 48.1% while the prevalence in four residence groups - urban, second city, suburban, and town/rural, were 45.8%, 46.9%, 53.7% and 50.1%, respectively. The results of WGLIMM analysis showed that there was residence effect (p<0.0001) and residence groups had significant interactions with gender, age group, education level, and employment status (p<0.05). Multiple logistic regression analysis revealed that age, race, marital status, education level, employment stats, binge drinking, and smoking status were associated with CRC screening (p<0.05). Stratified by residence regions, age and poverty level showed associations with CRC screening in all four residence groups. Education level was positively associated with CRC screening in second city and suburban. Infrequent binge drinking was associated with CRC screening in urban and suburban; while current smoking was a protective factor in urban and town/rural groups. Conclusions: Mixed models are useful to deal with the clustered survey data. Social factors and behavioral factors (binge drinking and smoking) were associated with CRC screening and the associations were affected by living areas such as urban and rural regions. PMID:28952708

Generalized Linear Mixed Model Analysis of Urban-Rural Differences in Social and Behavioral Factors for Colorectal Cancer Screening

PubMed

Wang, Ke-Sheng; Liu, Xuefeng; Ategbole, Muyiwa; Xie, Xin; Liu, Ying; Xu, Chun; Xie, Changchun; Sha, Zhanxin

2017-09-27

Objective: Screening for colorectal cancer (CRC) can reduce disease incidence, morbidity, and mortality. However, few studies have investigated the urban-rural differences in social and behavioral factors influencing CRC screening. The objective of the study was to investigate the potential factors across urban-rural groups on the usage of CRC screening. Methods: A total of 38,505 adults (aged ≥40 years) were selected from the 2009 California Health Interview Survey (CHIS) data - the latest CHIS data on CRC screening. The weighted generalized linear mixed-model (WGLIMM) was used to deal with this hierarchical structure data. Weighted simple and multiple mixed logistic regression analyses in SAS ver. 9.4 were used to obtain the odds ratios (ORs) and their 95% confidence intervals (CIs). Results: The overall prevalence of CRC screening was 48.1% while the prevalence in four residence groups - urban, second city, suburban, and town/rural, were 45.8%, 46.9%, 53.7% and 50.1%, respectively. The results of WGLIMM analysis showed that there was residence effect (p<0.0001) and residence groups had significant interactions with gender, age group, education level, and employment status (p<0.05). Multiple logistic regression analysis revealed that age, race, marital status, education level, employment stats, binge drinking, and smoking status were associated with CRC screening (p<0.05). Stratified by residence regions, age and poverty level showed associations with CRC screening in all four residence groups. Education level was positively associated with CRC screening in second city and suburban. Infrequent binge drinking was associated with CRC screening in urban and suburban; while current smoking was a protective factor in urban and town/rural groups. Conclusions: Mixed models are useful to deal with the clustered survey data. Social factors and behavioral factors (binge drinking and smoking) were associated with CRC screening and the associations were affected by living areas such as urban and rural regions. Creative Commons Attribution License

Comparison of a rational vs. high throughput approach for rapid salt screening and selection.

PubMed

Collman, Benjamin M; Miller, Jonathan M; Seadeek, Christopher; Stambek, Julie A; Blackburn, Anthony C

2013-01-01

In recent years, high throughput (HT) screening has become the most widely used approach for early phase salt screening and selection in a drug discovery/development setting. The purpose of this study was to compare a rational approach for salt screening and selection to those results previously generated using a HT approach. The rational approach involved a much smaller number of initial trials (one salt synthesis attempt per counterion) that were selected based on a few strategic solubility determinations of the free form combined with a theoretical analysis of the ideal solvent solubility conditions for salt formation. Salt screening results for sertraline, tamoxifen, and trazodone using the rational approach were compared to those previously generated by HT screening. The rational approach produced similar results to HT screening, including identification of the commercially chosen salt forms, but with a fraction of the crystallization attempts. Moreover, the rational approach provided enough solid from the very initial crystallization of a salt for more thorough and reliable solid-state characterization and thus rapid decision-making. The crystallization techniques used in the rational approach mimic larger-scale process crystallization, allowing smoother technical transfer of the selected salt to the process chemist.

Challenges in fecal donor selection and screening for fecal microbiota transplantation: A review.

PubMed

Woodworth, Michael H; Carpentieri, Cynthia; Sitchenko, Kaitlin L; Kraft, Colleen S

2017-05-04

Fecal microbiota transplantation is best understood as an effective and inexpensive therapy for recurrent Clostridium difficile infection but fecal donor selection and screening should be periodically revised. Here, we review current recommendations for selection and screening of fecal donors for fecal microbiota transplantation. We recommend considering diabetes mellitus, prior cardiovascular events, and clinical healthcare exposure as fecal donor exclusion criteria until more is known about the association of these conditions with the human gut microbiome. We review the non-bacterial members of the human gut microbiome, associations of the gut microbiome with colorectal malignancies, the human gut resistome and how these may impact future donor screening recommendations. Collaboration between clinicians, clinical laboratory scientists, industry and regulatory agencies will be critically important for continued improvement in donor selection and screening.

Identification of compounds protective against G93A-SOD1 toxicity for the treatment of amyotrophic lateral sclerosis.

PubMed

Benmohamed, Radhia; Arvanites, Anthony C; Kim, Jinho; Ferrante, Robert J; Silverman, Richard B; Morimoto, Richard I; Kirsch, Donald R

2011-03-01

The underlying cause of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder, remains unknown. However, there is strong evidence that one pathophysiological mechanism, toxic protein misfolding and/or aggregation, may trigger motor neuron dysfunction and loss. Since the clinical and pathological features of sporadic and familial ALS are indistinguishable, all forms of the disease may be better understood and ultimately treated by studying pathogenesis and therapy in models expressing mutant forms of SOD1. We developed a cellular model in which cell death depended on the expression of G93A-SOD1, a mutant form of superoxide dismutase found in familial ALS patients that produces toxic protein aggregates. This cellular model was optimized for high throughput screening to identify protective compounds from a >50,000 member chemical library. Three novel chemical scaffolds were selected for further study following screen implementation, counter-screening and secondary testing, including studies with purchased analogs. All three scaffolds blocked SOD1 aggregation in high content screening assays and data on the optimization and further characterization of these compounds will be reported separately. These data suggest that optimization of these chemicals scaffolds may produce therapeutic candidates for ALS patients.

Advanced colorectal neoplasia risk stratification by penalized logistic regression.

PubMed

Lin, Yunzhi; Yu, Menggang; Wang, Sijian; Chappell, Richard; Imperiale, Thomas F

2016-08-01

Colorectal cancer is the second leading cause of death from cancer in the United States. To facilitate the efficiency of colorectal cancer screening, there is a need to stratify risk for colorectal cancer among the 90% of US residents who are considered "average risk." In this article, we investigate such risk stratification rules for advanced colorectal neoplasia (colorectal cancer and advanced, precancerous polyps). We use a recently completed large cohort study of subjects who underwent a first screening colonoscopy. Logistic regression models have been used in the literature to estimate the risk of advanced colorectal neoplasia based on quantifiable risk factors. However, logistic regression may be prone to overfitting and instability in variable selection. Since most of the risk factors in our study have several categories, it was tempting to collapse these categories into fewer risk groups. We propose a penalized logistic regression method that automatically and simultaneously selects variables, groups categories, and estimates their coefficients by penalizing the [Formula: see text]-norm of both the coefficients and their differences. Hence, it encourages sparsity in the categories, i.e. grouping of the categories, and sparsity in the variables, i.e. variable selection. We apply the penalized logistic regression method to our data. The important variables are selected, with close categories simultaneously grouped, by penalized regression models with and without the interactions terms. The models are validated with 10-fold cross-validation. The receiver operating characteristic curves of the penalized regression models dominate the receiver operating characteristic curve of naive logistic regressions, indicating a superior discriminative performance. © The Author(s) 2013.

Collaborative Modeling: Experience of the U.S. Preventive Services Task Force.

PubMed

Petitti, Diana B; Lin, Jennifer S; Owens, Douglas K; Croswell, Jennifer M; Feuer, Eric J

2018-01-01

Models can be valuable tools to address uncertainty, trade-offs, and preferences when trying to understand the effects of interventions. Availability of results from two or more independently developed models that examine the same question (comparative modeling) allows systematic exploration of differences between models and the effect of these differences on model findings. Guideline groups sometimes commission comparative modeling to support their recommendation process. In this commissioned collaborative modeling, modelers work with the people who are developing a recommendation or policy not only to define the questions to be addressed but ideally, work side-by-side with each other and with systematic reviewers to standardize selected inputs and incorporate selected common assumptions. This paper describes the use of commissioned collaborative modeling by the U.S. Preventive Services Task Force (USPSTF), highlighting the general challenges and opportunities encountered and specific challenges for some topics. It delineates other approaches to use modeling to support evidence-based recommendations and the many strengths of collaborative modeling compared with other approaches. Unlike systematic reviews prepared for the USPSTF, the commissioned collaborative modeling reports used by the USPSTF in making recommendations about screening have not been required to follow a common format, sometimes making it challenging to understand key model features. This paper presents a checklist developed to critically appraise commissioned collaborative modeling reports about cancer screening topics prepared for the USPSTF. Copyright © 2017 American Journal of Preventive Medicine. All rights reserved.

Novel Hybrid Virtual Screening Protocol Based on Molecular Docking and Structure-Based Pharmacophore for Discovery of Methionyl-tRNA Synthetase Inhibitors as Antibacterial Agents

PubMed Central

Liu, Chi; He, Gu; Jiang, Qinglin; Han, Bo; Peng, Cheng

2013-01-01

Methione tRNA synthetase (MetRS) is an essential enzyme involved in protein biosynthesis in all living organisms and is a potential antibacterial target. In the current study, the structure-based pharmacophore (SBP)-guided method has been suggested to generate a comprehensive pharmacophore of MetRS based on fourteen crystal structures of MetRS-inhibitor complexes. In this investigation, a hybrid protocol of a virtual screening method, comprised of pharmacophore model-based virtual screening (PBVS), rigid and flexible docking-based virtual screenings (DBVS), is used for retrieving new MetRS inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen the Specs (202,408 compounds) database, a structurally diverse chemical database. Fifteen hit compounds were selected from the final hits and shifted to experimental studies. These results may provide important information for further research of novel MetRS inhibitors as antibacterial agents. PMID:23839093

Screening for Psychopathology Versus Selecting for Suitability: Ethical and Legal Considerations

NASA Technical Reports Server (NTRS)

Holland, Albert W.; Galarza, Laura; Arvey, Richard; Hysong, Sylvia; Sackett, Paul; Cascio, Wayne

2000-01-01

The current system for psychological selection of U.S. astronauts is divided into two phases: The select-out phase and the select-in phase. The select-out phase screens candidates for psychopathology; candidates who do not meet the baseline psychiatric requirements are immediately disqualified. The select-in phase assesses candidates for suitability to fly short- and long-duration missions. Suitability ratings are given for ten factors found to be critical for short and long-duration space missions. There are qualitative differences in the purpose of the two phases (select-in vs. select-out) and in the nature of the information collected in each phase. Furthermore, there are different logistic, ethical, and legal issues related to a medical or psychiatric (select-out) screening versus a suitability (select-in) psychological screening process . The purpose of this presentation is to contrast the ethical and legal environment surrounding the select-out and select-in phases of the psychological selection system. Issues such as data collection, data storage and management, the federal statutory environment, and personnel training will be discussed. Further, a summary of the new standards for psychological testing is presented, along with their implications for astronaut selection.

Improvement of selective screening strategy for gestational diabetes through a more accurate definition of high-risk groups.

PubMed

Pintaudi, Basilio; Di Vieste, Giacoma; Corrado, Francesco; Lucisano, Giuseppe; Pellegrini, Fabio; Giunta, Loretta; Nicolucci, Antonio; D'Anna, Rosario; Di Benedetto, Antonino

2014-01-01

This study aimed to assess the predictive value of risk factors (RFs) for gestational diabetes mellitus (GDM) established by selective screening (SS) and to identify subgroups of women at a higher risk of developing GDM. A retrospective, single-center study design was employed. Data of 1015 women screened for GDM at 24-28 weeks of gestation and diagnosed according to the International Association of Diabetes and Pregnancy Study Groups criteria were evaluated. Information on RFs established by SS was also collected and their association with GDM was determined. To identify distinct and homogeneous subgroups of patients at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 113 (11.1%) women were diagnosed as having GDM. The application of the SS criteria would result in the execution of an oral glucose tolerance test (OGTT) in 58.3% of women and 26 (23.0%) cases of GDM would not be detected due to the absence of any RF. The RECPAM analysis identified high-risk subgroups characterized by fasting plasma glucose values >5.1 mmol/l (odds ratio (OR)=26.5; 95% CI 14.3-49.0) and pre-pregnancy BMI (OR=7.0; 95% CI 3.9-12.8 for overweight women). In a final logistic model including RECPAM classes, previous macrosomia (OR=3.6; 95% CI 1.1-11.6), and family history of diabetes (OR=1.8; 95% CI 1.1-2.8), but not maternal age, were also found to be associated with an increased risk of developing GDM. A screening approach based on the RECPAM model would reduce by over 50% (23.0 vs 10.6%) the number of undiagnosed GDM cases when compared with the current SS approach, at the expense of 50 additional OGTTs required. A screening approach based on our RECPAM model results in a significant reduction in the number of undetected GDM cases compared with the current SS procedure.

[Chemical databases and virtual screening].

PubMed

Rognan, Didier; Bonnet, Pascal

2014-12-01

A prerequisite to any virtual screening is the definition of compound libraries to be screened. As we describe here, various sources are available. The selection of the proper library is usually project-dependent but at least as important as the screening method itself. This review details the main compound libraries that are available for virtual screening and guide the reader to the best possible selection according to its needs. © 2014 médecine/sciences – Inserm.

Feature Screening in Ultrahigh Dimensional Cox's Model.

PubMed

Yang, Guangren; Yu, Ye; Li, Runze; Buu, Anne

Survival data with ultrahigh dimensional covariates such as genetic markers have been collected in medical studies and other fields. In this work, we propose a feature screening procedure for the Cox model with ultrahigh dimensional covariates. The proposed procedure is distinguished from the existing sure independence screening (SIS) procedures (Fan, Feng and Wu, 2010, Zhao and Li, 2012) in that the proposed procedure is based on joint likelihood of potential active predictors, and therefore is not a marginal screening procedure. The proposed procedure can effectively identify active predictors that are jointly dependent but marginally independent of the response without performing an iterative procedure. We develop a computationally effective algorithm to carry out the proposed procedure and establish the ascent property of the proposed algorithm. We further prove that the proposed procedure possesses the sure screening property. That is, with the probability tending to one, the selected variable set includes the actual active predictors. We conduct Monte Carlo simulation to evaluate the finite sample performance of the proposed procedure and further compare the proposed procedure and existing SIS procedures. The proposed methodology is also demonstrated through an empirical analysis of a real data example.

Evaluation of the "Angelina Jolie Effect" on Screening Mammography Utilization in an Academic Center.

PubMed

Huesch, Marco D; Schetter, Susann; Segel, Joel; Chetlen, Alison

2017-08-01

The aim of this study was to understand the impact on screening mammography at our institution, comparing weekly utilization in the 2 years before and the 2 years after Ms Angelina Jolie disclosed in the New York Times on May 13, 2013, that she had had a prophylactic double mastectomy. All 48,110 consecutive screening mammograms conducted at our institution between May 16, 2011, and May 16, 2015, were selected from our electronic medical record system. We used interrupted time series statistical models and graphical methods on utilization data to understand utilization changes before and after Ms Jolie's news. The graphed trend of weekly screening mammogram utilization failed to show changes around the time of interest. Analytical models and statistical tests also failed to show a step change increase or acceleration of utilization around May 2013. However, graphical and time series analyses showed a flattening of utilization in the middle of 2014. In our well-powered analysis in a large regional breast imaging center, we found no support for the hypothesis that this celebrity news drove increased screening. Copyright © 2017 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Association between background parenchymal enhancement of breast MRI and BIRADS rating change in the subsequent screening

NASA Astrophysics Data System (ADS)

Aghaei, Faranak; Mirniaharikandehei, Seyedehnafiseh; Hollingsworth, Alan B.; Stoug, Rebecca G.; Pearce, Melanie; Liu, Hong; Zheng, Bin

2018-03-01

Although breast magnetic resonance imaging (MRI) has been used as a breast cancer screening modality for high-risk women, its cancer detection yield remains low (i.e., <= 3%). Thus, increasing breast MRI screening efficacy and cancer detection yield is an important clinical issue in breast cancer screening. In this study, we investigated association between the background parenchymal enhancement (BPE) of breast MRI and the change of diagnostic (BIRADS) status in the next subsequent breast MRI screening. A dataset with 65 breast MRI screening cases was retrospectively assembled. All cases were rated BIRADS-2 (benign findings). In the subsequent screening, 4 cases were malignant (BIRADS-6), 48 remained BIRADS-2 and 13 were downgraded to negative (BIRADS-1). A computer-aided detection scheme was applied to process images of the first set of breast MRI screening. Total of 33 features were computed including texture feature and global BPE features. Texture features were computed from either a gray-level co-occurrence matrix or a gray level run length matrix. Ten global BPE features were also initially computed from two breast regions and bilateral difference between the left and right breasts. Box-plot based analysis shows positive association between texture features and BIRADS rating levels in the second screening. Furthermore, a logistic regression model was built using optimal features selected by a CFS based feature selection method. Using a leave-one-case-out based cross-validation method, classification yielded an overall 75% accuracy in predicting the improvement (or downgrade) of diagnostic status (to BIRAD-1) in the subsequent breast MRI screening. This study demonstrated potential of developing a new quantitative imaging marker to predict diagnostic status change in the short-term, which may help eliminate a high fraction of unnecessary repeated breast MRI screenings and increase the cancer detection yield.

[A brief review of research on chronic disease management based on collaborative care model in China].

PubMed

Li, Huayan; Fuller, Jeffrey; Sun, Mei; Wang, Yong; Xu, Shuang; Feng, Hui

2014-11-01

To evaluate the situation for chronic disease management in China, and to seek the method for improving the collaborative management for chronic diseases in community. We searched literature between January 2008 and November 2013 from the Database, such as China Academic Journal Full-Text Database, and PubMed. The screening was strictly in accordance with the inclusion and exclusion criteria and a summary was made among the selected literature based on a collaboration model. We got 698 articles after rough screen and finally selected 33. All studies were involved in patient's self-management support, but only 9 studies mentioned the communication within the team, and 11 showed a clear team division of labor. Chronic disease community management in China displays some disadvantages. It really needs a general service team with clear roles and responsibilities for team members to improve the service ability of team members and provide patients with various forms of self management services.

Predictive model for ionic liquid extraction solvents for rare earth elements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grabda, Mariusz; Oleszek, Sylwia; Institute of Environmental Engineering of the Polish Academy of Sciences, ul. M. Sklodowskiej-Curie 34, 41-819, Zabrze

2015-12-31

The purpose of our study was to select the most effective ionic liquid extraction solvents for dysprosium (III) fluoride using a theoretical approach. Conductor-like Screening Model for Real Solvents (COSMO-RS), based on quantum chemistry and the statistical thermodynamics of predefined DyF{sub 3}-ionic liquid systems, was applied to reach the target. Chemical potentials of the salt were predicted in 4,400 different ionic liquids. On the base of these predictions set of ionic liquids’ ions, manifesting significant decrease of the chemical potentials, were selected. Considering the calculated physicochemical properties (hydrophobicity, viscosity) of the ionic liquids containing these specific ions, the most effectivemore » extraction solvents for liquid-liquid extraction of DyF{sub 3} were proposed. The obtained results indicate that the COSMO-RS approach can be applied to quickly screen the affinity of any rare earth element for a large number of ionic liquid systems, before extensive experimental tests.« less

Dual-Screened Vertical Circulation Wells for Groundwater Lowering in Unconfined Aquifers.

PubMed

Jin, Yulan; Holzbecher, Ekkehard; Sauter, Martin

2016-01-01

A new type of vertical circulation well (VCW) is used for groundwater dewatering at construction sites. This type of VCW consists of an abstraction screen in the upper part and an injection screen in the lower part of a borehole, whereby drawdown is achieved without net withdrawal of groundwater from the aquifer. The objective of this study is to evaluate the operation of such wells including the identification of relevant factors and parameters based on field data of a test site and comprehensive numerical simulations. The numerical model is able to delineate the drawdown of groundwater table, defined as free-surface, by coupling the arbitrary Lagrangian-Eulerian algorithm with the groundwater flow equation. Model validation is achieved by comparing the field observations with the model results. Eventually, the influences of selected well operation and aquifer parameters on drawdown and on the groundwater flow field are investigated by means of parameter sensitivity analysis. The results show that the drawdown is proportional to the flow rate, inversely proportional to the aquifer conductivity, and almost independent of the aquifer anisotropy in the direct vicinity of the well. The position of the abstraction screen has a stronger effect on drawdown than the position of the injection screen. The streamline pattern depends strongly on the separation length of the screens and on the aquifer anisotropy, but not on the flow rate and the horizontal hydraulic conductivity. © 2015, National Ground Water Association.

Pharmacophore modeling and virtual screening to identify potential RET kinase inhibitors.

PubMed

Shih, Kuei-Chung; Shiau, Chung-Wai; Chen, Ting-Shou; Ko, Ching-Huai; Lin, Chih-Lung; Lin, Chun-Yuan; Hwang, Chrong-Shiong; Tang, Chuan-Yi; Chen, Wan-Ru; Huang, Jui-Wen

2011-08-01

Chemical features based 3D pharmacophore model for REarranged during Transfection (RET) tyrosine kinase were developed by using a training set of 26 structurally diverse known RET inhibitors. The best pharmacophore hypothesis, which identified inhibitors with an associated correlation coefficient of 0.90 between their experimental and estimated anti-RET values, contained one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic, and one ring aromatic features. The model was further validated by a testing set, Fischer's randomization test, and goodness of hit (GH) test. We applied this pharmacophore model to screen NCI database for potential RET inhibitors. The hits were docked to RET with GOLD and CDOCKER after filtering by Lipinski's rules. Ultimately, 24 molecules were selected as potential RET inhibitors for further investigation. Copyright © 2011 Elsevier Ltd. All rights reserved.

A strategy for clone selection under different production conditions.

PubMed

Legmann, Rachel; Benoit, Brian; Fedechko, Ronald W; Deppeler, Cynthia L; Srinivasan, Sriram; Robins, Russell H; McCormick, Ellen L; Ferrick, David A; Rodgers, Seth T; Russo, A Peter

2011-01-01

Top performing clones have failed at the manufacturing scale while the true best performer may have been rejected early in the screening process. Therefore, the ability to screen multiple clones in complex fed-batch processes using multiple process variations can be used to assess robustness and to identify critical factors. This dynamic ranking of clones' strategy requires the execution of many parallel experiments than traditional approaches. Therefore, this approach is best suited for micro-bioreactor models which can perform hundreds of experiments quickly and efficiently. In this study, a fully monitored and controlled small scale platform was used to screen eight CHO clones producing a recombinant monoclonal antibody across several process variations, including different feeding strategies, temperature shifts and pH control profiles. The first screen utilized 240 micro-bioreactors were run for two weeks for this assessment of the scale-down model as a high-throughput tool for clone evaluation. The richness of the outcome data enable to clearly identify the best and worst clone as well as process in term of maximum monoclonal antibody titer. The follow-up comparison study utilized 180 micro-bioreactors in a full factorial design and a subset of 12 clone/process combinations was selected to be run parallel in duplicate shake flasks. Good correlation between the micro-bioreactor predictions and those made in shake flasks with a Pearson correlation value of 0.94. The results also demonstrate that this micro-scale system can perform clone screening and process optimization for gaining significant titer improvements simultaneously. This dynamic ranking strategy can support better choices of production clones. Copyright © 2011 American Institute of Chemical Engineers (AIChE).

Risk of malnutrition (over and under-nutrition): validation of the JaNuS screening tool.

PubMed

Donini, Lorenzo M; Ricciardi, Laura Maria; Neri, Barbara; Lenzi, Andrea; Marchesini, Giulio

2014-12-01

Malnutrition (over and under-nutrition) is highly prevalent in patients admitted to hospital and it is a well-known risk factor for increased morbidity and mortality. Nutritional problems are often misdiagnosed, and especially the coexistence of over and undernutrition is not usually recognized. We aimed to develop and validate a screening tool for the easy detection and reporting of both undernutrition and overnutrition, specifically identifying the clinical conditions where the two types of malnutrition coexist. The study consisted of three phases: 1) selection of an appropriate study population (estimation sample) and of the hospital admission parameters to identify overnutrition and undernutrition; 2) combination of selected variables to create a screening tool to assess the nutritional risk in case of undernutrition, overnutrition, or the copresence of both the conditions, to be used by non-specialist health care professionals; 3) validation of the screening tool in a different patient sample (validation sample). Two groups of variables (12 for undernutrition, 7 for overnutrition) were identified in separate logistic models for their correlation with the outcome variables. Both models showed high efficacy, sensitivity and specificity (overnutrition, 97.7%, 99.6%, 66.6%, respectively; undernutrition, 84.4%, 83.6%, 84.8%). The logistic models were used to construct a two-faced test (named JaNuS - Just A Nutritional Screening) fitting into a two-dimension Cartesian coordinate graphic system. In the validation sample the JaNuS test confirmed its predictive value. Internal consistency and test-retest analysis provide evidence for the reliability of the test. The study provides a screening tool for the assessment of the nutritional risk, based on parameters easy-to-use by health care personnel lacking nutritional competence and characterized by excellent predictive validity. The test might be confidently applied in the clinical setting to determine the importance of malnutrition (including the copresence of over and undernutrition) as a risk factor for morbidity and mortality. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Differentiation of AmpC beta-lactamase binders vs. decoys using classification kNN QSAR modeling and application of the QSAR classifier to virtual screening

NASA Astrophysics Data System (ADS)

Hsieh, Jui-Hua; Wang, Xiang S.; Teotico, Denise; Golbraikh, Alexander; Tropsha, Alexander

2008-09-01

The use of inaccurate scoring functions in docking algorithms may result in the selection of compounds with high predicted binding affinity that nevertheless are known experimentally not to bind to the target receptor. Such falsely predicted binders have been termed `binding decoys'. We posed a question as to whether true binders and decoys could be distinguished based only on their structural chemical descriptors using approaches commonly used in ligand based drug design. We have applied the k-Nearest Neighbor ( kNN) classification QSAR approach to a dataset of compounds characterized as binders or binding decoys of AmpC beta-lactamase. Models were subjected to rigorous internal and external validation as part of our standard workflow and a special QSAR modeling scheme was employed that took into account the imbalanced ratio of inhibitors to non-binders (1:4) in this dataset. 342 predictive models were obtained with correct classification rate (CCR) for both training and test sets as high as 0.90 or higher. The prediction accuracy was as high as 100% (CCR = 1.00) for the external validation set composed of 10 compounds (5 true binders and 5 decoys) selected randomly from the original dataset. For an additional external set of 50 known non-binders, we have achieved the CCR of 0.87 using very conservative model applicability domain threshold. The validated binary kNN QSAR models were further employed for mining the NCGC AmpC screening dataset (69653 compounds). The consensus prediction of 64 compounds identified as screening hits in the AmpC PubChem assay disagreed with their annotation in PubChem but was in agreement with the results of secondary assays. At the same time, 15 compounds were identified as potential binders contrary to their annotation in PubChem. Five of them were tested experimentally and showed inhibitory activities in millimolar range with the highest binding constant Ki of 135 μM. Our studies suggest that validated QSAR models could complement structure based docking and scoring approaches in identifying promising hits by virtual screening of molecular libraries.

Preliminary selection and evaluation of the binding of aptamers against a Hantavirus antigen using fluorescence spectroscopy and modeling

NASA Astrophysics Data System (ADS)

Missailidis, Sotiris; de Oliveira, Renata Carvalho; Silva, Dilson; Cortez, Célia Martins; Guterres, Alexandro; Vicente, Luciana Helena Bassan; de Godoy, Daniela Tupy; Lemos, Elba

2015-12-01

In this study we have aimed to develop novel aptamers against the Hantavirus nucleoprotein N, a valid antigen already used in the Hantavirus reference laboratory of the Institute Oswaldo Cruz in Rio de Janeiro, Brazil. Such aptamers, if they are found to bind with high affinity and specificity for the selected hantavirus antigen, they could be translated into novel diagnostic assays with the ability to provide early detection for hantaviroses and their related disease syndromes. In a preliminary screening, we have managed to identify three aptamer species. We have analyzed a short and a long version of these aptamer using fluorescence spectroscopy and modelled their binding. We have identified Stern-Volmer constants for the selected aptamers, which have shown affinity for their target, with a different binding between the short and the long versions of them. Short aptamers have shown to have a higher Stern-Volmer constant and the ability to potentially bind to more than one binding site on the antigen. The information provided by the spectroscopic screening has been invaluable in allowing us to define candidates for further development into diagnostic assays.

Correction factors for self-selection when evaluating screening programmes.

PubMed

Spix, Claudia; Berthold, Frank; Hero, Barbara; Michaelis, Jörg; Schilling, Freimut H

2016-03-01

In screening programmes there is recognized bias introduced through participant self-selection (the healthy screenee bias). Methods used to evaluate screening programmes include Intention-to-screen, per-protocol, and the "post hoc" approach in which, after introducing screening for everyone, the only evaluation option is participants versus non-participants. All methods are prone to bias through self-selection. We present an overview of approaches to correct for this bias. We considered four methods to quantify and correct for self-selection bias. Simple calculations revealed that these corrections are actually all identical, and can be converted into each other. Based on this, correction factors for further situations and measures were derived. The application of these correction factors requires a number of assumptions. Using as an example the German Neuroblastoma Screening Study, no relevant reduction in mortality or stage 4 incidence due to screening was observed. The largest bias (in favour of screening) was observed when comparing participants with non-participants. Correcting for bias is particularly necessary when using the post hoc evaluation approach, however, in this situation not all required data are available. External data or further assumptions may be required for estimation. © The Author(s) 2015.

Uncertainty Quantification in High Throughput Screening ...

EPA Pesticide Factsheets

Using uncertainty quantification, we aim to improve the quality of modeling data from high throughput screening assays for use in risk assessment. ToxCast is a large-scale screening program that analyzes thousands of chemicals using over 800 assays representing hundreds of biochemical and cellular processes, including endocrine disruption, cytotoxicity, and zebrafish development. Over 2.6 million concentration response curves are fit to models to extract parameters related to potency and efficacy. Models built on ToxCast results are being used to rank and prioritize the toxicological risk of tested chemicals and to predict the toxicity of tens of thousands of chemicals not yet tested in vivo. However, the data size also presents challenges. When fitting the data, the choice of models, model selection strategy, and hit call criteria must reflect the need for computational efficiency and robustness, requiring hard and somewhat arbitrary cutoffs. When coupled with unavoidable noise in the experimental concentration response data, these hard cutoffs cause uncertainty in model parameters and the hit call itself. The uncertainty will then propagate through all of the models built on the data. Left unquantified, this uncertainty makes it difficult to fully interpret the data for risk assessment. We used bootstrap resampling methods to quantify the uncertainty in fitting models to the concentration response data. Bootstrap resampling determines confidence intervals for

Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics.

PubMed

Kaczor, Agnieszka A; Silva, Andrea G; Loza, María I; Kolb, Peter; Castro, Marián; Poso, Antti

2016-04-05

Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Selecting a mix of prevention strategies against cervical cancer for maximum efficiency with an optimization program.

PubMed

Demarteau, Nadia; Breuer, Thomas; Standaert, Baudouin

2012-04-01

Screening and vaccination against human papillomavirus (HPV) can protect against cervical cancer. Neither alone can provide 100% protection. Consequently it raises the important question about the most efficient combination of screening at specified time intervals and vaccination to prevent cervical cancer. Our objective was to identify the mix of cervical cancer prevention strategies (screening and/or vaccination against HPV) that achieves maximum reduction in cancer cases within a fixed budget. We assessed the optimal mix of strategies for the prevention of cervical cancer using an optimization program. The evaluation used two models. One was a Markov cohort model used as the evaluation model to estimate the costs and outcomes of 52 different prevention strategies. The other was an optimization model in which the results of each prevention strategy of the previous model were entered as input data. The latter model determined the combination of the different prevention options to minimize cervical cancer under budget, screening coverage and vaccination coverage constraints. We applied the model in two countries with different healthcare organizations, epidemiology, screening practices, resource settings and treatment costs: the UK and Brazil. 100,000 women aged 12 years and above across the whole population over a 1-year period at steady state were included. The intervention was papanicolaou (Pap) smear screening programmes and/or vaccination against HPV with the bivalent HPV 16/18 vaccine (Cervarix® [Cervarix is a registered trademark of the GlaxoSmithKline group of companies]). The main outcome measures were optimal distribution of the population between different interventions (screening, vaccination, screening plus vaccination and no screening or vaccination) with the resulting number of cervical cancer and associated costs. In the base-case analysis (= same budget as today), the optimal prevention strategy would be, after introducing vaccination with a coverage rate of 80% in girls aged 12 years and retaining screening coverage at pre-vaccination levels (65% in the UK, 50% in Brazil), to increase the screening interval to 6 years (from 3) in the UK and to 5 years (from 3) in Brazil. This would result in a reduction of cervical cancer by 41% in the UK and by 54% in Brazil from pre-vaccination levels with no budget increase. Sensitivity analysis shows that vaccination alone at 80% coverage with no screening would achieve a cervical cancer reduction rate of 20% in the UK and 43% in Brazil compared with the pre-vaccination situation with a budget reduction of 30% and 14%, respectively. In both countries, the sharp reduction in cervical cancer is seen when the vaccine coverage rate exceeds the maximum screening coverage rate, or when screening coverage rate exceeds the maximum vaccine coverage rate, while maintaining the budget. As with any model, there are limitations to the value of predictions depending upon the assumptions made in each model. Spending the same budget that was used for screening and treatment of cervical cancer in the pre-vaccination era, results of the optimization program show that it would be possible to substantially reduce the number of cases by implementing an optimal combination of HPV vaccination (80% coverage) and screening at pre-vaccination coverage (65% UK, 50% Brazil) while extending the screening interval to every 6 years in the UK and 5 years in Brazil.

Selection of appropriate training and validation set chemicals for modelling dermal permeability by U-optimal design.

PubMed

Xu, G; Hughes-Oliver, J M; Brooks, J D; Yeatts, J L; Baynes, R E

2013-01-01

Quantitative structure-activity relationship (QSAR) models are being used increasingly in skin permeation studies. The main idea of QSAR modelling is to quantify the relationship between biological activities and chemical properties, and thus to predict the activity of chemical solutes. As a key step, the selection of a representative and structurally diverse training set is critical to the prediction power of a QSAR model. Early QSAR models selected training sets in a subjective way and solutes in the training set were relatively homogenous. More recently, statistical methods such as D-optimal design or space-filling design have been applied but such methods are not always ideal. This paper describes a comprehensive procedure to select training sets from a large candidate set of 4534 solutes. A newly proposed 'Baynes' rule', which is a modification of Lipinski's 'rule of five', was used to screen out solutes that were not qualified for the study. U-optimality was used as the selection criterion. A principal component analysis showed that the selected training set was representative of the chemical space. Gas chromatograph amenability was verified. A model built using the training set was shown to have greater predictive power than a model built using a previous dataset [1].

Applications of self-organizing neural networks in virtual screening and diversity selection.

PubMed

Selzer, Paul; Ertl, Peter

2006-01-01

Artificial neural networks provide a powerful technique for the analysis and modeling of nonlinear relationships between molecular structures and pharmacological activity. Many network types, including Kohonen and counterpropagation, also provide an intuitive method for the visual assessment of correspondence between the input and output data. This work shows how a combination of neural networks and radial distribution function molecular descriptors can be applied in various areas of industrial pharmaceutical research. These applications include the prediction of biological activity, the selection of screening candidates (cherry picking), and the extraction of representative subsets from large compound collections such as combinatorial libraries. The methods described have also been implemented as an easy-to-use Web tool, allowing chemists to perform interactive neural network experiments on the Novartis intranet.

Therapeutic Targeting of Spliceosomal-Mutant Acquired Bone Marrow Failure Disorders

DTIC Science & Technology

2017-05-01

we have completed both a negative selection shRNA screen and a genome-wide CRISPR dropout screen to identify genes selectively required in...level of protein. Aim 2: We have recently completed a genome-wide CRISPR dropout screen in the same cells in which the shRNA screen was performed...Project: Janine performed the CRISPR screen in Aim 2. Funding Support: US National Institutes of Health (NIH)-NHLBI grant R01 HL128239 10

Using information from historical high-throughput screens to predict active compounds.

PubMed

Riniker, Sereina; Wang, Yuan; Jenkins, Jeremy L; Landrum, Gregory A

2014-07-28

Modern high-throughput screening (HTS) is a well-established approach for hit finding in drug discovery that is routinely employed in the pharmaceutical industry to screen more than a million compounds within a few weeks. However, as the industry shifts to more disease-relevant but more complex phenotypic screens, the focus has moved to piloting smaller but smarter chemically/biologically diverse subsets followed by an expansion around hit compounds. One standard method for doing this is to train a machine-learning (ML) model with the chemical fingerprints of the tested subset of molecules and then select the next compounds based on the predictions of this model. An alternative approach would be to take advantage of the wealth of bioactivity information contained in older (full-deck) screens using so-called HTS fingerprints, where each element of the fingerprint corresponds to the outcome of a particular assay, as input to machine-learning algorithms. We constructed HTS fingerprints using two collections of data: 93 in-house assays and 95 publicly available assays from PubChem. For each source, an additional set of 51 and 46 assays, respectively, was collected for testing. Three different ML methods, random forest (RF), logistic regression (LR), and naïve Bayes (NB), were investigated for both the HTS fingerprint and a chemical fingerprint, Morgan2. RF was found to be best suited for learning from HTS fingerprints yielding area under the receiver operating characteristic curve (AUC) values >0.8 for 78% of the internal assays and enrichment factors at 5% (EF(5%)) >10 for 55% of the assays. The RF(HTS-fp) generally outperformed the LR trained with Morgan2, which was the best ML method for the chemical fingerprint, for the majority of assays. In addition, HTS fingerprints were found to retrieve more diverse chemotypes. Combining the two models through heterogeneous classifier fusion led to a similar or better performance than the best individual model for all assays. Further validation using a pair of in-house assays and data from a confirmatory screen--including a prospective set of around 2000 compounds selected based on our approach--confirmed the good performance. Thus, the combination of machine-learning with HTS fingerprints and chemical fingerprints utilizes information from both domains and presents a very promising approach for hit expansion, leading to more hits. The source code used with the public data is provided.

Development of a Protocol and a Screening Tool for Selection of DNAPL Source Area Remediation

DTIC Science & Technology

2012-02-01

the different remedial time frames used in the modeling case studies. • Matrix Diffusion: Modeling results demonstrated that in fractured rock ...being used for the ISCO, EISB and SEAR fractured rock numerical simulations at the field scale. Figure 2-4 presents the distribution of intrinsic...sedimentary limestone, sandstone, and shale, igneous basalts and granites, and metamorphous rock . For the modeling sites, three general geologies are

Analogue Study of Actinide Transport at Sites in Russia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Novikov, A P; Simmons, A M; Halsey, W G

2003-02-12

The U. S. Department of Energy (DOE) and the Russian Academy of Sciences (RAS) are engaged in a three-year cooperative study to observe the behavior of actinides in the natural environment at selected disposal sites and/or contamination sites in Russia. The purpose is to develop experimental data and models for actinide speciation, mobilization and transport processes in support of geologic repository design, safety and performance analyses. Currently at the mid-point of the study, the accomplishments to date include: evaluation of existing data and data needs, site screening and selection, initial data acquisition, and development of preliminary conceptual models.

Children's accuracy of portion size estimation using digital food images: effects of interface design and size of image on computer screen.

PubMed

Baranowski, Tom; Baranowski, Janice C; Watson, Kathleen B; Martin, Shelby; Beltran, Alicia; Islam, Noemi; Dadabhoy, Hafza; Adame, Su-heyla; Cullen, Karen; Thompson, Debbe; Buday, Richard; Subar, Amy

2011-03-01

To test the effect of image size and presence of size cues on the accuracy of portion size estimation by children. Children were randomly assigned to seeing images with or without food size cues (utensils and checked tablecloth) and were presented with sixteen food models (foods commonly eaten by children) in varying portion sizes, one at a time. They estimated each food model's portion size by selecting a digital food image. The same food images were presented in two ways: (i) as small, graduated portion size images all on one screen or (ii) by scrolling across large, graduated portion size images, one per sequential screen. Laboratory-based with computer and food models. Volunteer multi-ethnic sample of 120 children, equally distributed by gender and ages (8 to 13 years) in 2008-2009. Average percentage of correctly classified foods was 60·3 %. There were no differences in accuracy by any design factor or demographic characteristic. Multiple small pictures on the screen at once took half the time to estimate portion size compared with scrolling through large pictures. Larger pictures had more overestimation of size. Multiple images of successively larger portion sizes of a food on one computer screen facilitated quicker portion size responses with no decrease in accuracy. This is the method of choice for portion size estimation on a computer.

Road screening and distribution route multi-objective robust optimization for hazardous materials based on neural network and genetic algorithm.

PubMed

Ma, Changxi; Hao, Wei; Pan, Fuquan; Xiang, Wang

2018-01-01

Route optimization of hazardous materials transportation is one of the basic steps in ensuring the safety of hazardous materials transportation. The optimization scheme may be a security risk if road screening is not completed before the distribution route is optimized. For road screening issues of hazardous materials transportation, a road screening algorithm of hazardous materials transportation is built based on genetic algorithm and Levenberg-Marquardt neural network (GA-LM-NN) by analyzing 15 attributes data of each road network section. A multi-objective robust optimization model with adjustable robustness is constructed for the hazardous materials transportation problem of single distribution center to minimize transportation risk and time. A multi-objective genetic algorithm is designed to solve the problem according to the characteristics of the model. The algorithm uses an improved strategy to complete the selection operation, applies partial matching cross shift and single ortho swap methods to complete the crossover and mutation operation, and employs an exclusive method to construct Pareto optimal solutions. Studies show that the sets of hazardous materials transportation road can be found quickly through the proposed road screening algorithm based on GA-LM-NN, whereas the distribution route Pareto solutions with different levels of robustness can be found rapidly through the proposed multi-objective robust optimization model and algorithm.

Focused Screening of ECM-Selective Adhesion Peptides on Cellulose-Bound Peptide Microarrays.

PubMed

Kanie, Kei; Kondo, Yuto; Owaki, Junki; Ikeda, Yurika; Narita, Yuji; Kato, Ryuji; Honda, Hiroyuki

2016-11-19

The coating of surfaces with bio-functional proteins is a promising strategy for the creation of highly biocompatible medical implants. Bio-functional proteins from the extracellular matrix (ECM) provide effective surface functions for controlling cellular behavior. We have previously screened bio-functional tripeptides for feasibility of mass production with the aim of identifying those that are medically useful, such as cell-selective peptides. In this work, we focused on the screening of tripeptides that selectively accumulate collagen type IV (Col IV), an ECM protein that accelerates the re-endothelialization of medical implants. A SPOT peptide microarray was selected for screening owing to its unique cellulose membrane platform, which can mimic fibrous scaffolds used in regenerative medicine. However, since the library size on the SPOT microarray was limited, physicochemical clustering was used to provide broader variation than that of random peptide selection. Using the custom focused microarray of 500 selected peptides, we assayed the relative binding rates of tripeptides to Col IV, collagen type I (Col I), and albumin. We discovered a cluster of Col IV-selective adhesion peptides that exhibit bio-safety with endothelial cells. The results from this study can be used to improve the screening of regeneration-enhancing peptides.

Focused Screening of ECM-Selective Adhesion Peptides on Cellulose-Bound Peptide Microarrays

PubMed Central

Kanie, Kei; Kondo, Yuto; Owaki, Junki; Ikeda, Yurika; Narita, Yuji; Kato, Ryuji; Honda, Hiroyuki

2016-01-01

The coating of surfaces with bio-functional proteins is a promising strategy for the creation of highly biocompatible medical implants. Bio-functional proteins from the extracellular matrix (ECM) provide effective surface functions for controlling cellular behavior. We have previously screened bio-functional tripeptides for feasibility of mass production with the aim of identifying those that are medically useful, such as cell-selective peptides. In this work, we focused on the screening of tripeptides that selectively accumulate collagen type IV (Col IV), an ECM protein that accelerates the re-endothelialization of medical implants. A SPOT peptide microarray was selected for screening owing to its unique cellulose membrane platform, which can mimic fibrous scaffolds used in regenerative medicine. However, since the library size on the SPOT microarray was limited, physicochemical clustering was used to provide broader variation than that of random peptide selection. Using the custom focused microarray of 500 selected peptides, we assayed the relative binding rates of tripeptides to Col IV, collagen type I (Col I), and albumin. We discovered a cluster of Col IV-selective adhesion peptides that exhibit bio-safety with endothelial cells. The results from this study can be used to improve the screening of regeneration-enhancing peptides. PMID:28952593

Antimalarial drug discovery: screening of Brazilian medicinal plants and purified compounds.

PubMed

Krettli, Antoniana Ursine

2009-02-01

Malaria is the most important parasitic disease and its control depends on specific chemotherapy, now complicated by Plasmodium falciparum that has become resistant to most commonly available antimalarials. Treatment of the disease requires quinine or drug combinations of artemisinin derivatives and other antimalarials. Further drug resistance is expected. New active compounds need to be discovered. To find new antimalarials from medicinal and randomly collected plants, crude extracts are screened against P. falciparum in cultures and in malaria animal models, following bioassays of purified fractions, and cytotoxicity tests. For antimalarial research, screening medicinal plants is more efficient than screening randomly chosen plants. Biomonitored fractionation allows selection of new active molecules identified as potential antimalarials in multidisciplinary projects in Brazil; no new molecule is available for human testing. The advantages of projects based on ethnopharmacology are discussed.

NATURE OF BINDING INTERACTION OF SELECTED CHEMICALS WITH RAT ESTROGEN RECEPTORS

EPA Science Inventory

The US EPA is currently validating a rat uterine estrogen receptor (ER) binding assay as part of the Tier 1 Screening Battery for the Endocrine Disruptor Program. An eventual goal is to use interactive data to create computerized structure-activity models. However, more informati...

Development of a Sigma-2 Receptor affinity filter through a Monte Carlo based QSAR analysis.

PubMed

Rescifina, Antonio; Floresta, Giuseppe; Marrazzo, Agostino; Parenti, Carmela; Prezzavento, Orazio; Nastasi, Giovanni; Dichiara, Maria; Amata, Emanuele

2017-08-30

For the first time in sigma-2 (σ 2 ) receptor field, a quantitative structure-activity relationship (QSAR) model has been built using pK i values of the whole set of known selective σ 2 receptor ligands (548 compounds), taken from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) (http://www.researchdsf.unict.it/S2RSLDB/), through the Monte Carlo technique and employing the software CORAL. The model has been developed by using a large and structurally diverse set of compounds, allowing for a prediction of different populations of chemical compounds endpoint (σ 2 receptor pK i ). The statistical quality reached, suggested that model for pK i determination is robust and possesses a satisfactory predictive potential. The statistical quality is high for both visible and invisible sets. The screening of the FDA approved drugs, external to our dataset, suggested that sixteen compounds might be repositioned as σ 2 receptor ligands (predicted pK i ≥8). A literature check showed that six of these compounds have already been tested for affinity at σ 2 receptor and, of these, two (Flunarizine and Terbinafine) have shown an experimental σ 2 receptor pK i >7. This suggests that this QSAR model may be used as focusing screening filter in order to prospectively find or repurpose new drugs with high affinity for the σ 2 receptor, and overall allowing for an enhanced hit rate respect to a random screening. Copyright © 2017 Elsevier B.V. All rights reserved.

Rational Methods for the Selection of Diverse Screening Compounds

PubMed Central

Huggins, David J.; Venkitaraman, Ashok R.; Spring, David R.

2016-01-01

Traditionally a pursuit of large pharmaceutical companies, high-throughput screening assays are becoming increasingly common within academic and government laboratories. This shift has been instrumental in enabling projects that have not been commercially viable, such as chemical probe discovery and screening against high risk targets. Once an assay has been prepared and validated, it must be fed with screening compounds. Crafting a successful collection of small molecules for screening poses a significant challenge. An optimized collection will minimize false positives whilst maximizing hit rates of compounds that are amenable to lead generation and optimization. Without due consideration of the relevant protein targets and the downstream screening assays, compound filtering and selection can fail to explore the great extent of chemical diversity and eschew valuable novelty. Herein, we discuss the different factors to be considered and methods that may be employed when assembling a structurally diverse compound screening collection. Rational methods for selecting diverse chemical libraries are essential for their effective use in high-throughput screens. PMID:21261294

Screening Genetic Resources of Capsicum Peppers in Their Primary Center of Diversity in Bolivia and Peru.

PubMed

van Zonneveld, Maarten; Ramirez, Marleni; Williams, David E; Petz, Michael; Meckelmann, Sven; Avila, Teresa; Bejarano, Carlos; Ríos, Llermé; Peña, Karla; Jäger, Matthias; Libreros, Dimary; Amaya, Karen; Scheldeman, Xavier

2015-01-01

For most crops, like Capsicum, their diversity remains under-researched for traits of interest for food, nutrition and other purposes. A small investment in screening this diversity for a wide range of traits is likely to reveal many traditional varieties with distinguished values. One objective of this study was to demonstrate, with Capsicum as model crop, the application of indicators of phenotypic and geographic diversity as effective criteria for selecting promising genebank accessions for multiple uses from crop centers of diversity. A second objective was to evaluate the expression of biochemical and agromorphological properties of the selected Capsicum accessions in different conditions. Four steps were involved: 1) Develop the necessary diversity by expanding genebank collections in Bolivia and Peru; 2) Establish representative subsets of ~100 accessions for biochemical screening of Capsicum fruits; 3) Select promising accessions for different uses after screening; and 4) Examine how these promising accessions express biochemical and agromorphological properties when grown in different environmental conditions. The Peruvian Capsicum collection now contains 712 accessions encompassing all five domesticated species (C. annuum, C. chinense, C. frutescens, C. baccatum, and C. pubescens). The collection in Bolivia now contains 487 accessions, representing all five domesticates plus four wild taxa (C. baccatum var. baccatum, C. caballeroi, C. cardenasii, and C. eximium). Following the biochemical screening, 44 Bolivian and 39 Peruvian accessions were selected as promising, representing wide variation in levels of antioxidant capacity, capsaicinoids, fat, flavonoids, polyphenols, quercetins, tocopherols, and color. In Peru, 23 promising accessions performed well in different environments, while each of the promising Bolivian accessions only performed well in a certain environment. Differences in Capsicum diversity and local contexts led to distinct outcomes in each country. In Peru, mild landraces with high values in health-related attributes were of interest to entrepreneurs. In Bolivia, wild Capsicum have high commercial demand.

Screening Genetic Resources of Capsicum Peppers in Their Primary Center of Diversity in Bolivia and Peru

PubMed Central

van Zonneveld, Maarten; Ramirez, Marleni; Williams, David E.; Petz, Michael; Meckelmann, Sven; Avila, Teresa; Bejarano, Carlos; Peña, Karla; Jäger, Matthias; Libreros, Dimary; Amaya, Karen; Scheldeman, Xavier

2015-01-01

For most crops, like Capsicum, their diversity remains under-researched for traits of interest for food, nutrition and other purposes. A small investment in screening this diversity for a wide range of traits is likely to reveal many traditional varieties with distinguished values. One objective of this study was to demonstrate, with Capsicum as model crop, the application of indicators of phenotypic and geographic diversity as effective criteria for selecting promising genebank accessions for multiple uses from crop centers of diversity. A second objective was to evaluate the expression of biochemical and agromorphological properties of the selected Capsicum accessions in different conditions. Four steps were involved: 1) Develop the necessary diversity by expanding genebank collections in Bolivia and Peru; 2) Establish representative subsets of ~100 accessions for biochemical screening of Capsicum fruits; 3) Select promising accessions for different uses after screening; and 4) Examine how these promising accessions express biochemical and agromorphological properties when grown in different environmental conditions. The Peruvian Capsicum collection now contains 712 accessions encompassing all five domesticated species (C. annuum, C. chinense, C. frutescens, C. baccatum, and C. pubescens). The collection in Bolivia now contains 487 accessions, representing all five domesticates plus four wild taxa (C. baccatum var. baccatum, C. caballeroi, C. cardenasii, and C. eximium). Following the biochemical screening, 44 Bolivian and 39 Peruvian accessions were selected as promising, representing wide variation in levels of antioxidant capacity, capsaicinoids, fat, flavonoids, polyphenols, quercetins, tocopherols, and color. In Peru, 23 promising accessions performed well in different environments, while each of the promising Bolivian accessions only performed well in a certain environment. Differences in Capsicum diversity and local contexts led to distinct outcomes in each country. In Peru, mild landraces with high values in health-related attributes were of interest to entrepreneurs. In Bolivia, wild Capsicum have high commercial demand. PMID:26402618

Human Systems Integration Design Environment (HSIDE)

DTIC Science & Technology

2012-04-09

quality of the resulting HSI products. 15. SUBJECT TERMS HSI , Manning Estimation and Validation , Risk Assessment, I POE, PLM, BPMN , Workflow...business process model in Business Process Modeling Notation ( BPMN ) or the actual workflow template associated with the specific functional area, again...as filtered by the user settings in the high level interface. Figure 3 shows the initial screen which allows the user to select either the BPMN or

Electrophysiological characterization of 14-benzoyltalatisamine, a selective blocker of the delayed rectifier K+ channel found in virtual screening.

PubMed

Song, Ming-Ke; Liu, Hong; Jiang, Hua-Liang; Yue, Jian-Min; Hu, Guo-Yuan

2006-02-15

14-Benzoyltalatisamine is a potent and selective blocker of the delayed rectifier K+ channel found in a computational virtual screening study. The compound was found to block the K+ channel from the extracellular side. However, it is unclear whether 14-benzoyltalatisamine shares the same block mechanism with tetraethylammonium (TEA). In order to elucidate how the hit compound found by the virtual screening interacts with the outer vestibule of the K+ channel, the effects of 14-benzoyltalatisamine and TEA on the delayed rectifier K+ current of rat dissociated hippocampal neurons were compared using whole-cell voltage-clamp recording. External application of 14-benzoyltalatisamine and TEA reversibly inhibited the current with IC50 values of 10.1+/-2.2 microM and 1.05+/-0.21 mM, respectively. 14-Benzoyltalatisamine exerted voltage-dependent inhibition, markedly accelerated the decay of the current, and caused a significant hyperpolarizing shift of the steady-state activation curve, whereas TEA caused voltage-independent inhibition, without affecting the kinetic parameters of the current. The blockade by 14-benzoyltalatisamine, but not by TEA, was significantly diminished in a high K+ (60 mM) external solution. The potency of 14-benzoyltalatisamine was markedly reduced in the presence of 15 mM TEA. The results suggest that 14-benzoyltalatisamine bind to the external pore entry of the delayed rectifier K+ channel with partial insertion into the selectivity filter, which is in conformity with that predicted by the molecular docking model in the virtual screening.

Withdrawing low risk women from cervical screening programmes: mathematical modelling study.

PubMed

Sherlaw-Johnson, C; Gallivan, S; Jenkins, D

1999-02-06

To evaluate the impact of policies for removing women before the recommended age of 64 from screening programmes for cervical cancer in the United Kingdom. A mathematical model of the clinical course of precancerous lesions which accounts for the influence of infection with the human papillomavirus, the effects of screening on the progression of disease, and the accuracy of the testing procedures. Two policies are compared: one in which women are withdrawn from the programme if their current smear is negative and they have a recent history of regular, negative results and one in which women are withdrawn if their current smear test is negative and a simultaneous test is negative for exposure to high risk types of human papillomavirus. United Kingdom cervical screening programme. The incidence of invasive cervical cancer and the use of resources. Early withdrawal of selected women from the programme is predicted to give rise to resource savings of up to 25% for smear tests and 18% for colposcopies when withdrawal occurs from age 50, the youngest age considered in the study. An increase in the incidence of invasive cervical cancer, by up to 2 cases/100 000 women each year is predicted. Testing for human papillomavirus infection to determine which women should be withdrawn from the programme makes little difference to outcome. This model systematically analyses the consequences of screening options using available data and the clinical course of precancerous lesions. If further audit studies confirm the model's forecasts, a policy of early withdrawal might be considered. This would be likely to release substantial resources which could be channelled into other aspects of health care or may be more effectively used within the cervical screening programme to counteract the possible increase in cancer incidence that early withdrawal might bring.

Comparative Normal/Failing Rat Myocardium Cell Membrane Chromatographic Analysis System for Screening Specific Components That Counteract Doxorubicin-Induced Heart Failure from Acontium carmichaeli

PubMed Central

2015-01-01

Cell membrane chromatography (CMC) derived from pathological tissues is ideal for screening specific components acting on specific diseases from complex medicines owing to the maximum simulation of in vivo drug-receptor interactions. However, there are no pathological tissue-derived CMC models that have ever been developed, as well as no visualized affinity comparison of potential active components between normal and pathological CMC columns. In this study, a novel comparative normal/failing rat myocardium CMC analysis system based on online column selection and comprehensive two-dimensional (2D) chromatography/monolithic column/time-of-flight mass spectrometry was developed for parallel comparison of the chromatographic behaviors on both normal and pathological CMC columns, as well as rapid screening of the specific therapeutic agents that counteract doxorubicin (DOX)-induced heart failure from Acontium carmichaeli (Fuzi). In total, 16 potential active alkaloid components with similar structures in Fuzi were retained on both normal and failing myocardium CMC models. Most of them had obvious decreases of affinities on failing myocardium CMC compared with normal CMC model except for four components, talatizamine (TALA), 14-acetyl-TALA, hetisine, and 14-benzoylneoline. One compound TALA with the highest affinity was isolated for further in vitro pharmacodynamic validation and target identification to validate the screen results. Voltage-dependent K+ channel was confirmed as a binding target of TALA and 14-acetyl-TALA with high affinities. The online high throughput comparative CMC analysis method is suitable for screening specific active components from herbal medicines by increasing the specificity of screened results and can also be applied to other biological chromatography models. PMID:24731167

Selection, application, and validation of a set of molecular descriptors for nuclear receptor ligands.

PubMed

Stewart, Eugene L; Brown, Peter J; Bentley, James A; Willson, Timothy M

2004-08-01

A methodology for the selection and validation of nuclear receptor ligand chemical descriptors is described. After descriptors for a targeted chemical space were selected, a virtual screening methodology utilizing this space was formulated for the identification of potential NR ligands from our corporate collection. Using simple descriptors and our virtual screening method, we are able to quickly identify potential NR ligands from a large collection of compounds. As validation of the virtual screening procedure, an 8, 000-membered NR targeted set and a 24, 000-membered diverse control set of compounds were selected from our in-house general screening collection and screened in parallel across a number of orphan NR FRET assays. For the two assays that provided at least one hit per set by the established minimum pEC(50) for activity, the results showed a 2-fold increase in the hit-rate of the targeted compound set over the diverse set.

Hospital evaluation of health literacy and associated outcomes in patients after acute myocardial infarction.

PubMed

Rymer, Jennifer A; Kaltenbach, Lisa A; Anstrom, Kevin J; Fonarow, Gregg C; Erskine, Nathaniel; Peterson, Eric D; Wang, Tracy Y

2018-04-01

Low health literacy is common in the United States and may affect outcomes after myocardial infarction (MI). How often hospitals screen for low health literacy is unknown. We surveyed 122 hospitals in the TRANSLATE-ACS study and divided them into those that reported routinely (>75% of patients), selectively (1%-75%), or never (0%) screening MI patients for low health literacy prior to discharge. We performed logistic regression with random intercepts to compare 6-week and 6-month patient-reported medication adherence and multivariable Cox regression to compare 1-year major adverse cardiovascular events and all-cause readmission risks between hospital groups. Overall, 25 (20.5%), 47 (38.5%), and 50 (41.0%) hospitals reported routinely, selectively, or never screening patients for low health literacy, respectively. Patients discharged from hospitals that routinely screened were more likely to report 6-week medication adherence [routinely: adjusted odds ratio (OR) 1.26, 95% CI 1.01-1.57; selectively: adjusted OR 1.19, 95% CI 1.00-1.43, both referenced to those discharged from hospitals that never screened]. Compared with hospitals that never screened health literacy, 1-year major adverse cardiovascular events were similar for hospitals that reported routinely screening (adjusted HR 0.92, 95% CI 0.75-1.14) or selectively screening (adjusted HR 1.01, 95% CI 0.84-1.21). Hospitals that reported selectively screening health literacy were associated with a lower adjusted risk of 1-year all-cause readmission (adjusted HR 0.89, 95% CI 0.79-1.00, P=.041). Only a minority of US hospitals routinely screen MI patients for low health literacy. Hospital screening was associated with higher medication adherence and lower readmission risk. Further investigation is needed to understand how inpatient screening can be implemented to improve longitudinal post-MI care. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation

PubMed Central

Szelag, Malgorzata; Czerwoniec, Anna; Wesoly, Joanna; Bluyssen, Hans A. R.

2015-01-01

Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the ‘STAT-comparative binding affinity value’ and ‘ligand binding pose variation’ as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our understanding of the functional role of these STATs in different diseases and benefit the clinical need for more drugable STAT inhibitors with high specificity, potency and excellent bioavailability. PMID:25710482

ILP-2 modeling and virtual screening of an FDA-approved library:a possible anticancer therapy.

PubMed

Khalili, Saeed; Mohammadpour, Hemn; Shokrollahi Barough, Mahideh; Kokhaei, Parviz

2016-06-23

The members of the inhibitors of apoptosis protein (IAP) family inhibit diverse components of the caspase signaling pathway, notably caspase 3, 7, and 9. ILP-2 (BIRC-8) is the most recently identified member of the IAPs, mainly interacting with caspase 9. This interaction would eventually lead to death resistance in the case of cancerous cells. Therefore, structural modeling of ILP-2 and finding applicable inhibitors of its interaction with caspase 9 are a compelling challenge. Three main protein modeling approaches along with various model refinement measures were harnessed to achieve a reliable 3D model, using state-of-the-art software. Thereafter, the selected model was employed to perform virtual screening of an FDA approved library. A model built by a combinatorial approach (homology and ab initio approaches) was chosen as the best model. Model refinement processes successfully bolstered the model quality. Virtual screening of the compound library introduced several high affinity inhibitor candidates that interact with functional residues of ILP2. Given the 3D structure of the ILP2 molecule, we found promising inhibitory molecules. In addition to high affinity towards the ILP2 molecule, these molecules interact with residues that play pivotal rules in ILP2-caspase interaction. These molecules would inhibit ILP2-caspase interaction and consequently would lead to reactivated cell apoptosis through the caspases pathway.

Model tracking system for low-level radioactive waste disposal facilities: License application interrogatories and responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benbennick, M.E.; Broton, M.S.; Fuoto, J.S.

This report describes a model tracking system for a low-level radioactive waste (LLW) disposal facility license application. In particular, the model tracks interrogatories (questions, requests for information, comments) and responses. A set of requirements and desired features for the model tracking system was developed, including required structure and computer screens. Nine tracking systems were then reviewed against the model system requirements and only two were found to meet all requirements. Using Kepner-Tregoe decision analysis, a model tracking system was selected.

High throughput selection of novel plant growth regulators: Assessing the translatability of small bioactive molecules from Arabidopsis to crops.

PubMed

Rodriguez-Furlán, Cecilia; Miranda, Giovanna; Reggiardo, Martín; Hicks, Glenn R; Norambuena, Lorena

2016-04-01

Plant growth regulators (PGRs) have become an integral part of agricultural and horticultural practices. Accordingly, there is an increased demand for new and cost-effective products. Nevertheless, the market is limited by insufficient innovation. In this context chemical genomics has gained increasing attention as a powerful approach addressing specific traits. Here is described the successful implementation of a highly specific, sensitive and efficient high throughput screening approach using Arabidopsis as a model. Using a combination of techniques, 10,000 diverse compounds were screened and evaluated for several important plant growth traits including root and leaf growth. The phenotype-based selection allowed the compilation of a collection of putative Arabidopsis growth regulators with a broad range of activities and specificities. A subset was selected for evaluating their bioactivity in agronomically valuable plants. Their validation as growth regulators in commercial species such as tomato, lettuce, carrot, maize and turfgrasses reinforced the success of the screening in Arabidopsis and indicated that small molecules activity can be efficiently translated to commercial species. Therefore, the chemical genomics approach in Arabidopsis is a promising field that can be incorporated in PGR discovery programs and has a great potential to develop new products that can be efficiently used in crops. Copyright © 2016. Published by Elsevier Ireland Ltd.

MicroRNAs derived from circulating exosomes as non-invasive biomarkers for screening and diagnose lung cancer

PubMed Central

Cazzoli, Riccardo; Buttitta, Fiamma; Di Nicola, Marta; Malatesta, Sara; Marchetti, Antonio; Pass, Harvey I.

2013-01-01

Introduction Lung cancer is formerly the highest cause of mortality among tumor pathologies worldwide. There are no validated techniques for an early detection of pulmonary cancer lesions other than low-dose helical CT-scan. Unfortunately, this method have some downside effects. Recent studies have laid the basis for development of exosomes-based techniques to screen/diagnose lung cancers. As the isolation of circulating exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostic applications. Methods We used a first set of 30 plasma samples from as many patients, including 10 patients affected by Lung Adenocarcinomas, 10 with Lung Granulomas and 10 healthy smokers matched for age and sex as negative controls. Wide range microRNAs analysis (742 microRNAs) was performed by quantitative RT-PCR. Data were compared by lesion characteristics using WEKA software for statistics and modeling. Subsequently, selected microRNAs were evaluated on an independent larger group of samples (105 specimens: 50 Lung Adenocarcinomas, 30 Lung Granulomas and 25 healthy smokers). Results This analysis led to the selection of 4 microRNAs to perform a screening test (miR-378a, miR-379, miR-139-5p and miR-200b-5p), useful to divide population into 2 groups: nodule (lung adenocarcinomas+carcinomas) and non-nodule (healthy former smokers). Six microRNAs (miR-151a-5p, miR-30a-3p, miR-200b-5p, miR-629, miR-100 and miR-154-3p) were selected for a second test on the “nodule” population to discriminate between lung adenocarcinoma and granuloma. Conclusions “Screening test” has shown 97.5% sensitivity, 72.0% specificity, AUC ROC of 90.8%. “Diagnostic test” had 96.0% sensitivity, 60.0% specificity, AUC ROC of 76.0%. Further evaluation is needed to confirm the predictive power of those models on higher cohorts of samples. PMID:23945385

Trade-offs between enzyme fitness and solubility illuminated by deep mutational scanning

PubMed Central

Bacik, John-Paul; Wrenbeck, Emily E.; Michalczyk, Ryszard; Whitehead, Timothy A.

2017-01-01

Proteins are marginally stable, and an understanding of the sequence determinants for improved protein solubility is highly desired. For enzymes, it is well known that many mutations that increase protein solubility decrease catalytic activity. These competing effects frustrate efforts to design and engineer stable, active enzymes without laborious high-throughput activity screens. To address the trade-off between enzyme solubility and activity, we performed deep mutational scanning using two different screens/selections that purport to gauge protein solubility for two full-length enzymes. We assayed a TEM-1 beta-lactamase variant and levoglucosan kinase (LGK) using yeast surface display (YSD) screening and a twin-arginine translocation pathway selection. We then compared these scans with published experimental fitness landscapes. Results from the YSD screen could explain 37% of the variance in the fitness landscapes for one enzyme. Five percent to 10% of all single missense mutations improve solubility, matching theoretical predictions of global protein stability. For a given solubility-enhancing mutation, the probability that it would retain wild-type fitness was correlated with evolutionary conservation and distance to active site, and anticorrelated with contact number. Hybrid classification models were developed that could predict solubility-enhancing mutations that maintain wild-type fitness with an accuracy of 90%. The downside of using such classification models is the removal of rare mutations that improve both fitness and solubility. To reveal the biophysical basis of enhanced protein solubility and function, we determined the crystallographic structure of one such LGK mutant. Beyond fundamental insights into trade-offs between stability and activity, these results have potential biotechnological applications. PMID:28196882

Microbicide safety/efficacy studies in animals: macaques and small animal models.

PubMed

Veazey, Ronald S

2008-09-01

A number of microbicide candidates have failed to prevent HIV transmission in human clinical trials, and there is uncertainty as to how many additional trials can be supported by the field. Regardless, there are far too many microbicide candidates in development, and a logical and consistent method for screening and selecting candidates for human clinical trials is desperately needed. The unique host and cell specificity of HIV, however, provides challenges for microbicide safety and efficacy screening, that can only be addressed by rigorous testing in relevant laboratory animal models. A number of laboratory animal model systems ranging from rodents to nonhuman primates, and single versus multiple dose challenges have recently been developed to test microbicide candidates. These models have shed light on both the safety and efficacy of candidate microbicides as well as the early mechanisms involved in transmission. This article summarizes the major advantages and disadvantages of the relevant animal models for microbicide safety and efficacy testing. Currently, nonhuman primates are the only relevant and effective laboratory model for screening microbicide candidates. Given the consistent failures of prior strategies, it is now clear that rigorous safety and efficacy testing in nonhuman primates should be a prerequisite for advancing additional microbicide candidates to human clinical trials.

Microbicide Safety/Efficacy studies in animals -macaques and small animal models

PubMed Central

Veazey, Ronald S.

2009-01-01

Purpose of review A number of microbicide candidates have failed to prevent HIV transmission in human clinical trials, and there is uncertainty as to how many additional trials can be supported by the field. Regardless, there are far too many microbicide candidates in development, and a logical and consistent method for screening and selecting candidates for human clinical trials is desperately needed. However, the unique host and cell specificity of HIV provides challenges for microbicide safety and efficacy screening, that can only be addressed by rigorous testing in relevant laboratory animal models. Recent findings A number of laboratory animal model systems ranging from rodents to nonhuman primates, and single versus multiple dose challenges have recently been developed to test microbicide candidates. These models have shed light on both the safety and efficacy of candidate microbicides as well as the early mechanisms involved in transmission. This article summarizes the major advantages and disadvantages of the relevant animal models for microbicide safety and efficacy testing. Summary Currently, nonhuman primates are the only relevant and effective laboratory model for screening microbicide candidates. Given the consistent failures of prior strategies, it is now clear that rigorous safety and efficacy testing in nonhuman primates should be a pre-requisite for advancing additional microbicide candidates to human clinical trials. PMID:19373023

Pharmacophore Models and Pharmacophore-Based Virtual Screening: Concepts and Applications Exemplified on Hydroxysteroid Dehydrogenases.

PubMed

Kaserer, Teresa; Beck, Katharina R; Akram, Muhammad; Odermatt, Alex; Schuster, Daniela

2015-12-19

Computational methods are well-established tools in the drug discovery process and can be employed for a variety of tasks. Common applications include lead identification and scaffold hopping, as well as lead optimization by structure-activity relationship analysis and selectivity profiling. In addition, compound-target interactions associated with potentially harmful effects can be identified and investigated. This review focuses on pharmacophore-based virtual screening campaigns specifically addressing the target class of hydroxysteroid dehydrogenases. Many members of this enzyme family are associated with specific pathological conditions, and pharmacological modulation of their activity may represent promising therapeutic strategies. On the other hand, unintended interference with their biological functions, e.g., upon inhibition by xenobiotics, can disrupt steroid hormone-mediated effects, thereby contributing to the development and progression of major diseases. Besides a general introduction to pharmacophore modeling and pharmacophore-based virtual screening, exemplary case studies from the field of short-chain dehydrogenase/reductase (SDR) research are presented. These success stories highlight the suitability of pharmacophore modeling for the various application fields and suggest its application also in futures studies.

Establishment of apoptotic regulatory network for genetic markers of colorectal cancer and optimal selection of traditional Chinese medicine target.

PubMed

Tian, Tongde; Chen, Chuanliang; Yang, Feng; Tang, Jingwen; Pei, Junwen; Shi, Bian; Zhang, Ning; Zhang, Jianhua

2017-03-01

The paper aimed to screen out genetic markers applicable to early diagnosis for colorectal cancer and establish apoptotic regulatory network model for colorectal cancer, and to analyze the current situation of traditional Chinese medicine (TCM) target, thereby providing theoretical evidence for early diagnosis and targeted therapy of colorectal cancer. Taking databases including CNKI, VIP, Wanfang data, Pub Med, and MEDLINE as main sources of literature retrieval, literatures associated with genetic markers that are applied to early diagnosis of colorectal cancer were searched and performed comprehensive and quantitative analysis by Meta analysis, hence screening genetic markers used in early diagnosis of colorectal cancer. KEGG analysis was employed to establish apoptotic regulatory network model based on screened genetic markers, and optimization was conducted on TCM targets. Through Meta analysis, seven genetic markers were screened out, including WWOX, K-ras, COX-2, P53, APC, DCC and PTEN, among which DCC has the highest diagnostic efficiency. Apoptotic regulatory network was built by KEGG analysis. Currently, it was reported that TCM has regulatory function on gene locus in apoptotic regulatory network. The apoptotic regulatory model of colorectal cancer established in this study provides theoretical evidence for early diagnosis and TCM targeted therapy of colorectal cancer in clinic.

Cost-effectiveness of the screening of blood donations for hepatitis E virus in the Netherlands.

PubMed

de Vos, Anneke S; Janssen, Mart P; Zaaijer, Hans L; Hogema, Boris M

2017-02-01

The incidence of hepatitis E virus (HEV) has increased substantially in Europe recently, thereby threatening blood safety. A cost-effectiveness analysis for HEV screening of blood donations in the Netherlands was performed. A simulation model was developed to mimic the process of donation, infections in the donor population, donation testing, and transmission to transfusion recipients. The variability of viral loads among donors was modeled using observed loads. The number of (incurable) chronic HEV infections among organ and stem cell transplant patients and the costs avoided by implementing blood screening were estimated. HEV screening of whole blood donations in pools of 24 would prevent 4.52 of the 4.94 transfusion-associated chronic HEV infections expected annually, at approximately €310,000 per prevented chronic case. Per case not curable by ribavirin prevention, costs are approximately 10 times higher. Selective screening, if logistically feasible, could reduce screening costs by 85%. Sensitivity analyses show that uncertainty in the HEV transmissibility and the frequency of HEV clearing greatly impact the estimated cost-effectiveness. Of all HEV infections nationwide one in 700 is estimated to be due to blood transfusion, while for chronic infections this is one in 3.5. Despite uncertainties in our estimates, preventing HEV transmission by screening of blood donations appears not excessively expensive compared to other blood-screening measures in the Netherlands. However, the impact on HEV disease burden may be relatively small as only a minority of all HEV cases is transmitted by blood transfusion. © 2017 AABB.

A sensitive electrochemical immunosensor based on poly(2-aminobenzylamine) film modified screen-printed carbon electrode for label-free detection of human immunoglobulin G.

PubMed

Putnin, Thitirat; Jumpathong, Watthanachai; Laocharoensuk, Rawiwan; Jakmunee, Jaroon; Ounnunkad, Kontad

2018-08-01

This work focuses on fabricating poly(2-aminobenzylamine)-modified screen-printed carbon electrode as an electrochemical immunosensor for the label-free detection of human immunoglobulin G. To selectively detect immunoglobulin G, the anti-immunoglobulin G antibody with high affinity to immunoglobulin G was covalently linked with the amine group of poly(2-aminobenzylamine) film-deposited screen-printed carbon electrode. The selectivity for immunoglobulin G was subsequently assured by being challenged with redox-active interferences and adventitious adsorption did not significantly interfere the analyte signal. To obviate the use of costly secondary antibody, the [Fe(CN) 6 ] 4-/3- redox probe was instead applied to measure the number of human immunoglobulin G through the immunocomplex formation that is quantitatively related to the level of the differential pulse voltammetric current. The resulting immunosensor exhibited good sensitivity with the detection limit of 0.15 ng mL -1 , limit of quantitation of 0.50 ng mL -1 and the linear range from 1.0 to 50 ng mL -1 . Given those striking analytical performances and the affordability arising from using cheap screen-printed carbon electrode with label-free detection, the immunosensor serves as a promising model for the next-step development of a diagnostic tool.

Incorporating thyroid markers in Down syndrome screening protocols.

PubMed

Dhaifalah, Ishraq; Salek, Tomas; Langova, Dagmar; Cuckle, Howard

2017-05-01

The article aimed to assess the benefit of incorporating maternal serum thyroid disease marker levels (thyroid-stimulating hormone and free thyroxine) into first trimester Down syndrome screening protocols. Statistical modelling was used to predict performance with and without the thyroid markers. Two protocols were considered: the combined test and the contingent cell-free DNA (cfDNA) test, where 15-40% women are selected for cfDNA because of increased risk based on combined test results. Published parameters were used for the combined test, cfDNA and the Down syndrome means for thyroid-stimulating hormone and free thyroxine; other parameters were derived from a series of 5230 women screened for both thyroid disease and Down syndrome. Combined test: For a fixed 85% detection rate, the predicted false positive rate was reduced from 5.3% to 3.6% with the addition of the thyroid markers. Contingent cfDNA test: For a fixed 95% detection rate, the proportion of women selected for cfDNA was reduced from 25.6% to 20.2%. When screening simultaneously for maternal thyroid disease and Down syndrome, thyroid marker levels should be used in the calculation of Down syndrome risk. The benefit is modest but can be achieved with no additional cost. © 2017 John Wiley & Sons, Ltd. © 2017 John Wiley & Sons, Ltd.

Cost-effectiveness analysis of colorectal cancer screening methods in Iran.

PubMed

Allameh, Zahra; Davari, Majid; Emami, Mohammad Hasan

2011-03-01

Screening can prevent colorectal cancer from becoming advanced by early detection of precancerous lesions. Cost-effectiveness analysis of colorectal cancer screening methods is highly necessary due to increased prevalence, decreased age at onset and the limited budget in Iran. Methods of screening currently available in Iran were selected. A systematic search revealed the sensitivity and specificity of each method. For this study, a model for a 20 year screening period of a population of 100,000 apparently healthy persons of ages 45-65 years in Isfahan Province was used. The cost-effectiveness of each method and the ratio of cost-effectiveness were calculated based on this model. The most and the least effective methods were CT colonography and fecal occult blood test, respectively. The highest and lowest expenditures in the governmental sector were related to fecal occult blood test and flexible sigmoidoscopy and in the private sector, to CT colonography and fecal occult blood test, respectively. The cost per cancer detected in 20 years of screening in the governmental sector was 0.28, 0.22 and 0.42 billion Rials, respectively for screening by colonoscopy, flexible sigmoidoscopy and fecal occult blood test. In the private sector, these were 1.54 (colonoscopy), 1.68 (flexible sigmoidoscopy), and 1.60 (fecal occult blood test) billion and 2.58 billion Rials for CT colonography, respectively. Although CT colonography is the most effective method, it needs a budget of 2.58 billion Rials for each screened patient. If costs in the governmental sector are considered, flexible sigmoidoscopy would be the most cost-effective method for screening the 45 - 65-year-old population in Iran.

Binary classification of aqueous solubility using support vector machines with reduction and recombination feature selection.

PubMed

Cheng, Tiejun; Li, Qingliang; Wang, Yanli; Bryant, Stephen H

2011-02-28

Aqueous solubility is recognized as a critical parameter in both the early- and late-stage drug discovery. Therefore, in silico modeling of solubility has attracted extensive interests in recent years. Most previous studies have been limited in using relatively small data sets with limited diversity, which in turn limits the predictability of derived models. In this work, we present a support vector machines model for the binary classification of solubility by taking advantage of the largest known public data set that contains over 46 000 compounds with experimental solubility. Our model was optimized in combination with a reduction and recombination feature selection strategy. The best model demonstrated robust performance in both cross-validation and prediction of two independent test sets, indicating it could be a practical tool to select soluble compounds for screening, purchasing, and synthesizing. Moreover, our work may be used for comparative evaluation of solubility classification studies ascribe to the use of completely public resources.

Predictions of BuChE inhibitors using support vector machine and naive Bayesian classification techniques in drug discovery.

PubMed

Fang, Jiansong; Yang, Ranyao; Gao, Li; Zhou, Dan; Yang, Shengqian; Liu, Ai-Lin; Du, Guan-hua

2013-11-25

Butyrylcholinesterase (BuChE, EC 3.1.1.8) is an important pharmacological target for Alzheimer's disease (AD) treatment. However, the currently available BuChE inhibitor screening assays are expensive, labor-intensive, and compound-dependent. It is necessary to develop robust in silico methods to predict the activities of BuChE inhibitors for the lead identification. In this investigation, support vector machine (SVM) models and naive Bayesian models were built to discriminate BuChE inhibitors (BuChEIs) from the noninhibitors. Each molecule was initially represented in 1870 structural descriptors (1235 from ADRIANA.Code, 334 from MOE, and 301 from Discovery studio). Correlation analysis and stepwise variable selection method were applied to figure out activity-related descriptors for prediction models. Additionally, structural fingerprint descriptors were added to improve the predictive ability of models, which were measured by cross-validation, a test set validation with 1001 compounds and an external test set validation with 317 diverse chemicals. The best two models gave Matthews correlation coefficient of 0.9551 and 0.9550 for the test set and 0.9132 and 0.9221 for the external test set. To demonstrate the practical applicability of the models in virtual screening, we screened an in-house data set with 3601 compounds, and 30 compounds were selected for further bioactivity assay. The assay results showed that 10 out of 30 compounds exerted significant BuChE inhibitory activities with IC50 values ranging from 0.32 to 22.22 μM, at which three new scaffolds as BuChE inhibitors were identified for the first time. To our best knowledge, this is the first report on BuChE inhibitors using machine learning approaches. The models generated from SVM and naive Bayesian approaches successfully predicted BuChE inhibitors. The study proved the feasibility of a new method for predicting bioactivities of ligands and discovering novel lead compounds.

Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.

PubMed

Germain, Andrew R; Carmody, Leigh C; Nag, Partha P; Morgan, Barbara; Verplank, Lynn; Fernandez, Cristina; Donckele, Etienne; Feng, Yuxiong; Perez, Jose R; Dandapani, Sivaraman; Palmer, Michelle; Lander, Eric S; Gupta, Piyush B; Schreiber, Stuart L; Munoz, Benito

2013-03-15

A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations. Copyright © 2013. Published by Elsevier Ltd.

Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Graham F.; Altman, Michael D.; Andresen, Brian

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

Review of a two-year methicillin-resistant Staphylococcus aureus screening program and cost-effectiveness analysis in Singapore.

PubMed

Win, Mar-Kyaw; Soliman, Tarek Abdellatif Aly; Lee, Linda Kay; Wong, Chia Siong; Chow, Angela; Ang, Brenda; Roman, Carrasco L; Leo, Yee-Sin

2015-09-29

Methicillin-resistant Staphylococcus aureus (MRSA) poses an increasingly large disease and economic burden worldwide. The effectiveness of screening programs in the tropics is poorly understood. The aims of this study are: (i) to analyze the factors affecting MRSA colonization at admission and acquisition during hospitalization and (ii) to evaluate the cost-effectiveness of a screening program which aims to control MRSA incidence during hospitalization. We conducted a retrospective case-control study of patients admitted to the Communicable Disease Centre (CDC) in Singapore between Jan 2009 and Dec 2010 when there was an ongoing selective screening and isolation program. Risk factors contributing to MRSA colonization on admission and acquisition during hospital stay were evaluated using a logistic regression model. In addition, a cost-effectiveness analysis was conducted to determine the cost per disability-adjusted life year (DALY) averted due to implementing the screening and isolation program. The average prevalence rate of screened patients at admission and the average acquisition rate at discharge during the study period were 12.1 and 4.8 % respectively. Logistic regression models showed that older age (adjusted odds ratio (OR) 1.03, 95 % CI 1.02-1.04, p < 0.001) and dermatological conditions (adjusted OR 1.49, 95 % CI 1.11-1.20, p = 0.008) were independently associated with an increased risk of MRSA colonization at admission. Age (adjusted OR 1.02, 95 % CI 1.01-1.03, p = 0.002) and length of stay in hospital (adjusted OR 1.04, 95 % CI 1.03-1.06, p < 0.001) were independent factors associated with MRSA acquisition during hospitalization. The screening and isolation program reduced the acquisition rate by 1.6 % and was found to be cost saving. For the whole study period, the program cost US$129,916, while it offset hospitalization costs of US$103,869 and loss of productivity costs of US$50,453 with -400 $/DALY averted. This study is the first to our knowledge that evaluates the cost-effectiveness of screening and isolation of MRSA patients in a tropical country. Another unique feature of the analysis is the evaluation of acquisition rates among specific types of patients (dermatological, HIV and infectious disease patients)and the comparison of the cost-effectiveness of screening and isolation between them. Overall our results indicate high MRSA prevalence that can be cost effectively reduced by selective screening and isolation programs in Singapore.

Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery.

PubMed

Macrae, Calum A

2010-07-01

IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. AREAS COVERED IN THIS REVIEW: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. WHAT THE READER WILL GAIN: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. TAKE HOME MESSAGE: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease biology, but emphasizes the importance of the rigor of the disease model.

Improving compliance to colorectal cancer screening using blood and stool based tests in patients refusing screening colonoscopy in Germany.

PubMed

Adler, Andreas; Geiger, Sebastian; Keil, Anne; Bias, Harald; Schatz, Philipp; deVos, Theo; Dhein, Jens; Zimmermann, Mathias; Tauber, Rudolf; Wiedenmann, Bertram

2014-10-17

Despite strong recommendations for colorectal cancer (CRC) screening, participation rates are low. Understanding factors that affect screening choices is essential to developing future screening strategies. Therefore, this study assessed patient willingness to use non-invasive stool or blood based screening tests after refusing colonoscopy. Participants were recruited during regular consultations. Demographic, health, psychological and socioeconomic factors were recorded. All subjects were advised to undergo screening by colonoscopy. Subjects who refused colonoscopy were offered a choice of non-invasive tests. Subjects who selected stool testing received a collection kit and instructions; subjects who selected plasma testing had a blood draw during the office visit. Stool samples were tested with the Hb/Hp Complex Elisa test, and blood samples were tested with the Epi proColon® 2.0 test. Patients who were positive for either were advised to have a diagnostic colonoscopy. 63 of 172 subjects were compliant to screening colonoscopy (37%). 106 of the 109 subjects who refused colonoscopy accepted an alternative non-invasive method (97%). 90 selected the Septin9 blood test (83%), 16 selected a stool test (15%) and 3 refused any test (3%). Reasons for blood test preference included convenience of an office draw, overall convenience and less time consuming procedure. 97% of subjects refusing colonoscopy accepted a non-invasive screening test of which 83% chose the Septin9 blood test. The observation that participation can be increased by offering non-invasive tests, and that a blood test is the preferred option should be validated in a prospective trial in the screening setting.

A Solution to Separation and Multicollinearity in Multiple Logistic Regression

PubMed Central

Shen, Jianzhao; Gao, Sujuan

2010-01-01

In dementia screening tests, item selection for shortening an existing screening test can be achieved using multiple logistic regression. However, maximum likelihood estimates for such logistic regression models often experience serious bias or even non-existence because of separation and multicollinearity problems resulting from a large number of highly correlated items. Firth (1993, Biometrika, 80(1), 27–38) proposed a penalized likelihood estimator for generalized linear models and it was shown to reduce bias and the non-existence problems. The ridge regression has been used in logistic regression to stabilize the estimates in cases of multicollinearity. However, neither solves the problems for each other. In this paper, we propose a double penalized maximum likelihood estimator combining Firth’s penalized likelihood equation with a ridge parameter. We present a simulation study evaluating the empirical performance of the double penalized likelihood estimator in small to moderate sample sizes. We demonstrate the proposed approach using a current screening data from a community-based dementia study. PMID:20376286

A Solution to Separation and Multicollinearity in Multiple Logistic Regression.

PubMed

Shen, Jianzhao; Gao, Sujuan

2008-10-01

In dementia screening tests, item selection for shortening an existing screening test can be achieved using multiple logistic regression. However, maximum likelihood estimates for such logistic regression models often experience serious bias or even non-existence because of separation and multicollinearity problems resulting from a large number of highly correlated items. Firth (1993, Biometrika, 80(1), 27-38) proposed a penalized likelihood estimator for generalized linear models and it was shown to reduce bias and the non-existence problems. The ridge regression has been used in logistic regression to stabilize the estimates in cases of multicollinearity. However, neither solves the problems for each other. In this paper, we propose a double penalized maximum likelihood estimator combining Firth's penalized likelihood equation with a ridge parameter. We present a simulation study evaluating the empirical performance of the double penalized likelihood estimator in small to moderate sample sizes. We demonstrate the proposed approach using a current screening data from a community-based dementia study.

Development and validation of the assessment of health literacy in breast and cervical cancer screening.

PubMed

Han, Hae-Ra; Huh, Boyun; Kim, Miyong T; Kim, Jiyun; Nguyen, Tam

2014-01-01

For many people limited health literacy is a major barrier to effective preventive health behavior such as cancer screening, yet a comprehensive health literacy measure that is specific to breast and cervical cancer screening is not readily available. The purpose of this article is to describe the development and testing of a new instrument to measure health literacy in the context of breast and cervical cancer screening, the Assessment of Health Literacy in Cancer Screening (AHL-C). The AHL-C is based on Baker's conceptualization of health literacy and modeled from the two most popular health literacy tests, the Rapid Estimate of Adult Literacy in Medicine and the Test of Functional Health Literacy in Adults. The AHL-C consists of four subscales; print literacy, numeracy, comprehension, and familiarity. We used baseline data from 560 Korean American immigrant women who participated in a community-based randomized trial designed to test the effect of a health literacy-focused intervention to promote breast and cervical cancer screening. Rigorous psychometric testing supports that the AHL-C is reliable, valid, and significantly correlated with theoretically selected variables. Future research is needed to test the utility of the AHL-C in predicting cancer screening outcomes.

Cervical cancer screening among Lebanese women.

PubMed

Bou-Orm, I R; Sakr, R E; Adib, S M

2018-02-01

Cervical cancer is a very common malignancy amongst women worldwide. Pap smear is an effective and inexpensive screening test in asymptomatic women. The aim of this paper was to assess the prevalence of Pap smear screening for cervical cancer among Lebanese women and to determine associated sociodemographic and psychosocial characteristics. This national survey included 2255 women, selected by multi-stage random cluster sampling across Lebanon. A questionnaire about practices and perceptions related to cervical cancer screening was developed based on the "Health Belief Model". The weighted national prevalence of "ever-use" of the Pap smear for screening purposes was 35%. Most important determinants of screening behavior were: residence within Greater Beirut, higher socio-economic status and educational attainment, marriage status, presence of a health coverage, awareness of Pap smear usefulness, knowing someone who had already done it, and a balance between perceived benefits and perceived barriers to Pap smear screening. Regular information campaigns regarding the availability and effectiveness of the test should be devised, targeting in priority the sexually vulnerable women in Lebanon. Moreover, healthcare providers should be encouraged to discuss with their patients the opportunity of obtaining a Pap smear. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Priestley, E. Scott; De Lucca, Indawati; Zhou, Jinglan

A 6-amidinotetrahydroquinoline screening hit was driven to a structurally novel, potent, and selective FVIIa inhibitor through a combination of library synthesis and rational design. An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial thrombosis model. A crystal structure of BMS-593214 bound to FVIIa highlights key contacts with Asp 189, Lys 192, and the S2 pocket.

Prediction of small-for-gestational-age neonates: screening by uterine artery Doppler and mean arterial pressure at 19-24 weeks.

PubMed

Lesmes, C; Gallo, D M; Saiid, Y; Poon, L C; Nicolaides, K H

2015-09-01

To investigate the potential value of uterine artery (UtA) pulsatility index (PI) and mean arterial pressure (MAP) at 19-24 weeks' gestation, in combination with maternal characteristics and medical history and fetal biometry in the prediction of delivery of small-for-gestational-age (SGA) neonates in the absence of pre-eclampsia (PE) and to examine the potential value of such assessment in deciding whether the third-trimester scan should be performed at 32 and/or 36 weeks' gestation. This was a screening study in 63 975 singleton pregnancies, including 3702 (5.8%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ) in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, fetal head circumference (HC), abdominal circumference (AC), femur length (FL), UtA-PI and MAP had significant contribution in predicting SGA neonates. A model was developed to select gestational age for the third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. The detection rates (DRs) of combined screening by maternal factors, fetal biometry and UtA-PI at 19-24 weeks were 90%, 68% and 44% for SGA < 5(th) delivering < 32, 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. The performance of screening was not improved by the addition of MAP. The DR of SGA < 5(th) delivering at 32-36 weeks improved from 68% to 90% with screening at 32 rather than at 19-24 weeks. Similarly, the DR of SGA < 5(th) delivering ≥ 37 weeks improved from 44% with screening at 19-24 weeks to 59% and 76% when screening at 32 and 36 weeks, respectively. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 17% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 38% to be reassessed at 36 weeks; 62% would not require a third-trimester scan. Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Developing and validating predictive decision tree models from mining chemical structural fingerprints and high-throughput screening data in PubChem.

PubMed

Han, Lianyi; Wang, Yanli; Bryant, Stephen H

2008-09-25

Recent advances in high-throughput screening (HTS) techniques and readily available compound libraries generated using combinatorial chemistry or derived from natural products enable the testing of millions of compounds in a matter of days. Due to the amount of information produced by HTS assays, it is a very challenging task to mine the HTS data for potential interest in drug development research. Computational approaches for the analysis of HTS results face great challenges due to the large quantity of information and significant amounts of erroneous data produced. In this study, Decision Trees (DT) based models were developed to discriminate compound bioactivities by using their chemical structure fingerprints provided in the PubChem system http://pubchem.ncbi.nlm.nih.gov. The DT models were examined for filtering biological activity data contained in four assays deposited in the PubChem Bioassay Database including assays tested for 5HT1a agonists, antagonists, and HIV-1 RT-RNase H inhibitors. The 10-fold Cross Validation (CV) sensitivity, specificity and Matthews Correlation Coefficient (MCC) for the models are 57.2 approximately 80.5%, 97.3 approximately 99.0%, 0.4 approximately 0.5 respectively. A further evaluation was also performed for DT models built for two independent bioassays, where inhibitors for the same HIV RNase target were screened using different compound libraries, this experiment yields enrichment factor of 4.4 and 9.7. Our results suggest that the designed DT models can be used as a virtual screening technique as well as a complement to traditional approaches for hits selection.

Sputtering phenomena of discharge chamber components in a 30-cm diameter Hg ion thruster

NASA Technical Reports Server (NTRS)

Mantenieks, M. A.; Rawlin, V. K.

1976-01-01

Sputtering and deposition rates were measured for discharge chamber components of a 30-cm diameter mercury ion thruster. It was found that sputtering rates of the screen grid and cathode baffle were strongly affected by geometry of the baffle holder. Sputtering rates of the baffle and screen grid were reduced to 80 and 125 A/hr, respectively, by combination of appropriate geometry and materials selections. Sputtering rates such as these are commensurate with thruster lifetimes of 15,000 hours or more. A semiempirical sputtering model showed good agreement with the measured values.

Relationship between High School Students' Facebook Addiction and Loneliness Status

ERIC Educational Resources Information Center

Karakose, Turgut; Yirci, Ramazan; Uygun, Harun; Ozdemir, Tuncay Yavuz

2016-01-01

This study was conducted in order to analyze the relation between high school students' Facebook addiction and loneliness levels. The study was conducted with the relational screening model. The sample of the study consists of 712 randomly selected high school students. The data was collected using the Bergen Facebook Addiction Scale (BFAS) to…

Software Graphical User Interface For Analysis Of Images

NASA Technical Reports Server (NTRS)

Leonard, Desiree M.; Nolf, Scott R.; Avis, Elizabeth L.; Stacy, Kathryn

1992-01-01

CAMTOOL software provides graphical interface between Sun Microsystems workstation and Eikonix Model 1412 digitizing camera system. Camera scans and digitizes images, halftones, reflectives, transmissives, rigid or flexible flat material, or three-dimensional objects. Users digitize images and select from three destinations: work-station display screen, magnetic-tape drive, or hard disk. Written in C.

The Relationship between Prospective Teachers' Critical Thinking Dispositions and Their Educational Philosophies

ERIC Educational Resources Information Center

Aybek, Birsel; Aslan, Serkan

2017-01-01

The aim of this research is to investigate the relationship between prospective teachers' critical thinking dispositions and their educational philosophies. The research used relational screening model. The study hosts a total of 429 prospective teachers selected by the simple random sampling method. Research data has been collected through…

Microarray-based cancer prediction using soft computing approach.

PubMed

Wang, Xiaosheng; Gotoh, Osamu

2009-05-26

One of the difficulties in using gene expression profiles to predict cancer is how to effectively select a few informative genes to construct accurate prediction models from thousands or ten thousands of genes. We screen highly discriminative genes and gene pairs to create simple prediction models involved in single genes or gene pairs on the basis of soft computing approach and rough set theory. Accurate cancerous prediction is obtained when we apply the simple prediction models for four cancerous gene expression datasets: CNS tumor, colon tumor, lung cancer and DLBCL. Some genes closely correlated with the pathogenesis of specific or general cancers are identified. In contrast with other models, our models are simple, effective and robust. Meanwhile, our models are interpretable for they are based on decision rules. Our results demonstrate that very simple models may perform well on cancerous molecular prediction and important gene markers of cancer can be detected if the gene selection approach is chosen reasonably.

Using model-based screening to help discover unknown environmental contaminants.

PubMed

McLachlan, Michael S; Kierkegaard, Amelie; Radke, Michael; Sobek, Anna; Malmvärn, Anna; Alsberg, Tomas; Arnot, Jon A; Brown, Trevor N; Wania, Frank; Breivik, Knut; Xu, Shihe

2014-07-01

Of the tens of thousands of chemicals in use, only a small fraction have been analyzed in environmental samples. To effectively identify environmental contaminants, methods to prioritize chemicals for analytical method development are required. We used a high-throughput model of chemical emissions, fate, and bioaccumulation to identify chemicals likely to have high concentrations in specific environmental media, and we prioritized these for target analysis. This model-based screening was applied to 215 organosilicon chemicals culled from industrial chemical production statistics. The model-based screening prioritized several recognized organosilicon contaminants and generated hypotheses leading to the selection of three chemicals that have not previously been identified as potential environmental contaminants for target analysis. Trace analytical methods were developed, and the chemicals were analyzed in air, sewage sludge, and sediment. All three substances were found to be environmental contaminants. Phenyl-tris(trimethylsiloxy)silane was present in all samples analyzed, with concentrations of ∼50 pg m(-3) in Stockholm air and ∼0.5 ng g(-1) dw in sediment from the Stockholm archipelago. Tris(trifluoropropyl)trimethyl-cyclotrisiloxane and tetrakis(trifluoropropyl)tetramethyl-cyclotetrasiloxane were found in sediments from Lake Mjøsa at ∼1 ng g(-1) dw. The discovery of three novel environmental contaminants shows that models can be useful for prioritizing chemicals for exploratory assessment.

Comparison of a homology model and the crystallographic structure of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a structure-based identification of inhibitors

NASA Astrophysics Data System (ADS)

Miguet, Laurence; Zhang, Ziding; Barbier, Maryse; Grigorov, Martin G.

2006-02-01

Human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of cortisone into active cortisol. 11βHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11βHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11βHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11βHSD1 inhibitors or substrates and non-inhibitors. The homology model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening experiments on both the homology model and the crystallographic structure with a database of 114'000 natural molecules. Among these, 15 molecules were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homology model. Among these putative 11βHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme.

Design checkpoint kinase 2 inhibitors by pharmacophore modeling and virtual screening techniques.

PubMed

Wang, Yen-Ling; Lin, Chun-Yuan; Shih, Kuei-Chung; Huang, Jui-Wen; Tang, Chuan-Yi

2013-12-01

Damage to DNA is caused by ionizing radiation, genotoxic chemicals or collapsed replication forks. When DNA is damaged or cells fail to respond, a mutation that is associated with breast or ovarian cancer may occur. Mammalian cells control and stabilize the genome using a cell cycle checkpoint to prevent damage to DNA or to repair damaged DNA. Checkpoint kinase 2 (Chk2) is one of the important kinases, which strongly affects DNA-damage and plays an important role in the response to the breakage of DNA double-strands and related lesions. Therefore, this study concerns Chk2. Its purpose is to find potential inhibitors using the pharmacophore hypotheses (PhModels) and virtual screening techniques. PhModels can identify inhibitors with high biological activities and virtual screening techniques are used to screen the database of the National Cancer Institute (NCI) to retrieve compounds that exhibit all of the pharmacophoric features of potential inhibitors with high interaction energy. Ten PhModels were generated using the HypoGen best algorithm. The established PhModel, Hypo01, was evaluated by performing a cost function analysis of its correlation coefficient (r), root mean square deviation (RMSD), cost difference, and configuration cost, with the values 0.955, 1.28, 192.51, and 16.07, respectively. The result of Fischer's cross-validation test for the Hypo01 model yielded a 95% confidence level, and the correlation coefficient of the testing set (rtest) had a best value of 0.81. The potential inhibitors were then chosen from the NCI database by Hypo01 model screening and molecular docking using the cdocker docking program. Finally, the selected compounds exhibited the identified pharmacophoric features and had a high interaction energy between the ligand and the receptor. Eighty-three potential inhibitors for Chk2 are retrieved for further study. Copyright © 2013 Elsevier Ltd. All rights reserved.

Perceived Neighborhood Quality and Cancer Screening Behavior: Evidence from the Survey of the Health of Wisconsin.

PubMed

Beyer, Kirsten M M; Malecki, Kristen M; Hoormann, Kelly A; Szabo, Aniko; Nattinger, Ann B

2016-02-01

Socioeconomic disparities in colorectal and breast cancer screening persist, partially accounting for disparities in cancer outcomes. Some neighborhood characteristics--particularly area level socioeconomic factors--have been linked to cancer screening behavior, but few studies have examined the relationship between perceived neighborhood quality and screening behavior, which may provide more insight into the ways in which neighborhood environments shape cancer related behaviors. This study examines the relationship between several aspects of the perceived neighborhood environment and breast and colorectal cancer screening behavior among a population-based sample of Wisconsin residents. A sub-goal was to compare the relevance of different perceived neighborhood factors for different screening tests. This is a cross-sectional study of 2008-2012 data from the Survey of the Health of Wisconsin, a population-based annual survey of Wisconsin residents. An average risk sample of Black, Hispanic and White women age 50 and older (n = 1265) were selected. Survey regression analyses examined predictors of screening, as well as adherence to screening guidelines. Models controlled for individual socio-demographic information and insurance status. Perceptions of social and physical disorder, including fear of crime and visible garbage, were associated with screening rates. Findings emphasize the particular importance of these factors for colorectal cancer screening, indicating the necessity of improving screening rates in areas characterized by social disorganization, crime, and physical disorder. Additional work should be done to further investigate the pathways that explain the linkage between neighborhood conditions, perceived neighborhood risks and cancer screening behavior.

How to select the correct education strategy: when not to go online.

PubMed

Klingbeil, Carol G; Johnson, Norah L; Totka, Joan P; Doyle, Lynn

2009-01-01

Screening for intimate partner violence is an important injury prevention strategy. Nurses who develop staff education, to promote screening, need to select a method that is sensitive to learners. Online learning, although convenient, is not well suited to sensitive topics such as screening for intimate partner violence. The purpose of this article is to describe a curriculum for intimate partner violence screening based on self-efficacy theory, which includes a hospital-produced video, a role play, and a discussion.

Carbon nuclear magnetic resonance spectroscopic fingerprinting of commercial gasoline: pattern-recognition analyses for screening quality control purposes.

PubMed

Flumignan, Danilo Luiz; Boralle, Nivaldo; Oliveira, José Eduardo de

2010-06-30

In this work, the combination of carbon nuclear magnetic resonance ((13)C NMR) fingerprinting with pattern-recognition analyses provides an original and alternative approach to screening commercial gasoline quality. Soft Independent Modelling of Class Analogy (SIMCA) was performed on spectroscopic fingerprints to classify representative commercial gasoline samples, which were selected by Hierarchical Cluster Analyses (HCA) over several months in retails services of gas stations, into previously quality-defined classes. Following optimized (13)C NMR-SIMCA algorithm, sensitivity values were obtained in the training set (99.0%), with leave-one-out cross-validation, and external prediction set (92.0%). Governmental laboratories could employ this method as a rapid screening analysis to discourage adulteration practices. Copyright 2010 Elsevier B.V. All rights reserved.

Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction

PubMed Central

Chaudhury, Sidhartha; Abdulhameed, Mohamed Diwan M.; Singh, Narender; Tawa, Gregory J.; D’haeseleer, Patrik M.; Zemla, Adam T.; Navid, Ali; Zhou, Carol E.; Franklin, Matthew C.; Cheung, Jonah; Rudolph, Michael J.; Love, James; Graf, John F.; Rozak, David A.; Dankmeyer, Jennifer L.; Amemiya, Kei; Daefler, Simon; Wallqvist, Anders

2013-01-01

In the future, we may be faced with the need to provide treatment for an emergent biological threat against which existing vaccines and drugs have limited efficacy or availability. To prepare for this eventuality, our objective was to use a metabolic network-based approach to rapidly identify potential drug targets and prospectively screen and validate novel small-molecule antimicrobials. Our target organism was the fully virulent Francisella tularensis subspecies tularensis Schu S4 strain, a highly infectious intracellular pathogen that is the causative agent of tularemia and is classified as a category A biological agent by the Centers for Disease Control and Prevention. We proceeded with a staggered computational and experimental workflow that used a strain-specific metabolic network model, homology modeling and X-ray crystallography of protein targets, and ligand- and structure-based drug design. Selected compounds were subsequently filtered based on physiological-based pharmacokinetic modeling, and we selected a final set of 40 compounds for experimental validation of antimicrobial activity. We began screening these compounds in whole bacterial cell-based assays in biosafety level 3 facilities in the 20th week of the study and completed the screens within 12 weeks. Six compounds showed significant growth inhibition of F. tularensis, and we determined their respective minimum inhibitory concentrations and mammalian cell cytotoxicities. The most promising compound had a low molecular weight, was non-toxic, and abolished bacterial growth at 13 µM, with putative activity against pantetheine-phosphate adenylyltransferase, an enzyme involved in the biosynthesis of coenzyme A, encoded by gene coaD. The novel antimicrobial compounds identified in this study serve as starting points for lead optimization, animal testing, and drug development against tularemia. Our integrated in silico/in vitro approach had an overall 15% success rate in terms of active versus tested compounds over an elapsed time period of 32 weeks, from pathogen strain identification to selection and validation of novel antimicrobial compounds. PMID:23704901

Comparison of Cardiovascular Risk Screening Methods and Mortality Data among Hungarian Primary Care Population: Preliminary Results of the First Government-Financed Managed Care Program.

PubMed

Móczár, Csaba; Rurik, Imre

2015-09-01

Besides participation in the primary prevention, screening as secondary prevention is an important requirement for primary care services. The effect of this work is influenced by the characteristics of individual primary care practices and doctors' screening habits, as well as by the regulation of screening processes and available financial resources. Between 1999 and 2009, a managed care program was introduced and carried out in Hungary, financed by the government. This financial support and motivation gave the opportunity to increase the number of screenings. 4,462 patients of 40 primary care practices were screened on the basis of SCORE risk assessment. The results of the screening were compared on the basis of two groups of patients, namely: those who had been pre-screened (pre-screening method) for known risk factors in their medical history (smoking, BMI, age, family cardiovascular history), and those randomly screened. The authors also compared the mortality data of participating primary care practices with the regional and national data. The average score was significantly higher in the pre-screened group of patients, regardless of whether the risk factors were considered one by one or in combination. Mortality was significantly lower in the participating primary practices than had been expected on the basis of the national mortality data. This government-financed program was a big step forward to establish a proper screening method within Hungarian primary care. Performing cardiovascular screening of a selected target group is presumably more appropriate than screening within a randomly selected population. Both methods resulted in a visible improvement in regional mortality data, though it is very likely that with pre-screening a more cost-effective selection for screening may be obtained.

[Mokken scaling of the Cognitive Screening Test].

PubMed

Diesfeldt, H F A

2009-10-01

The Cognitive Screening Test (CST) is a twenty-item orientation questionnaire in Dutch, that is commonly used to evaluate cognitive impairment. This study applied Mokken Scale Analysis, a non-parametric set of techniques derived from item response theory (IRT), to CST-data of 466 consecutive participants in psychogeriatric day care. The full item set and the standard short version of fourteen items both met the assumptions of the monotone homogeneity model, with scalability coefficient H = 0.39, which is considered weak. In order to select items that would fulfil the assumption of invariant item ordering or the double monotonicity model, the subjects were randomly partitioned into a training set (50% of the sample) and a test set (the remaining half). By means of an automated item selection eleven items were found to measure one latent trait, with H = 0.67 and item H coefficients larger than 0.51. Cross-validation of the item analysis in the remaining half of the subjects gave comparable values (H = 0.66; item H coefficients larger than 0.56). The selected items involve year, place of residence, birth date, the monarch's and prime minister's names, and their predecessors. Applying optimal discriminant analysis (ODA) it was found that the full set of twenty CST items performed best in distinguishing two predefined groups of patients of lower or higher cognitive ability, as established by an independent criterion derived from the Amsterdam Dementia Screening Test. The chance corrected predictive value or prognostic utility was 47.5% for the full item set, 45.2% for the fourteen items of the standard short version of the CST, and 46.1% for the homogeneous, unidimensional set of selected eleven items. The results of the item analysis support the application of the CST in cognitive assessment, and revealed a more reliable 'short' version of the CST than the standard short version (CST14).

Identification of 5-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2-Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition.

PubMed

Kaplan, Alan P; Keenan, Terence; Scott, Roderick; Zhou, Xianbo; Bourchouladze, Rusiko; McRiner, Andrew J; Wilson, Mark E; Romashko, Darlene; Miller, Regina; Bletsch, Matthew; Anderson, Gary; Stanley, Jennifer; Zhang, Adia; Lee, Dong; Nikpur, John

2017-12-20

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy

PubMed Central

2013-01-01

Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays. PMID:24900590

The MORPHEUS II protein crystallization screen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gorrec, Fabrice, E-mail: fgorrec@mrc-lmb.cam.ac.uk

2015-06-27

MORPHEUS II is a 96-condition initial crystallization screen formulated de novo. The screen incorporates reagents selected from the Protein Data Bank to yield crystals that are not observed in traditional conditions. In addition, the formulation facilitates the optimization and cryoprotection of crystals. High-quality macromolecular crystals are a prerequisite for the process of protein structure determination by X-ray diffraction. Unfortunately, the relative yield of diffraction-quality crystals from crystallization experiments is often very low. In this context, innovative crystallization screen formulations are continuously being developed. In the past, MORPHEUS, a screen in which each condition integrates a mix of additives selected frommore » the Protein Data Bank, a cryoprotectant and a buffer system, was developed. Here, MORPHEUS II, a follow-up to the original 96-condition initial screen, is described. Reagents were selected to yield crystals when none might be observed in traditional initial screens. Besides, the screen includes heavy atoms for experimental phasing and small polyols to ensure the cryoprotection of crystals. The suitability of the resulting novel conditions is shown by the crystallization of a broad variety of protein samples and their efficiency is compared with commercially available conditions.« less

Assessment of Uncertainty-Based Screening Volumes for NASA Robotic LEO and GEO Conjunction Risk Assessment

NASA Technical Reports Server (NTRS)

Narvet, Steven W.; Frigm, Ryan C.; Hejduk, Matthew D.

2011-01-01

Conjunction Assessment operations require screening assets against the space object catalog by placing a pre-determined spatial volume around each asset and predicting when another object will violate that volume. The selection of the screening volume used for each spacecraft is a trade-off between observing all conjunction events that may pose a potential risk to the primary spacecraft and the ability to analyze those predicted events. If the screening volumes are larger, then more conjunctions can be observed and therefore the probability of a missed detection of a high risk conjunction event is small; however, the amount of data which needs to be analyzed increases. This paper characterizes the sensitivity of screening volume size to capturing typical orbit uncertainties and the expected number of conjunction events observed. These sensitivities are quantified in the form of a trade space that allows for selection of appropriate screen-ing volumes to fit the desired concept of operations, system limitations, and tolerable analyst workloads. This analysis will specifically highlight the screening volume determination and selection process for use in the NASA Conjunction Assessment Risk Analysis process but will also provide a general framework for other Owner / Operators faced with similar decisions.

Risk factor assessment to anticipate performance in the National Developmental Screening Test in children from a disadvantaged area.

PubMed

Montes, Alejandro; Pazos, Gustavo

2016-02-01

Identifying children at risk of failing the National Developmental Screening Test by combining prevalences of children suspected of having inapparent developmental disorders (IDDs) and associated risk factors (RFs) would allow to save resources. 1. To estimate the prevalence of children suspected of having IDDs. 2. To identify associated RFs. 3. To assess three methods developed based on observed RFs and propose a pre-screening procedure. The National Developmental Screening Test was administered to 60 randomly selected children aged between 2 and 4 years old from a socioeconomically disadvantaged area from Puerto Madryn. Twenty-four biological and socioenvironmental outcome measures were assessed in order to identify potential RFs using bivariate and multivariate analyses. The likelihood of failing the screening test was estimated as follows: 1. a multivariate logistic regression model was developed; 2. a relationship was established between the number of RFs present in each child and the percentage of children who failed the test; 3. these two methods were combined. The prevalence of children suspected of having IDDs was 55.0% (95% confidence interval: 42.4%-67.6%). Six RFs were initially identified using the bivariate approach. Three of them (maternal education, number of health checkups and Z scores for height-for-age, and maternal age) were included in the logistic regression model, which has a greater explanatory power. The third method included in the assessment showed greater sensitivity and specificity (85% and 79%, respectively). The estimated prevalence of children suspected of having IDDs was four times higher than the national standards. Seven RFs were identified. Combining the analysis of risk factor accumulation and a multivariate model provides a firm basis for developing a sensitive, specific and practical pre-screening procedure for socioeconomically disadvantaged areas. Sociedad Argentina de Pediatría.

Cardiac Screening Prior to Stimulant Treatment of ADHD: A Survey of US-Based Pediatricians

PubMed Central

Rodday, Angie Mae; Saunders, Tully S.; Cohen, Joshua T.; Wong, John B.; Parsons, Susan K.

2012-01-01

OBJECTIVES: To determine pediatricians’ attitudes, barriers, and practices regarding cardiac screening before initiating treatment with stimulants for attention-deficit/hyperactivity disorder. METHODS: A survey of 1600 randomly selected, practicing US pediatricians with American Academy of Pediatrics membership was conducted. Multivariate models were created for 3 screening practices: (1) performing an in-depth cardiac history and physical (H & P) examination, (2) discussing potential stimulant-related cardiac risks, and (3) ordering an electrocardiogram (ECG). RESULTS: Of 817 respondents (51%), 525 (64%) met eligibility criteria. Regarding attitudes, pediatricians agreed that both the risk for sudden cardiac death (SCD) (24%) and legal liability (30%) were sufficiently high to warrant cardiac assessment; 75% agreed that physicians were responsible for informing families about SCD risk. When identifying cardiac disorders, few (18%) recognized performing an in-depth cardiac H & P as a barrier; in contrast, 71% recognized interpreting a pediatric ECG as a barrier. When asked about cardiac screening practices before initiating stimulant treatment for a recent patient, 93% completed a routine H & P, 48% completed an in-depth cardiac H & P, and 15% ordered an ECG. Almost half (46%) reported discussing stimulant-related cardiac risks. Multivariate modeling indicated that ≥1 of these screening practices were associated with physicians’ attitudes about SCD risk, legal liability, their responsibility to inform about risk, their ability to perform an in-depth cardiac H & P, and family concerns about risk. CONCLUSIONS: Variable pediatrician attitudes and cardiac screening practices reflect the limited evidence base and conflicting guidelines regarding cardiac screening. Barriers to identifying cardiac disorders influence practice. PMID:22250023

Screen Twice, Cut Once: Assessing the Predictive Validity of Applicant Selection Tools

ERIC Educational Resources Information Center

Goldhaber, Dan; Grout, Cyrus; Huntington-Klein, Nick

2017-01-01

Despite their widespread use, there is little academic evidence on whether applicant selection instruments can improve teacher hiring. We examine the relationship between two screening instruments used by Spokane Public Schools to select classroom teachers and three teacher outcomes: value added, absences, and attrition. We observe all applicants…

Molecular dynamics, flexible docking, virtual screening, ADMET predictions, and molecular interaction field studies to design novel potential MAO-B inhibitors.

PubMed

Braun, Glaucia H; Jorge, Daniel M M; Ramos, Henrique P; Alves, Raquel M; da Silva, Vinicius B; Giuliatti, Silvana; Sampaio, Suley Vilela; Taft, Carlton A; Silva, Carlos H T P

2008-02-01

Monoamine oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant, Parkinson's disease, and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for the molecular modeling studies. In this work we have used molecular modeling, density functional theory with correlation, virtual screening, flexible docking, molecular dynamics, ADMET predictions, and molecular interaction field studies in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.

Quantum Monte Carlo Simulation of Frustrated Kondo Lattice Models

NASA Astrophysics Data System (ADS)

Sato, Toshihiro; Assaad, Fakher F.; Grover, Tarun

2018-03-01

The absence of the negative sign problem in quantum Monte Carlo simulations of spin and fermion systems has different origins. World-line based algorithms for spins require positivity of matrix elements whereas auxiliary field approaches for fermions depend on symmetries such as particle-hole symmetry. For negative-sign-free spin and fermionic systems, we show that one can formulate a negative-sign-free auxiliary field quantum Monte Carlo algorithm that allows Kondo coupling of fermions with the spins. Using this general approach, we study a half-filled Kondo lattice model on the honeycomb lattice with geometric frustration. In addition to the conventional Kondo insulator and antiferromagnetically ordered phases, we find a partial Kondo screened state where spins are selectively screened so as to alleviate frustration, and the lattice rotation symmetry is broken nematically.

Screening analysis and selection of emission reduction concepts for intermittent combustion aircraft engines

NASA Technical Reports Server (NTRS)

Rezy, B. J.; Meyers, J. E.; Tucker, J. R.; Stuckas, S. J.

1976-01-01

An analysis was conducted to screen, evaluate, and select three engine exhaust emission reduction concepts from a group of 14 candidate alternatives. A comprehensive literature search was conducted to survey the emission reduction technology state-of-the-art and establish contact with firms working on intermittent combustion engine development and pollution reduction problems. Concept development, advantages, disadvantages, and expected emission reduction responses are stated. A set of cost effectiveness criteria was developed, appraised for relative importance, and traded off against each concept so that its merit could be determined. A decision model was used to aid the evaluators in managing the criteria, making consistent judgements, calculating merit scores, and ranking the concepts. An Improved Fuel Injection System, Improved Cooling Combustion Chamber, and a Variable Timing Ignition System were recommended to NASA for approval and further concept development. An alternate concept, Air Injection, was also recommended.

Orthogonal Luciferase-Luciferin Pairs for Bioluminescence Imaging.

PubMed

Jones, Krysten A; Porterfield, William B; Rathbun, Colin M; McCutcheon, David C; Paley, Miranda A; Prescher, Jennifer A

2017-02-15

Bioluminescence imaging with luciferase-luciferin pairs is widely used in biomedical research. Several luciferases have been identified in nature, and many have been adapted for tracking cells in whole animals. Unfortunately, the optimal luciferases for imaging in vivo utilize the same substrate and therefore cannot easily differentiate multiple cell types in a single subject. To develop a broader set of distinguishable probes, we crafted custom luciferins that can be selectively processed by engineered luciferases. Libraries of mutant enzymes were iteratively screened with sterically modified luciferins, and orthogonal enzyme-substrate "hits" were identified. These tools produced light when complementary enzyme-substrate partners interacted both in vitro and in cultured cell models. Based on their selectivity, these designer pairs will bolster multicomponent imaging and enable the direct interrogation of cell networks not currently possible with existing tools. Our screening platform is also general and will expedite the identification of more unique luciferases and luciferins, further expanding the bioluminescence toolkit.

Optically transparent frequency selective surfaces on flexible thin plastic substrates

NASA Astrophysics Data System (ADS)

Dewani, Aliya A.; O'Keefe, Steven G.; Thiel, David V.; Galehdar, Amir

2015-02-01

A novel 2D simple low cost frequency selective surface was screen printed on thin (0.21 mm), flexible transparent plastic substrate (relative permittivity 3.2). It was designed, fabricated and tested in the frequency range 10-20 GHz. The plane wave transmission and reflection coefficients agreed with numerical modelling. The effective permittivity and thickness of the backing sheet has a significant effect on the frequency characteristics. The stop band frequency reduced from 15GHz (no backing) to 12.5GHz with polycarbonate. The plastic substrate thickness beyond 1.8mm has minimal effect on the resonant frequency. While the inner element spacing controls the stop-band frequency, the substrate thickness controls the bandwidth. The screen printing technique provided a simple, low cost FSS fabrication method to produce flexible, conformal, optically transparent and bio-degradable FSS structures which can find their use in electromagnetic shielding and filtering applications in radomes, reflector antennas, beam splitters and polarizers.

Performance evaluation of structure based and ligand based virtual screening methods on ten selected anti-cancer targets.

PubMed

Ramasamy, Thilagavathi; Selvam, Chelliah

2015-10-15

Virtual screening has become an important tool in drug discovery process. Structure based and ligand based approaches are generally used in virtual screening process. To date, several benchmark sets for evaluating the performance of the virtual screening tool are available. In this study, our aim is to compare the performance of both structure based and ligand based virtual screening methods. Ten anti-cancer targets and their corresponding benchmark sets from 'Demanding Evaluation Kits for Objective In silico Screening' (DEKOIS) library were selected. X-ray crystal structures of protein-ligand complexes were selected based on their resolution. Openeye tools such as FRED, vROCS were used and the results were carefully analyzed. At EF1%, vROCS produced better results but at EF5% and EF10%, both FRED and ROCS produced almost similar results. It was noticed that the enrichment factor values were decreased while going from EF1% to EF5% and EF10% in many cases. Published by Elsevier Ltd.

Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge

NASA Astrophysics Data System (ADS)

Kumar, Ashutosh; Zhang, Kam Y. J.

2012-05-01

SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges.

Black Americans' Perspectives of Barriers and Facilitators of Community Screening for Kidney Disease.

PubMed

Umeukeje, Ebele M; Wild, Marcus G; Maripuri, Saugar; Davidson, Teresa; Rutherford, Margaret; Abdel-Kader, Khaled; Lewis, Julia; Wilkins, Consuelo H; Cavanaugh, Kerri

2018-04-06

Incidence of ESKD is three times higher in black Americans than in whites, and CKD prevalence continues to rise among black Americans. Community-based kidney disease screening may increase early identification and awareness of black Americans at risk, but it is challenging to implement. This study aimed to identify participants' perspectives of community kidney disease screening. The Health Belief Model provides a theoretic framework for conceptualization of these perspectives and optimization of community kidney disease screening activities. Researchers in collaboration with the Tennessee Kidney Foundation conducted three focus groups of adults in black American churches in Nashville, Tennessee. Questions examined views on CKD information, access to care, and priorities of kidney disease health. Content analysis was used. Guided by the Health Belief Model, a priori themes were generated, and additional themes were derived from the data using an inductive approach. Thirty-two black Americans completed the study in 2014. Participants were mostly women (79%) with a mean age of 56 years old (range, 24-78). Two major categories of barriers to kidney disease screening were identified: ( 1 ) participant factors, including limited kidney disease knowledge, spiritual/religious beliefs, emotions, and culture of the individual; and ( 2 ) logistic factors, including lack of convenience and incentives and poor advertisement. Potential facilitators of CKD screening included provision of CKD education, convenience of screening activities, and use of culturally sensitive and enhanced communication strategies. Program recommendations included partnering with trusted community members, selecting convenient locations, tailored advertising, and provision of compensation. Findings of this study suggest that provider-delivered culturally sensitive education and stakeholder engagement are critical to increase trust, decrease fear, and maximize participation and early identification of kidney disease among black Americans considering community screening. Copyright © 2018 by the American Society of Nephrology.

Evaluation of the Mycobacterium smegmatis and BCG models for the discovery of Mycobacterium tuberculosis inhibitors.

PubMed

Altaf, Mudassar; Miller, Christopher H; Bellows, David S; O'Toole, Ronan

2010-11-01

The objective of this study was to measure the efficacy of Mycobacterium smegmatis as a surrogate in vitro model for the detection of compounds which are inhibitory to the growth of Mycobacterium tuberculosis. A chemical screen of the LOPAC library for anti-mycobacterial compounds was performed using M. smegmatis. Parallel screens were conducted with another tuberculosis model, Mycobacterium bovis BCG, and with M. tuberculosis under identical growth conditions and the inhibitors detected across the three species were compared. 50% of compounds that were detected as active against M. tuberculosis were not detected using M. smegmatis compared to 21% of compounds using M. bovis BCG. To examine whether these findings were unique to LOPAC, screens were performed with the NIH Diversity Set and Spectrum Collection. An even higher proportion of M. tuberculosis inhibitors were not detected from the NIH Diversity Set and Spectrum Collection using M. smegmatis compared to M. bovis BCG. These data reveal that a significant proportion of M. tuberculosis inhibitors are missed in library screening with M. smegmatis. The basis of the variation in the inhibitory profiles of M. smegmatis and M. tuberculosis has yet to be fully determined, however, our genomic comparisons indicate that approximately 30% of M. tuberculosis proteins lack conserved orthologues in M. smegmatis compared to 3% being absent in M. bovis BCG. In conclusion, although M. smegmatis offers some technical benefits such as a shorter generation time and negligible risk to laboratory workers, it is significantly less effective in the detection of anti-M. tuberculosis compounds relative to M. bovis BCG. This limitation needs to be taken into consideration when selecting an in vitro screening model for tuberculosis drug discovery. Copyright © 2010 Elsevier Ltd. All rights reserved.

Screening for Syphilis and Other Sexually Transmitted Infections in Pregnant Women - Guam, 2014.

PubMed

Cha, Susan; Malik, Tasneem; Abara, Winston E; DeSimone, Mia S; Schumann, Bernadette; Mallada, Esther; Klemme, Michael; Aguon, Vince; Santos, Anne Marie; Peterman, Thomas A; Bolan, Gail; Kamb, Mary L

2017-06-23

Prenatal screening and treatment for sexually transmitted infections (STIs) can prevent adverse perinatal outcomes. In Guam, the largest of the three U.S. territories in the Pacific, primary and secondary syphilis rates among women increased 473%, from 1.1 to 6.3 per 100,000 during 2009-2013 (1). In 2013, the first congenital syphilis case after no cases since 2008 was reported (1,2). Little is known about STI screening coverage and factors associated with inadequate screening among pregnant women in Guam. This study evaluated the prevalence of screening for syphilis, human immunodeficiency virus (HIV), chlamydia, and gonorrhea, and examined correlates of inadequate screening among pregnant women in Guam. Data came from the medical records of a randomly selected sample of mothers with live births in 2014 at a large public hospital. Bivariate analyses and multivariable models using Poisson regression were conducted to determine factors associated with inadequate screening for syphilis and other STIs. Although most (93.5%) women received syphilis screening during pregnancy, 26.8% were not screened sufficiently early to prevent adverse pregnancy outcomes. Many women were not screened for HIV infection (31.1%), chlamydia (25.3%), or gonorrhea (25.7%). Prenatal care and insurance were important factors affecting STI screening during pregnancy. Prenatal care providers play an important role in preventing congenital infections. Policies and programs increasing STI and HIV services for pregnant women and improved access to and use of prenatal care are essential for promoting healthy mothers and infants.

FDA-Approved Selective Estrogen Receptor Modulators Inhibit Ebola Virus Infection

PubMed Central

Johansen, Lisa M.; Brannan, Jennifer M.; Delos, Sue E.; Shoemaker, Charles J.; Stossel, Andrea; Lear, Calli; Hoffstrom, Benjamin G.; DeWald, Lisa Evans; Schornberg, Kathryn L.; Scully, Corinne; Lehár, Joseph; Hensley, Lisa E.; White, Judith M.; Olinger, Gene G.

2014-01-01

Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)– and ex–US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections. PMID:23785035

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model.

PubMed

Mondal, Sudip; Hegarty, Evan; Sahn, James J; Scott, Luisa L; Gökçe, Sertan Kutal; Martin, Chris; Ghorashian, Navid; Satarasinghe, Praveen Navoda; Iyer, Sangeetha; Sae-Lee, Wisath; Hodges, Timothy R; Pierce, Jonathan T; Martin, Stephen F; Ben-Yakar, Adela

2018-05-16

The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons. Our previous work with this model suggests that small molecule ligands of the sigma 2 receptor (σ2R), which was recently cloned and identified as transmembrane protein 97 (TMEM97), are neuroprotective. To determine structure-activity relationships for unexplored chemical space in our σ2R/Tmem97 ligand collection, we developed an in vivo high-content screening (HCS) assay to identify potential drug leads. The HCS assay uses our recently developed large-scale microfluidic immobilization chip and automated imaging platform. We discovered norbenzomorphans that reduced neurodegeneration in our C. elegans model, including two compounds that demonstrated significant neuroprotective activity at multiple doses. These findings provide further evidence that σ2R/Tmem97-binding norbenzomorphans may represent a new drug class for treating neurodegenerative diseases.

Screen and clean: a tool for identifying interactions in genome-wide association studies.

PubMed

Wu, Jing; Devlin, Bernie; Ringquist, Steven; Trucco, Massimo; Roeder, Kathryn

2010-04-01

Epistasis could be an important source of risk for disease. How interacting loci might be discovered is an open question for genome-wide association studies (GWAS). Most researchers limit their statistical analyses to testing individual pairwise interactions (i.e., marginal tests for association). A more effective means of identifying important predictors is to fit models that include many predictors simultaneously (i.e., higher-dimensional models). We explore a procedure called screen and clean (SC) for identifying liability loci, including interactions, by using the lasso procedure, which is a model selection tool for high-dimensional regression. We approach the problem by using a varying dictionary consisting of terms to include in the model. In the first step the lasso dictionary includes only main effects. The most promising single-nucleotide polymorphisms (SNPs) are identified using a screening procedure. Next the lasso dictionary is adjusted to include these main effects and the corresponding interaction terms. Again, promising terms are identified using lasso screening. Then significant terms are identified through the cleaning process. Implementation of SC for GWAS requires algorithms to explore the complex model space induced by the many SNPs genotyped and their interactions. We propose and explore a set of algorithms and find that SC successfully controls Type I error while yielding good power to identify risk loci and their interactions. When the method is applied to data obtained from the Wellcome Trust Case Control Consortium study of Type 1 Diabetes it uncovers evidence supporting interaction within the HLA class II region as well as within Chromosome 12q24.

Discovery of novel mGluR1 antagonists: a multistep virtual screening approach based on an SVM model and a pharmacophore hypothesis significantly increases the hit rate and enrichment factor.

PubMed

Li, Guo-Bo; Yang, Ling-Ling; Feng, Shan; Zhou, Jian-Ping; Huang, Qi; Xie, Huan-Zhang; Li, Lin-Li; Yang, Sheng-Yong

2011-03-15

Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor. In this investigation, we established a multistep ligand-based VS approach that is based on a support vector machine (SVM) classification model and a pharmacophore model. Performance evaluation of these methods in virtual screening against a large independent test set, M-MDDR, show that the multistep VS approach significantly increases the hit rate and enrichment factor compared with the individual SB-VS and PB-VS methods. The multistep VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally a total of 20 compounds were selected from the top ranking compounds, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future. Copyright © 2011 Elsevier Ltd. All rights reserved.

Biological Concerns on the Selection of Animal Models for Teratogenic Testing.

PubMed

Alves-Pimenta, Sofia; Colaço, Bruno; Oliveira, Paula A; Venâncio, Carlos

2018-01-01

During pregnancy fetus can be exposed to a variety of chemicals which may induce abortion and malformations. Due to the amounts of new substances coming into the market every year, a high demand for a rapid, reliable, and cost-effective method to detect potential toxicity is necessary. Different species have been used as animal models for teratogen screening, most of them sharing similar development processes with humans. However, the application of embryology knowledge to teratology is hampered by the complexity of the reproduction processes.The present chapter outlines the essential development periods in different models, and highlights the similarities and differences between species, advantages and disadvantages of each group, and specific sensitivities for teratogenic tests. These models can be organized into the following categories: (1) invertebrate species such Caenorhabditis elegans and Drosophila melanogaster, which have become ideal for screening simple mechanisms in the early periods of reproductive cycle, allowing for rapid results and minor ethical concerns; (2) vertebrate nonmammalian species such Xenopus laevis and Danio rerio, important models to assess teratogenic potential in later development with fewer ethical requirements; and (3) the mammalian species Mus musculus, Rattus norvegicus, and Oryctolagus cuniculus, phylogenetically more close to humans, essential to assess complex specialized processes, that occur later in development.Rules for development toxicology tests require the use of mammalian species. However, ethical concerns and costs limit their use in large-scale screening. By contrast, invertebrate and vertebrate nonmammalian species are increasing as alternative animal models, as these organisms combine less ethical requirements, low costs and culture conditions compatible with large-scale screening. In contrast to the in vitro techniques, their main advantage is to allow for high-throughput screening in a whole-animal context, not dependent on the prior identification of a target. In this chapter, the biological development of the animals most used in teratogenic tests is adressed with the aims of maximizing human translation, reducing the number of animals used, and the time to market for new drugs.

Experiential Learning and Community Service in a Business Program: A "Living Case Study" Model and Analysis.

ERIC Educational Resources Information Center

Zucca, Gary; And Others

National University and Sierra College Small Business Development Center (SBDC) have jointly developed a program whereby small businesses become clients of the SBDC and are screened and selected as "living case studies" for National University's practicum for bachelor's and master's of business administration candidates. The new course replaces a…

Immobilized magnetic beads-based multi-target affinity selection coupled with HPLC-MS for screening active compounds from traditional Chinese medicine and natural products.

PubMed

Chen, Yaqi; Chen, Zhui; Wang, Yi

2015-01-01

Screening and identifying active compounds from traditional Chinese medicine (TCM) and other natural products plays an important role in drug discovery. Here, we describe a magnetic beads-based multi-target affinity selection-mass spectrometry approach for screening bioactive compounds from natural products. Key steps and parameters including activation of magnetic beads, enzyme/protein immobilization, characterization of functional magnetic beads, screening and identifying active compounds from a complex mixture by LC/MS, are illustrated. The proposed approach is rapid and efficient in screening and identification of bioactive compounds from complex natural products.

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

PubMed Central

Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

2017-01-01

Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free energy binding calculations using the g_mmpbsa technique. Prediction of inhibitory activities of the two lead compounds SEI (7.53) and ACI (6.84) using the 3D-QSAR model reaffirmed their inhibitory characteristics as potential anti-ataxia compounds. PMID:28119557

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach.

PubMed

Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

2016-01-01

Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient ( r 2 ) value of 0.6774, cross-validated correlation coefficient ( q 2 ) of 0.6157 and co-relation coefficient for external test set ( pred _ r 2 ) of 0.7570. A high F -test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of -10.097 and -9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free energy binding calculations using the g_mmpbsa technique. Prediction of inhibitory activities of the two lead compounds SEI (7.53) and ACI (6.84) using the 3D-QSAR model reaffirmed their inhibitory characteristics as potential anti-ataxia compounds.

When public health intervention is not successful: Cost sharing, crowd-out, and selection in Korea's National Cancer Screening Program.

PubMed

Kim, Hyuncheol Bryant; Lee, Sun-Mi

2017-05-01

This study investigates the impact of and behavioral responses to cost sharing in Korea's National Cancer Screening Program, which provides free stomach and breast cancer screenings to those with an income below a certain cutoff. Free cancer screening substantially increases the screening take up rate, yielding more cancer detections. However, the increase in cancer detection is quickly crowded out by cancer detection through other channels such as diagnostic testing and private cancer screening. Further, compliers are much less likely to have cancer than never takers. Crowd-out and selection help explain why the program has been unable to reduce cancer mortality. Copyright © 2017 Elsevier B.V. All rights reserved.

In Silico Identification of a Novel Hinge-Binding Scaffold for Kinase Inhibitor Discovery.

PubMed

Wang, Yanli; Sun, Yuze; Cao, Ran; Liu, Dan; Xie, Yuting; Li, Li; Qi, Xiangbing; Huang, Niu

2017-10-26

To explore novel kinase hinge-binding scaffolds, we carried out structure-based virtual screening against p38α MAPK as a model system. With the assistance of developed kinase-specific structural filters, we identify a novel lead compound that selectively inhibits a panel of kinases with threonine as the gatekeeper residue, including BTK and LCK. These kinases play important roles in lymphocyte activation, which encouraged us to design novel kinase inhibitors as drug candidates for ameliorating inflammatory diseases and cancers. Therefore, we chemically modified our substituted triazole-class lead compound to improve the binding affinity and selectivity via a "minimal decoration" strategy, which resulted in potent and selective kinase inhibitors against LCK (18 nM) and BTK (8 nM). Subsequent crystallographic experiments validated our design. These rationally designed compounds exhibit potent on-target inhibition against BTK in B cells or LCK in T cells, respectively. Our work demonstrates that structure-based virtual screening can be applied to facilitate the development of novel chemical entities in crowded chemical space in the field of kinase inhibitor discovery.

Thermal energy storage systems using fluidized bed heat exchangers

NASA Technical Reports Server (NTRS)

Ramanathan, V.; Weast, T. E.; Ananth, K. P.

1980-01-01

The viability of using fluidized bed heat exchangers (FBHX) for thermal energy storage (TES) in applications with potential for waste heat recovery was investigated. Of the candidate applications screened, cement plant rotary kilns and steel plant electric arc furnaces were identified, via the chosen selection criteria, as having the best potential for successful use of FBHX/TES system. A computer model of the FBHX/TES systems was developed and the technical feasibility of the two selected applications was verified. Economic and tradeoff evaluations in progress for final optimization of the systems and selection of the most promising system for further concept validation are described.

A computational approach to predicting ligand selectivity for the size-based separation of trivalent lanthanides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ivanov, Alexander S.; Bryantsev, Vyacheslav S.

An accurate description of solvation effects for trivalent lanthanide ions is a main stumbling block to the qualitative prediction of selectivity trends along the lanthanide series. In this work, we propose a simple model to describe the differential effect of solvation in the competitive binding of a ligand by lanthanide ions by including weakly co-ordinated counterions in the complexes of more than a +1 charge. The success of the approach to quantitatively reproduce selectivities obtained from aqueous phase complexation studies demonstrates its potential for the design and screening of new ligands for efficient size-based separation.

A computational approach to predicting ligand selectivity for the size-based separation of trivalent lanthanides

DOE PAGES

Ivanov, Alexander S.; Bryantsev, Vyacheslav S.

2016-06-20

An accurate description of solvation effects for trivalent lanthanide ions is a main stumbling block to the qualitative prediction of selectivity trends along the lanthanide series. In this work, we propose a simple model to describe the differential effect of solvation in the competitive binding of a ligand by lanthanide ions by including weakly co-ordinated counterions in the complexes of more than a +1 charge. The success of the approach to quantitatively reproduce selectivities obtained from aqueous phase complexation studies demonstrates its potential for the design and screening of new ligands for efficient size-based separation.

Genetic models of homosexuality: generating testable predictions

PubMed Central

Gavrilets, Sergey; Rice, William R

2006-01-01

Homosexuality is a common occurrence in humans and other species, yet its genetic and evolutionary basis is poorly understood. Here, we formulate and study a series of simple mathematical models for the purpose of predicting empirical patterns that can be used to determine the form of selection that leads to polymorphism of genes influencing homosexuality. Specifically, we develop theory to make contrasting predictions about the genetic characteristics of genes influencing homosexuality including: (i) chromosomal location, (ii) dominance among segregating alleles and (iii) effect sizes that distinguish between the two major models for their polymorphism: the overdominance and sexual antagonism models. We conclude that the measurement of the genetic characteristics of quantitative trait loci (QTLs) found in genomic screens for genes influencing homosexuality can be highly informative in resolving the form of natural selection maintaining their polymorphism. PMID:17015344

A combination of 2D similarity search, pharmacophore, and molecular docking techniques for the identification of vascular endothelial growth factor receptor-2 inhibitors.

PubMed

Ai, Guanhua; Tian, Caiping; Deng, Dawei; Fida, Guissi; Chen, Haiyan; Ma, Yuxiang; Ding, Li; Gu, Yueqing

2015-04-01

The human vascular endothelial growth factor receptor-2 (VEGFR-2) has been an attractive target for the inhibition of angiogenesis. In the current study, we used a hybrid protocol of virtual screening methods to retrieve new VEGFR-2 inhibitors from the Zinc-Specs Database (441 574 compounds). The hybrid protocol included the initial screening of candidates by comparing the 2D similarity to five reported top active inhibitors of 13 VEGFR-2 X-ray crystallography structures, followed by the pharmacophore modeling of virtual screening on the basis of receptor-ligand interactions and further narrowing by LibDOCK to obtain the final hits. Two compounds (AN-919/41439526 and AK-968/40939851) with a high libscore were selected as the final hits for a subsequent cell cytotoxicity study. The two compounds screened exerted significant inhibitory effects on the proliferation of cancer cells (U87 and MCF-7). The results indicated that the hybrid procedure is an effective approach for screening specific receptor inhibitors.

Cost-effectiveness of digital mammography breast cancer screening.

PubMed

Tosteson, Anna N A; Stout, Natasha K; Fryback, Dennis G; Acharyya, Suddhasatta; Herman, Benjamin A; Hannah, Lucy G; Pisano, Etta D

2008-01-01

The DMIST (Digital Mammography Imaging Screening Trial) reported improved breast cancer detection with digital mammography compared with film mammography in selected population subgroups, but it did not assess the economic value of digital relative to film mammography screening. To evaluate the cost-effectiveness of digital mammography screening for breast cancer. Validated, discrete-event simulation model. Data from DMIST and publicly available U.S. data. U.S. women age 40 years or older. Lifetime. Societal and Medicare. All-film mammography screening; all-digital mammography screening; and targeted digital mammography screening, which is age-targeted digital mammography (for women <50 years of age) and age- and density-targeted digital mammography (for women <50 years of age or women > or =50 years of age with dense breasts). Cost per quality-adjusted life-year (QALY) gained. All-digital mammography screening cost $331,000 (95% CI, $268,000 to $403,000) per QALY gained relative to all-film mammography screening but was more costly and less effective than targeted digital mammography screening. Targeted digital mammography screening resulted in more screen-detected cases of cancer and fewer deaths from cancer than either all-film or all-digital mammography screening, with cost-effectiveness estimates ranging from $26,500 (CI, $21,000 to $33,000) per QALY gained for age-targeted digital mammography to $84,500 (CI, $75,000 to $93,000) per QALY gained for age- and density-targeted digital mammography. In the Medicare population, the cost-effectiveness of density-targeted digital mammography screening varied from a base-case estimate of $97,000 (CI, $77,000 to $131,000) to $257,000 per QALY gained (CI, $91,000 to $536,000) in the alternative-case analyses, in which the sensitivity of film mammography was increased and the sensitivity of digital mammography in women with nondense breasts was decreased. Results were sensitive to the cost of digital mammography and to the prevalence of dense breasts. Results were dependent on model assumptions and DMIST findings. Relative to film mammography, screening for breast cancer by using all-digital mammography is not cost-effective. Age-targeted screening with digital mammography seems cost-effective, whereas density-targeted screening strategies are more costly and of uncertain value, particularly among women age 65 years or older.

Cost-Effectiveness Analysis of a National Neonatal Hearing Screening Program in China: Conditions for the Scale-Up

PubMed Central

Tobe, Ruoyan Gai; Mori, Rintaro; Huang, Lihui; Xu, Lingzhong; Han, Demin; Shibuya, Kenji

2013-01-01

Background In 2009, the Chinese Ministry of Health recommended scale-up of routine neonatal hearing screening - previously performed primarily only in select urban hospitals - throughout the entire country. Methods A decision analytical model for a simulated population of all live births in China was developed to compare the costs and health effects of five mutually exclusive interventions: 1) universal screening using Otoacoustic Emission (OAE) and Automated Auditory Brainstem Response (AABR); 2) universal OAE; 3) targeted OAE and AABR; 4) targeted OAE; and 5) no screening. Disability-Adjusted Life Years (DALYs) were calculated for health effects. Results and Discussion Based on the cost-effectiveness and potential health outcomes, the optimal path for scale-up would be to start with targeted OAE and then expand to universal OAE and universal OAE plus AABR. Accessibility of screening, diagnosis, and intervention services significantly affect decision of the options. Conclusion In conclusion, to achieve cost-effectiveness and best health outcomes of the NHS program, the accessibility of screening, diagnosis, and intervention services should be expanded to reach a larger population. The results are thus expected to be of particular benefit in terms of the ‘rolling out’ of the national plan. PMID:23341887

Evolution of the feruloyl esterase MtFae1a from Myceliophthora thermophila towards improved catalysts for antioxidants synthesis.

PubMed

Varriale, Simona; Cerullo, Gabriella; Antonopoulou, Io; Christakopoulos, Paul; Rova, Ulrika; Tron, Thierry; Fauré, Régis; Jütten, Peter; Piechot, Alexander; Brás, Joana L A; Fontes, Carlos M G A; Faraco, Vincenza

2018-06-01

The chemical syntheses currently employed for industrial purposes, including in the manufacture of cosmetics, present limitations such as unwanted side reactions and the need for harsh chemical reaction conditions. In order to overcome these drawbacks, novel enzymes are developed to catalyze the targeted bioconversions. In the present study, a methodology for the construction and the automated screening of evolved variants library of a Type B feruloyl esterase from Myceliophthora thermophila (MtFae1a) was developed and applied to generation of 30,000 mutants and their screening for selecting the variants with higher activity than the wild-type enzyme. The library was generated by error-prone PCR of mtfae1a cDNA and expressed in Saccharomyces cerevisiae. Screening for extracellular enzymatic activity towards 4-nitrocatechol-1-yl ferulate, a new substrate developed ad hoc for high-throughput assays of feruloyl esterases, led to the selection of 30 improved enzyme variants. The best four variants and the wild-type MtFae1a were investigated in docking experiments with hydroxycinnamic acid esters using a model of 3D structure of MtFae1a. These variants were also used as biocatalysts in transesterification reactions leading to different target products in detergentless microemulsions and showed enhanced synthetic activities, although the screening strategy had been based on improved hydrolytic activity.

Potential human cholesterol esterase inhibitor design: benefits from the molecular dynamics simulations and pharmacophore modeling studies.

PubMed

John, Shalini; Thangapandian, Sundarapandian; Lee, Keun Woo

2012-01-01

Human pancreatic cholesterol esterase (hCEase) is one of the lipases found to involve in the digestion of large and broad spectrum of substrates including triglycerides, phospholipids, cholesteryl esters, etc. The presence of bile salts is found to be very important for the activation of hCEase. Molecular dynamic simulations were performed for the apoform and bile salt complexed form of hCEase using the co-ordinates of two bile salts from bovine CEase. The stability of the systems throughout the simulation time was checked and two representative structures from the highly populated regions were selected using cluster analysis. These two representative structures were used in pharmacophore model generation. The generated pharmacophore models were validated and used in database screening. The screened hits were refined for their drug-like properties based on Lipinski's rule of five and ADMET properties. The drug-like compounds were further refined by molecular docking simulation using GOLD program based on the GOLD fitness score, mode of binding, and molecular interactions with the active site amino acids. Finally, three hits of novel scaffolds were selected as potential leads to be used in novel and potent hCEase inhibitor design. The stability of binding modes and molecular interactions of these final hits were re-assured by molecular dynamics simulations.

Therapeutic Remyelination Strategies in a Novel Model of Multiple Sclerosis: Japanese Macaque Encephalomyelitis

DTIC Science & Technology

2012-05-01

determined and compared to simian and human herpesvirus genomes representing alpha-herpesvi- ruses, beta- herpesviruses and gamma-1 and gamma-2 her...report the isolation of a previously unknown herpesvirus , JMRV, isolated from acute JME TABLE 2: Clustal W Alignment of JMRV Genome with Select Simian and...to use this model in pre-clinical screens of novel agents with the potential to inhibit MS attacks and to promote remyelination and regeneration

Discovery of novel urokinase plasminogen activator (uPA) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis.

PubMed

Al-Sha'er, Mahmoud A; Khanfar, Mohammad A; Taha, Mutasem O

2014-01-01

Urokinase plasminogen activator (uPA)-a serine protease-is thought to play a central role in tumor metastasis and angiogenesis and, therefore, inhibition of this enzyme could be beneficial in treating cancer. Toward this end, we explored the pharmacophoric space of 202 uPA inhibitors using seven diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, we employed genetic algorithm-based quantitative structure-activity relationship (QSAR) analysis as a competition arena to select the best possible combination of pharmacophoric models and physicochemical descriptors that can explain bioactivity variation within the training inhibitors (r (2) 162 = 0.74, F-statistic = 64.30, r (2) LOO = 0.71, r (2) PRESS against 40 test inhibitors = 0.79). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the uPA binding pocket. This conclusion was supported by receiver operating characteristic (ROC) curve analyses of the QSAR-selected pharmacophores. Moreover, the three pharmacophores were comparable with binding interactions seen in crystallographic structures of bound ligands within the uPA binding pocket. We employed the resulting pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds. The captured hits were tested in vitro. Overall, our modeling workflow identified new low micromolar anti-uPA hits.

Evaluating large-scale propensity score performance through real-world and synthetic data experiments.

PubMed

Tian, Yuxi; Schuemie, Martijn J; Suchard, Marc A

2018-06-22

Propensity score adjustment is a popular approach for confounding control in observational studies. Reliable frameworks are needed to determine relative propensity score performance in large-scale studies, and to establish optimal propensity score model selection methods. We detail a propensity score evaluation framework that includes synthetic and real-world data experiments. Our synthetic experimental design extends the 'plasmode' framework and simulates survival data under known effect sizes, and our real-world experiments use a set of negative control outcomes with presumed null effect sizes. In reproductions of two published cohort studies, we compare two propensity score estimation methods that contrast in their model selection approach: L1-regularized regression that conducts a penalized likelihood regression, and the 'high-dimensional propensity score' (hdPS) that employs a univariate covariate screen. We evaluate methods on a range of outcome-dependent and outcome-independent metrics. L1-regularization propensity score methods achieve superior model fit, covariate balance and negative control bias reduction compared with the hdPS. Simulation results are mixed and fluctuate with simulation parameters, revealing a limitation of simulation under the proportional hazards framework. Including regularization with the hdPS reduces commonly reported non-convergence issues but has little effect on propensity score performance. L1-regularization incorporates all covariates simultaneously into the propensity score model and offers propensity score performance superior to the hdPS marginal screen.

A Kappa Opioid Model of Atypical Altered Consciousness and Psychosis: U50488, DOI, AC90179 Effects on Prepulse Inhibition and Locomotion in Mice.

PubMed

Ruderman, Michael A; Powell, Susan B; Geyer, Mark A

2009-07-01

Sensorimortor gating and locomotion are behaviors that reflect pre-attentive sensory filtering and higher order, top-down, sensory processing, respectively. These processes are thought to affect either the perception of novelty in an environment (filtering) or cognition (higher order processing), salient features of models of altered states of consciousness (ASC). Drugs with highly selective receptor affinities that produce ASC can help to establish neural correlates, pathways, and mechanisms underlying ASC. Furthermore, screening for substances that selectively reverse drug-induced sensory processing departures is valuable for development of experimental antipsychotics. This study investigated the anomalous opioid sub-type, the kappa opioid (KA) system, within the two ASC models. Significant interaction and reversal effects between KA and the serotonin/2A (5-HT2A) system - the serotonin sub-type associated with classical psychedelics - were observed in three BPM measures. These measures showed that KA activation-induced effects could be reversed by 5-HT2A deactivation. These results suggest that KA could function as an atypical antipsychotic medications and/or as a screening tool for new antipsychotic medicines. The experimental work for this study comprised dose-response and reversal experiments with drugs that activate and deactivate kappa opioid and serotonin systems in the two behavioral models for the first time in mice.

Benchmark Dose Software (BMDS) Development and ...

EPA Pesticide Factsheets

This report is intended to provide an overview of beta version 1.0 of the implementation of a model of repeated measures data referred to as the Toxicodiffusion model. The implementation described here represents the first steps towards integration of the Toxicodiffusion model into the EPA benchmark dose software (BMDS). This version runs from within BMDS 2.0 using an option screen for making model selection, as is done for other models in the BMDS 2.0 suite. This report is intended to provide an overview of beta version 1.0 of the implementation of a model of repeated measures data referred to as the Toxicodiffusion model.

Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of β-Secretase.

PubMed

Jordan, John B; Whittington, Douglas A; Bartberger, Michael D; Sickmier, E Allen; Chen, Kui; Cheng, Yuan; Judd, Ted

2016-04-28

Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with (19)F NMR-based methods has been shown to provide several advantages over (1)H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of (19)F-based fragment screening by detailing the identification of a second-site fragment through (19)F NMR screening that binds to a specific pocket of the aspartic acid protease, β-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment-linking approach, which ultimately yielded a molecule exhibiting a more than 360-fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling.

Touch Interaction with 3D Geographical Visualization on Web: Selected Technological and User Issues

NASA Astrophysics Data System (ADS)

Herman, L.; Stachoň, Z.; Stuchlík, R.; Hladík, J.; Kubíček, P.

2016-10-01

The use of both 3D visualization and devices with touch displays is increasing. In this paper, we focused on the Web technologies for 3D visualization of spatial data and its interaction via touch screen gestures. At the first stage, we compared the support of touch interaction in selected JavaScript libraries on different hardware (desktop PCs with touch screens, tablets, and smartphones) and software platforms. Afterward, we realized simple empiric test (within-subject design, 6 participants, 2 simple tasks, LCD touch monitor Acer and digital terrain models as stimuli) focusing on the ability of users to solve simple spatial tasks via touch screens. An in-house testing web tool was developed and used based on JavaScript, PHP, and X3DOM languages and Hammer.js libraries. The correctness of answers, speed of users' performances, used gestures, and a simple gesture metric was recorded and analysed. Preliminary results revealed that the pan gesture is most frequently used by test participants and it is also supported by the majority of 3D libraries. Possible gesture metrics and future developments including the interpersonal differences are discussed in the conclusion.

Repurposing CRISPR/Cas9 for in situ functional assays.

PubMed

Malina, Abba; Mills, John R; Cencic, Regina; Yan, Yifei; Fraser, James; Schippers, Laura M; Paquet, Marilène; Dostie, Josée; Pelletier, Jerry

2013-12-01

RNAi combined with next-generation sequencing has proven to be a powerful and cost-effective genetic screening platform in mammalian cells. Still, this technology has its limitations and is incompatible with in situ mutagenesis screens on a genome-wide scale. Using p53 as a proof-of-principle target, we readapted the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR associated 9) genome-editing system to demonstrate the feasibility of this methodology for targeted gene disruption positive selection assays. By using novel "all-in-one" lentiviral and retroviral delivery vectors heterologously expressing both a codon-optimized Cas9 and its synthetic guide RNA (sgRNA), we show robust selection for the CRISPR-modified Trp53 locus following drug treatment. Furthermore, by linking Cas9 expression to GFP fluorescence, we use an "all-in-one" system to track disrupted Trp53 in chemoresistant lymphomas in the Eμ-myc mouse model. Deep sequencing analysis of the tumor-derived endogenous Cas9-modified Trp53 locus revealed a wide spectrum of mutants that were enriched with seemingly limited off-target effects. Taken together, these results establish Cas9 genome editing as a powerful and practical approach for positive in situ genetic screens.

Repurposing CRISPR/Cas9 for in situ functional assays

PubMed Central

Malina, Abba; Mills, John R.; Cencic, Regina; Yan, Yifei; Fraser, James; Schippers, Laura M.; Paquet, Marilène; Dostie, Josée; Pelletier, Jerry

2013-01-01

RNAi combined with next-generation sequencing has proven to be a powerful and cost-effective genetic screening platform in mammalian cells. Still, this technology has its limitations and is incompatible with in situ mutagenesis screens on a genome-wide scale. Using p53 as a proof-of-principle target, we readapted the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR associated 9) genome-editing system to demonstrate the feasibility of this methodology for targeted gene disruption positive selection assays. By using novel “all-in-one” lentiviral and retroviral delivery vectors heterologously expressing both a codon-optimized Cas9 and its synthetic guide RNA (sgRNA), we show robust selection for the CRISPR-modified Trp53 locus following drug treatment. Furthermore, by linking Cas9 expression to GFP fluorescence, we use an “all-in-one” system to track disrupted Trp53 in chemoresistant lymphomas in the Eμ-myc mouse model. Deep sequencing analysis of the tumor-derived endogenous Cas9-modified Trp53 locus revealed a wide spectrum of mutants that were enriched with seemingly limited off-target effects. Taken together, these results establish Cas9 genome editing as a powerful and practical approach for positive in situ genetic screens. PMID:24298059

Surface plasmon resonance biosensing: Approaches for screening and characterising antibodies for food diagnostics.

PubMed

Yakes, B J; Buijs, J; Elliott, C T; Campbell, K

2016-08-15

Research in biosensing approaches as alternative techniques for food diagnostics for the detection of chemical contaminants and foodborne pathogens has increased over the last twenty years. The key component of such tests is the biorecognition element whereby polyclonal or monoclonal antibodies still dominate the market. Traditionally the screening of sera or cell culture media for the selection of polyclonal or monoclonal candidate antibodies respectively has been performed by enzyme immunoassays. For niche toxin compounds, enzyme immunoassays can be expensive and/or prohibitive methodologies for antibody production due to limitations in toxin supply for conjugate production. Automated, self-regenerating, chip-based biosensors proven in food diagnostics may be utilised as rapid screening tools for antibody candidate selection. This work describes the use of both single channel and multi-channel surface plasmon resonance (SPR) biosensors for the selection and characterisation of antibodies, and their evaluation in shellfish tissue as standard techniques for the detection of domoic acid, as a model toxin compound. The key advantages in the use of these biosensor techniques for screening hybridomas in monoclonal antibody production were the real time observation of molecular interaction and rapid turnaround time in analysis compared to enzyme immunoassays. The multichannel prototype instrument was superior with 96 analyses completed in 2h compared to 12h for the single channel and over 24h for the ELISA immunoassay. Antibodies of high sensitivity, IC50's ranging from 4.8 to 6.9ng/mL for monoclonal and 2.3-6.0ng/mL for polyclonal, for the detection of domoic acid in a 1min analysis time were selected. Although there is a progression for biosensor technology towards low cost, multiplexed portable diagnostics for the food industry, there remains a place for laboratory-based SPR instrumentation for antibody development for food diagnostics as shown herein. Copyright © 2016 Elsevier B.V. All rights reserved.

Mathematical modeling for novel cancer drug discovery and development.

PubMed

Zhang, Ping; Brusic, Vladimir

2014-10-01

Mathematical modeling enables: the in silico classification of cancers, the prediction of disease outcomes, optimization of therapy, identification of promising drug targets and prediction of resistance to anticancer drugs. In silico pre-screened drug targets can be validated by a small number of carefully selected experiments. This review discusses the basics of mathematical modeling in cancer drug discovery and development. The topics include in silico discovery of novel molecular drug targets, optimization of immunotherapies, personalized medicine and guiding preclinical and clinical trials. Breast cancer has been used to demonstrate the applications of mathematical modeling in cancer diagnostics, the identification of high-risk population, cancer screening strategies, prediction of tumor growth and guiding cancer treatment. Mathematical models are the key components of the toolkit used in the fight against cancer. The combinatorial complexity of new drugs discovery is enormous, making systematic drug discovery, by experimentation, alone difficult if not impossible. The biggest challenges include seamless integration of growing data, information and knowledge, and making them available for a multiplicity of analyses. Mathematical models are essential for bringing cancer drug discovery into the era of Omics, Big Data and personalized medicine.

NREL Screens Universities for Solar and Battery Storage Potential

DOE Office of Scientific and Technical Information (OSTI.GOV)

In support of the U.S. Department of Energy's SunShot initiative, NREL provided solar photovoltaic (PV) screenings in 2016 for eight universities seeking to go solar. NREL conducted an initial technoeconomic assessment of PV and storage feasibility at the selected universities using the REopt model, an energy planning platform that can be used to evaluate RE options, estimate costs, and suggest a mix of RE technologies to meet defined assumptions and constraints. NREL provided each university with customized results, including the cost-effectiveness of PV and storage, recommended system size, estimated capital cost to implement the technology, and estimated life cycle costmore » savings.« less

Functional screening of pharmacological chaperones via restoration of enzyme activity upon denaturation.

PubMed

Shanmuganathan, Meera; Britz-McKibbin, Philip

2012-10-02

Pharmacological chaperones (PCs) are small molecules that stabilize and promote protein folding. Enzyme inhibition is widely used for PC selection; however, it does not accurately reflect chaperone activity. We introduce a functional assay for characterization of PCs based on their capacity to restore enzyme activity that is abolished upon chemical denaturation. Dose-dependent activity curves were performed as a function of urea to assess the chaperone potency of various ligands to β-glucocerebrosidase as a model system. Restoration of enzyme activity upon denaturation allows direct screening of PCs for treatment of genetic disorders associated with protein deficiency, such as Gaucher disease.

Hopping on the methadone bus.

PubMed

Lippert, Steffen; Schumacher, Christoph

2009-05-01

This paper investigates the impact of a 'free drug program' on the market equilibrium of drugs. We introduce a screening model of the hard drug market in which dealers use payment and punishment options to screen between high and low risk users. We show that, if a free drug program selects sufficiently many high-risk drug users, the pure-strategy separating market equilibrium ceases to exist and a symmetric mixed-strategy equilibrium results, in which drug users derive a higher expected utility. This encourages new drug users to enter the market. The novelty of the paper is the transmission mechanism for this effect, which is via the influence on market price.

Perceived Neighborhood Quality and Cancer Screening Behavior: Evidence from the Survey of the Health of Wisconsin

PubMed Central

Beyer, Kirsten M. M.; Malecki, Kristen M.; Hoormann, Kelly A.; Szabo, Aniko; Nattinger, Ann B.

2016-01-01

Socioeconomic disparities in colorectal and breast cancer screening persist, partially accounting for disparities in cancer outcomes. Some neighborhood characteristics – particularly area level socioeconomic factors – have been linked to cancer screening behavior, but few studies have examined the relationship between perceived neighborhood quality and screening behavior, which may provide more insight into the ways in which neighborhood environments shape cancer related behaviors. This study examines the relationship between several aspects of the perceived neighborhood environment and breast and colorectal cancer screening behavior among a population-based sample of Wisconsin residents. A sub-goal was to compare the relevance of different perceived neighborhood factors for different screening tests. This is a cross-sectional study of 2008–2012 data from the Survey of the Health of Wisconsin (SHOW), a population-based annual survey of Wisconsin residents. An average risk sample of Black, Hispanic and White women age 50 and older (n=1265) were selected. Survey regression analyses examined predictors of screening, as well as adherence to screening guidelines. Models controlled for individual socio-demographic information and insurance status. Perceptions of social and physical disorder, including fear of crime and visible garbage, were associated with screening rates. Findings emphasize the particular importance of these factors for colorectal cancer screening, indicating the necessity of improving screening rates in areas characterized by social disorganization, crime, and physical disorder. Additional work should be done to further investigate the pathways that explain the linkage between neighborhood conditions, perceived neighborhood risks and cancer screening behavior. PMID:26275881

Two-colored fluorescence correlation spectroscopy screening for LC3-P62 interaction inhibitors.

PubMed

Tsuganezawa, Keiko; Shinohara, Yoshiyasu; Ogawa, Naoko; Tsuboi, Shun; Okada, Norihisa; Mori, Masumi; Yokoyama, Shigeyuki; Noda, Nobuo N; Inagaki, Fuyuhiko; Ohsumi, Yoshinori; Tanaka, Akiko

2013-10-01

The fluorescence correlation spectroscopy (FCS)-based competitive binding assay to screen for protein-protein interaction inhibitors is a highly sensitive method as compared with the fluorescent polarization assay used conventionally. However, the FCS assay identifies many false-positive compounds, which requires specifically designed orthogonal screenings. A two-colored application of the FCS-based screening was newly developed, and inhibitors of a protein-protein interaction, involving selective autophagy, were selected. We focused on the interaction of LC3 with the adaptor protein p62, because the interaction is crucial to degrade the specific target proteins recruited by p62. First, about 10,000 compounds were subjected to the FCS-based competitive assay using a TAMRA-labeled p62-derived probe, and 29 hit compounds were selected. Next, the obtained hits were evaluated by the second FCS assay, using an Alexa647-labeled p62-derived probe to remove the false-positive compounds, and six hit compounds inhibited the interaction. Finally, we tested all 29 compounds by surface plasmon resonance-based competitive binding assay to evaluate their inhibition of the LC3-p62 interaction and selected two inhibitors with IC50 values less than 2 µM. The two-colored FCS-based screening was shown to be effective to screen for protein-protein interaction inhibitors.

Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain

PubMed Central

2016-01-01

The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors. PMID:26731131

Suicidal Ideation in Pregnancy: An Epidemiologic Review

PubMed Central

Gelaye, Bizu; Kajeepeta, Sandhya; Williams, Michelle A.

2016-01-01

Objective Suicidal behaviors are the leading causes of injury and death worldwide, and are leading causes of maternal deaths in some countries. One of the strongest risk factors, suicidal ideation, is considered a harbinger and distal predictor of later suicide attempt and completion, and also presents an opportunity for interventions prior to physical self-harm. The purpose of this systematic epidemiologic review is to synthesize available research on antepartum suicidal ideation. Data sources Original publications were identified through searches of the electronic databases using the search terms pregnancy, pregnant women, suicidal ideation, and pregnan* and suicid* as root searches. We also reviewed references of published articles. Study Selection We identified a total of 2,626 articles through the electronic database search. After irrelevant and redundant articles were excluded 57 articles were selected. The selected articles were original articles that focused on pregnancy and suicidal ideation. Results Of the 57 included articles, 20 reported prevalence, 26 reported risk factors, 21 reported consequences of antepartum suicidal ideation, and 5 reported on screening measures. Available evidence indicates that pregnant women are more likely than the general population to endorse suicidal ideation. Additionally, a number of risk factors for antepartum suicidal ideation were identified including intimate partner violence, <12 years education, and major depressive disorder. Conclusion There is a need for enhanced screening for antepartum suicidal ideation. The few screening instruments that exist are limited as they were primarily developed to measure antepartum and postpartum depression. Given a substantial proportion of women with suicidal ideation do not meet clinical thresholds of depression and given the stress–diathesis model that shows susceptibility to suicidal behavior independent of depressive disorders, innovative approaches to improve screening and detection of antepartum suicidal ideation are urgently needed. PMID:27324912

A SPR strategy for high-throughput ligand screenings based on synthetic peptides mimicking a selected subdomain of the target protein: a proof of concept on HER2 receptor.

PubMed

Monfregola, Luca; Vitale, Rosa Maria; Amodeo, Pietro; De Luca, Stefania

2009-10-01

The discovery of pharmaceutical agents is a complex, lengthy and costly process, critically depending on the availability of rapid and efficient screening methods. In particular, when targets are large, multidomain proteins, their complexity may affect unfavorably technical feasibility, costs and unambiguity of binding test interpretation. A possible strategy to overcome these problems relies on molecular design of receptor fragments that are: sensible targets for ligand screenings, conformationally stable also as standalone domains, easily synthesized and immobilized on chip for Biacore experiments. An additional desirable feature for new ligands is the ability of selectively targeting alternative conformational states typical of many proteins. To test the feasibility of such approach on a case with potential applicative interest, we developed a surface plasmon resonance (SPR)-based screening method for drug candidates toward HER2, a Tyr-kinase receptor targeted in anticancer therapies. HER2 was mimicked by HER2-DIVMP, a modified fragment of it immobilized onto the sensor surface specifically modeling HER2 domain IV in its bounded form, designed by structural comparison of HER2 alone and in complex with Herceptin, a monoclonal therapeutic anti-HER2 antibody. This design and its implementation in SPR devices was validated by investigating Herceptin- HER2-DIVMP affinity, measuring its dissociation constant (K(D)=19.2 nM). An efficient synthetic procedure to prepare the HER2-DIVMP peptide was also developed. The HER2-DIVMP conformational stability suggested by experimental and computational results, makes it also a valuable candidate as a mold to design new molecules selectively targeting domain IV of HER2.

Virtual Screening Techniques to Probe the Antimalarial Activity of some Traditionally Used Phytochemicals.

PubMed

Shibi, Indira G; Aswathy, Lilly; Jisha, Radhakrishnan S; Masand, Vijay H; Gajbhiye, Jayant M

2016-01-01

Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the 'rule of five' criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by 'Ligplot' analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.

Predictive features of breast cancer on Mexican screening mammography patients

NASA Astrophysics Data System (ADS)

Rodriguez-Rojas, Juan; Garza-Montemayor, Margarita; Trevino-Alvarado, Victor; Tamez-Pena, José Gerardo

2013-02-01

Breast cancer is the most common type of cancer worldwide. In response, breast cancer screening programs are becoming common around the world and public programs now serve millions of women worldwide. These programs are expensive, requiring many specialized radiologists to examine all images. Nevertheless, there is a lack of trained radiologists in many countries as in Mexico, which is a barrier towards decreasing breast cancer mortality, pointing at the need of a triaging system that prioritizes high risk cases for prompt interpretation. Therefore we explored in an image database of Mexican patients whether high risk cases can be distinguished using image features. We collected a set of 200 digital screening mammography cases from a hospital in Mexico, and assigned low or high risk labels according to its BIRADS score. Breast tissue segmentation was performed using an automatic procedure. Image features were obtained considering only the segmented region on each view and comparing the bilateral di erences of the obtained features. Predictive combinations of features were chosen using a genetic algorithms based feature selection procedure. The best model found was able to classify low-risk and high-risk cases with an area under the ROC curve of 0.88 on a 150-fold cross-validation test. The features selected were associated to the differences of signal distribution and tissue shape on bilateral views. The model found can be used to automatically identify high risk cases and trigger the necessary measures to provide prompt treatment.

Reconstruction of the metabolic network of Pseudomonas aeruginosa to interrogate virulence factor synthesis

NASA Astrophysics Data System (ADS)

Bartell, Jennifer A.; Blazier, Anna S.; Yen, Phillip; Thøgersen, Juliane C.; Jelsbak, Lars; Goldberg, Joanna B.; Papin, Jason A.

2017-03-01

Virulence-linked pathways in opportunistic pathogens are putative therapeutic targets that may be associated with less potential for resistance than targets in growth-essential pathways. However, efficacy of virulence-linked targets may be affected by the contribution of virulence-related genes to metabolism. We evaluate the complex interrelationships between growth and virulence-linked pathways using a genome-scale metabolic network reconstruction of Pseudomonas aeruginosa strain PA14 and an updated, expanded reconstruction of P. aeruginosa strain PAO1. The PA14 reconstruction accounts for the activity of 112 virulence-linked genes and virulence factor synthesis pathways that produce 17 unique compounds. We integrate eight published genome-scale mutant screens to validate gene essentiality predictions in rich media, contextualize intra-screen discrepancies and evaluate virulence-linked gene distribution across essentiality datasets. Computational screening further elucidates interconnectivity between inhibition of virulence factor synthesis and growth. Successful validation of selected gene perturbations using PA14 transposon mutants demonstrates the utility of model-driven screening of therapeutic targets.

Genome-scale CRISPR-Cas9 knockout screening in human cells.

PubMed

Shalem, Ophir; Sanjana, Neville E; Hartenian, Ella; Shi, Xi; Scott, David A; Mikkelson, Tarjei; Heckl, Dirk; Ebert, Benjamin L; Root, David E; Doench, John G; Zhang, Feng

2014-01-03

The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.

Recurrence predictive models for patients with hepatocellular carcinoma after radiofrequency ablation using support vector machines with feature selection methods.

PubMed

Liang, Ja-Der; Ping, Xiao-Ou; Tseng, Yi-Ju; Huang, Guan-Tarn; Lai, Feipei; Yang, Pei-Ming

2014-12-01

Recurrence of hepatocellular carcinoma (HCC) is an important issue despite effective treatments with tumor eradication. Identification of patients who are at high risk for recurrence may provide more efficacious screening and detection of tumor recurrence. The aim of this study was to develop recurrence predictive models for HCC patients who received radiofrequency ablation (RFA) treatment. From January 2007 to December 2009, 83 newly diagnosed HCC patients receiving RFA as their first treatment were enrolled. Five feature selection methods including genetic algorithm (GA), simulated annealing (SA) algorithm, random forests (RF) and hybrid methods (GA+RF and SA+RF) were utilized for selecting an important subset of features from a total of 16 clinical features. These feature selection methods were combined with support vector machine (SVM) for developing predictive models with better performance. Five-fold cross-validation was used to train and test SVM models. The developed SVM-based predictive models with hybrid feature selection methods and 5-fold cross-validation had averages of the sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the ROC curve as 67%, 86%, 82%, 69%, 90%, and 0.69, respectively. The SVM derived predictive model can provide suggestive high-risk recurrent patients, who should be closely followed up after complete RFA treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

40 CFR 761.353 - Second level of sample selection.

Code of Federal Regulations, 2012 CFR

2012-07-01

... reduction is to limit the amount of time required to manually cut up larger particles of the waste to pass through a 9.5 millimeter (mm) screen. (a) Selecting a portion of the subsample for particle size reduction... table to select one of these quarters. (b) Reduction of the particle size by the use of a 9.5 mm screen...

40 CFR 761.353 - Second level of sample selection.

Code of Federal Regulations, 2014 CFR

2014-07-01

... reduction is to limit the amount of time required to manually cut up larger particles of the waste to pass through a 9.5 millimeter (mm) screen. (a) Selecting a portion of the subsample for particle size reduction... table to select one of these quarters. (b) Reduction of the particle size by the use of a 9.5 mm screen...

40 CFR 761.353 - Second level of sample selection.

Code of Federal Regulations, 2013 CFR

2013-07-01

... reduction is to limit the amount of time required to manually cut up larger particles of the waste to pass through a 9.5 millimeter (mm) screen. (a) Selecting a portion of the subsample for particle size reduction... table to select one of these quarters. (b) Reduction of the particle size by the use of a 9.5 mm screen...

Stroop Color-Word Test: A Screening Measure of Selective Attention to Differentiate LD From Non LD Children.

ERIC Educational Resources Information Center

Lazarus, Philip J.; And Others

1984-01-01

Used the Stroop Color-Word Test to measure selective attention in learning disabled (N=45) and nonLD (N=50) children. Results indicated that LD children have a significant weakness in the process of selective attention compared to the nonLD children. Findings suggested that the Stroop is an effective screening measure. (JAC)

Directed evolution of stereoselective enzymes based on genetic selection as opposed to screening systems.

PubMed

Acevedo-Rocha, Carlos G; Agudo, Ruben; Reetz, Manfred T

2014-12-10

Directed evolution of stereoselective enzymes provides a means to generate useful biocatalysts for asymmetric transformations in organic chemistry and biotechnology. Almost all of the numerous examples reported in the literature utilize high-throughput screening systems based on suitable analytical techniques. Since the screening step is the bottleneck of the overall procedure, researchers have considered the use of genetic selection systems as an alternative to screening. In principle, selection would be the most elegant and efficient approach because it is based on growth advantage of host cells harboring stereoselective mutants, but devising such selection systems is very challenging. They must be designed so that the host organism profits from the presence of an enantioselective variant. Progress in this intriguing research area is summarized in this review, which also includes some examples of display systems designed for enantioselectivity as assayed by fluorescence-activated cell sorting (FACS). Although the combination of display systems and FACS is a powerful approach, we also envision innovative ideas combining metabolic engineering and genetic selection systems with protein directed evolution for the development of highly selective and efficient biocatalysts. Copyright © 2014 Elsevier B.V. All rights reserved.

Confirming the validity of the CONUT system for early detection and monitoring of clinical undernutrition: comparison with two logistic regression models developed using SGA as the gold standard.

PubMed

González-Madroño, A; Mancha, A; Rodríguez, F J; Culebras, J; de Ulibarri, J I

2012-01-01

To ratify previous validations of the CONUT nutritional screening tool by the development of two probabilistic models using the parameters included in the CONUT, to see if the CONUT´s effectiveness could be improved. It is a two step prospective study. In Step 1, 101 patients were randomly selected, and SGA and CONUT was made. With data obtained an unconditional logistic regression model was developed, and two variants of CONUT were constructed: Model 1 was made by a method of logistic regression. Model 2 was made by dividing the probabilities of undernutrition obtained in model 1 in seven regular intervals. In step 2, 60 patients were selected and underwent the SGA, the original CONUT and the new models developed. The diagnostic efficacy of the original CONUT and the new models was tested by means of ROC curves. Both samples 1 and 2 were put together to measure the agreement degree between the original CONUT and SGA, and diagnostic efficacy parameters were calculated. No statistically significant differences were found between sample 1 and 2, regarding age, sex and medical/surgical distribution and undernutrition rates were similar (over 40%). The AUC for the ROC curves were 0.862 for the original CONUT, and 0.839 and 0.874, for model 1 and 2 respectively. The kappa index for the CONUT and SGA was 0.680. The CONUT, with the original scores assigned by the authors is equally good than mathematical models and thus is a valuable tool, highly useful and efficient for the purpose of Clinical Undernutrition screening.

Selecting, Acquiring, and Using Small Molecule Libraries for High-Throughput Screening

PubMed Central

Dandapani, Sivaraman; Rosse, Gerard; Southall, Noel; Salvino, Joseph M.; Thomas, Craig J.

2015-01-01

The selection, acquisition and use of high quality small molecule libraries for screening is an essential aspect of drug discovery and chemical biology programs. Screening libraries continue to evolve as researchers gain a greater appreciation of the suitability of small molecules for specific biological targets, processes and environments. The decisions surrounding the make-up of any given small molecule library is informed by a multitude of variables and opinions vary on best-practices. The fitness of any collection relies upon upfront filtering to avoiding problematic compounds, assess appropriate physicochemical properties, install the ideal level of structural uniqueness and determine the desired extent of molecular complexity. These criteria are under constant evaluation and revision as academic and industrial organizations seek out collections that yield ever improving results from their screening portfolios. Practical questions including cost, compound management, screening sophistication and assay objective also play a significant role in the choice of library composition. This overview attempts to offer advice to all organizations engaged in small molecule screening based upon current best practices and theoretical considerations in library selection and acquisition. PMID:26705509

Selecting, Acquiring, and Using Small Molecule Libraries for High-Throughput Screening.

PubMed

Dandapani, Sivaraman; Rosse, Gerard; Southall, Noel; Salvino, Joseph M; Thomas, Craig J

The selection, acquisition and use of high quality small molecule libraries for screening is an essential aspect of drug discovery and chemical biology programs. Screening libraries continue to evolve as researchers gain a greater appreciation of the suitability of small molecules for specific biological targets, processes and environments. The decisions surrounding the make-up of any given small molecule library is informed by a multitude of variables and opinions vary on best-practices. The fitness of any collection relies upon upfront filtering to avoiding problematic compounds, assess appropriate physicochemical properties, install the ideal level of structural uniqueness and determine the desired extent of molecular complexity. These criteria are under constant evaluation and revision as academic and industrial organizations seek out collections that yield ever improving results from their screening portfolios. Practical questions including cost, compound management, screening sophistication and assay objective also play a significant role in the choice of library composition. This overview attempts to offer advice to all organizations engaged in small molecule screening based upon current best practices and theoretical considerations in library selection and acquisition.

Selected approaches for rational drug design and high throughput screening to identify anti-cancer molecules.

PubMed

Hedvat, Michael; Emdad, Luni; Das, Swadesh K; Kim, Keetae; Dasgupta, Santanu; Thomas, Shibu; Hu, Bin; Zhu, Shan; Dash, Rupesh; Quinn, Bridget A; Oyesanya, Regina A; Kegelman, Timothy P; Sokhi, Upneet K; Sarkar, Siddik; Erdogan, Eda; Menezes, Mitchell E; Bhoopathi, Praveen; Wang, Xiang-Yang; Pomper, Martin G; Wei, Jun; Wu, Bainan; Stebbins, John L; Diaz, Paul W; Reed, John C; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

2012-11-01

Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.

[Study on lipid-lowering traditional Chinese medicines based on pharmacophore technology and patent retrieval].

PubMed

Huo, Xiao-qian; He, Yu-su; Qiao, Lian-sheng; Sun, Zhi-yi; Zhang, Yan-ling

2014-12-01

The combined application of statins that inhibit HMG-CoA reductase and fibrates that activate PPAR-α can produce a better lipid-lowering effect than the simple application, but with stronger adverse reactions at the same time. In the treatment of hyperlipidemia, the combined administration of TCMs and HMG-CoA reductase inhibitor in treating hyperlipidemia shows stable efficacy and less adverse reactions, and provides a new option for the combined application of drugs. In this article, the pharmacophore technology was used to search chemical components of TCMs, trace their source herbs, and determine the potential common TCMs that could activate PPAR-α. Because there is no hyperlipidemia-related medication reference in modern TCM classics, to ensure the high safety and efficacy of all selected TCMs, we selected TCMs that are proved to be combined with statins in the World Traditional/Natural Medicine Patent Database, analyzed corresponding drugs in pharmacophore results based on that, and finally obtained common TCMs that can be applied in PPAR-α and combined with statins. Specifically, the pharmacophore model was based on eight receptor-ligand complexes of PPAR-α. The Receptor-Ligand Pharmacophore Generation module in the DS program was used to build the model, optimize with the Screen Library module, and get the best sub-pharmacophore, which consisted of two hydrogen bond acceptor, three hydrophobic groups and 19 excluded volumes, with the identification effectiveness index value N of 2. 82 and the comprehensive evaluation index CAI value of 1. 84. The model was used to screen the TCMD database, hit 5,235 kinds of chemical components and 1 193 natural animals and plants, and finally determine 62 TCMs. Through patent retrieval, we found 38 TCMs; After comparing with the virtual screening results, we finally got seven TCMs.

Efficient selective screening for heart failure in elderly men and women from the community: A diagnostic individual participant data meta-analysis

PubMed Central

Kievit, Rogier F; Hoes, Arno W; Bots, Michiel L; van Riet, Evelien ES; van Mourik, Yvonne; Bertens, Loes CM; Boonman-de Winter, Leandra JM; den Ruijter, Hester M; Rutten, Frans H

2018-01-01

Background Prevalence of undetected heart failure in older individuals is high in the community, with patients being at increased risk of morbidity and mortality due to the chronic and progressive nature of this complex syndrome. An essential, yet currently unavailable, strategy to pre-select candidates eligible for echocardiography to confirm or exclude heart failure would identify patients earlier, enable targeted interventions and prevent disease progression. The aim of this study was therefore to develop and validate such a model that can be implemented clinically. Methods and results Individual patient data from four primary care screening studies were analysed. From 1941 participants >60 years old, 462 were diagnosed with heart failure, according to criteria of the European Society of Cardiology heart failure guidelines. Prediction models were developed in each cohort followed by cross-validation, omitting each of the four cohorts in turn. The model consisted of five independent predictors; age, history of ischaemic heart disease, exercise-related shortness of breath, body mass index and a laterally displaced/broadened apex beat, with no significant interaction with sex. The c-statistic ranged from 0.70 (95% confidence interval (CI) 0.64–0.76) to 0.82 (95% CI 0.78–0.87) at cross-validation and the calibration was reasonable with Observed/Expected ratios ranging from 0.86 to 1.15. The clinical model improved with the addition of N-terminal pro B-type natriuretic peptide with the c-statistic increasing from 0.76 (95% CI 0.70–0.81) to 0.89 (95% CI 0.86–0.92) at cross-validation. Conclusion Easily obtainable patient characteristics can select older men and women from the community who are candidates for echocardiography to confirm or refute heart failure. PMID:29327942

Efficient selective screening for heart failure in elderly men and women from the community: A diagnostic individual participant data meta-analysis.

PubMed

Kievit, Rogier F; Gohar, Aisha; Hoes, Arno W; Bots, Michiel L; van Riet, Evelien Es; van Mourik, Yvonne; Bertens, Loes Cm; Boonman-de Winter, Leandra Jm; den Ruijter, Hester M; Rutten, Frans H

2018-03-01

Background Prevalence of undetected heart failure in older individuals is high in the community, with patients being at increased risk of morbidity and mortality due to the chronic and progressive nature of this complex syndrome. An essential, yet currently unavailable, strategy to pre-select candidates eligible for echocardiography to confirm or exclude heart failure would identify patients earlier, enable targeted interventions and prevent disease progression. The aim of this study was therefore to develop and validate such a model that can be implemented clinically. Methods and results Individual patient data from four primary care screening studies were analysed. From 1941 participants >60 years old, 462 were diagnosed with heart failure, according to criteria of the European Society of Cardiology heart failure guidelines. Prediction models were developed in each cohort followed by cross-validation, omitting each of the four cohorts in turn. The model consisted of five independent predictors; age, history of ischaemic heart disease, exercise-related shortness of breath, body mass index and a laterally displaced/broadened apex beat, with no significant interaction with sex. The c-statistic ranged from 0.70 (95% confidence interval (CI) 0.64-0.76) to 0.82 (95% CI 0.78-0.87) at cross-validation and the calibration was reasonable with Observed/Expected ratios ranging from 0.86 to 1.15. The clinical model improved with the addition of N-terminal pro B-type natriuretic peptide with the c-statistic increasing from 0.76 (95% CI 0.70-0.81) to 0.89 (95% CI 0.86-0.92) at cross-validation. Conclusion Easily obtainable patient characteristics can select older men and women from the community who are candidates for echocardiography to confirm or refute heart failure.

[Generalized cost-effectiveness of preventive interventions against cervical cancer in Mexican women: results of a Markov model from the public sector perspective].

PubMed

Gutiérrez-Delgado, Cristina; Báez-Mendoza, Camilo; González-Pier, Eduardo; de la Rosa, Alejandra Prieto; Witlen, Renee

2008-01-01

To develop a generalized cost-effectiveness analysis (GCEA) of the HPV vaccine, hybrid capture screening (HC) and Papanicolaou screening (Pap) in the Mexican context. From April to August 2007, in Mexico, a GCEA of the interventions was developed for 10 possible scenarios using a Markov model from the public sector perspective as payer. Scenarios considering 80% coverage show an ACER per DALY averted of $16678 pesos for Pap of women between ages 25 and 64, $17277 pesos for HC of women between ages 30 and 64, and $84008 pesos for vaccination of 12-year-old girls. Annual financing of $621, $741 and $2255 million pesos, respectively, is needed for these scenarios. A selective, combined introduction of Pap-HC screening that considers the comparative advantages of application in different populations and geographical areas is suggested. Additionally, it is suggested to introduce the vaccine once a threshold price of $181 pesos per dose -when the vaccine becomes equal in terms of cost-effectiveness to HC- has been achieved.

Discrete Fourier Transform-Based Multivariate Image Analysis: Application to Modeling of Aromatase Inhibitory Activity.

PubMed

Barigye, Stephen J; Freitas, Matheus P; Ausina, Priscila; Zancan, Patricia; Sola-Penna, Mauro; Castillo-Garit, Juan A

2018-02-12

We recently generalized the formerly alignment-dependent multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) method through the application of the discrete Fourier transform (DFT), allowing for its application to noncongruent and structurally diverse chemical compound data sets. Here we report the first practical application of this method in the screening of molecular entities of therapeutic interest, with human aromatase inhibitory activity as the case study. We developed an ensemble classification model based on the two-dimensional (2D) DFT MIA-QSAR descriptors, with which we screened the NCI Diversity Set V (1593 compounds) and obtained 34 chemical compounds with possible aromatase inhibitory activity. These compounds were docked into the aromatase active site, and the 10 most promising compounds were selected for in vitro experimental validation. Of these compounds, 7419 (nonsteroidal) and 89 201 (steroidal) demonstrated satisfactory antiproliferative and aromatase inhibitory activities. The obtained results suggest that the 2D-DFT MIA-QSAR method may be useful in ligand-based virtual screening of new molecular entities of therapeutic utility.

A Risk Prediction Index for Advanced Colorectal Neoplasia at Screening Colonoscopy.

PubMed

Schroy, Paul C; Wong, John B; O'Brien, Michael J; Chen, Clara A; Griffith, John L

2015-07-01

Eliciting patient preferences within the context of shared decision making has been advocated for colorectal cancer screening. Risk stratification for advanced colorectal neoplasia (ACN) might facilitate more effective shared decision making when selecting an appropriate screening option. Our objective was to develop and validate a clinical index for estimating the probability of ACN at screening colonoscopy. We conducted a cross-sectional analysis of 3,543 asymptomatic, mostly average-risk patients 50-79 years of age undergoing screening colonoscopy at two urban safety net hospitals. Predictors of ACN were identified using multiple logistic regression. Model performance was internally validated using bootstrapping methods. The final index consisted of five independent predictors of risk (age, smoking, alcohol intake, height, and a combined sex/race/ethnicity variable). Smoking was the strongest predictor (net reclassification improvement (NRI), 8.4%) and height the weakest (NRI, 1.5%). Using a simplified weighted scoring system based on 0.5 increments of the adjusted odds ratio, the risk of ACN ranged from 3.2% (95% confidence interval (CI), 2.6-3.9) for the low-risk group (score ≤2) to 8.6% (95% CI, 7.4-9.7) for the intermediate/high-risk group (score 3-11). The model had moderate to good overall discrimination (C-statistic, 0.69; 95% CI, 0.66-0.72) and good calibration (P=0.73-0.93). A simple 5-item risk index based on readily available clinical data accurately stratifies average-risk patients into low- and intermediate/high-risk categories for ACN at screening colonoscopy. Uptake into clinical practice could facilitate more effective shared decision-making for CRC screening, particularly in situations where patient and provider test preferences differ.

Building synthetic gene circuits from combinatorial libraries: screening and selection strategies.

PubMed

Schaerli, Yolanda; Isalan, Mark

2013-07-01

The promise of wide-ranging biotechnology applications inspires synthetic biologists to design novel genetic circuits. However, building such circuits rationally is still not straightforward and often involves painstaking trial-and-error. Mimicking the process of natural selection can help us to bridge the gap between our incomplete understanding of nature's design rules and our desire to build functional networks. By adopting the powerful method of directed evolution, which is usually applied to protein engineering, functional networks can be obtained through screening or selecting from randomised combinatorial libraries. This review first highlights the practical options to introduce combinatorial diversity into gene circuits and then examines strategies for identifying the potentially rare library members with desired functions, either by screening or selection.

Development of a 3D Tissue Culture-Based High-Content Screening Platform That Uses Phenotypic Profiling to Discriminate Selective Inhibitors of Receptor Tyrosine Kinases.

PubMed

Booij, Tijmen H; Klop, Maarten J D; Yan, Kuan; Szántai-Kis, Csaba; Szokol, Balint; Orfi, Laszlo; van de Water, Bob; Keri, Gyorgy; Price, Leo S

2016-10-01

3D tissue cultures provide a more physiologically relevant context for the screening of compounds, compared with 2D cell cultures. Cells cultured in 3D hydrogels also show complex phenotypes, increasing the scope for phenotypic profiling. Here we describe a high-content screening platform that uses invasive human prostate cancer cells cultured in 3D in standard 384-well assay plates to study the activity of potential therapeutic small molecules and antibody biologics. Image analysis tools were developed to process 3D image data to measure over 800 phenotypic parameters. Multiparametric analysis was used to evaluate the effect of compounds on tissue morphology. We applied this screening platform to measure the activity and selectivity of inhibitors of the c-Met and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases in 3D cultured prostate carcinoma cells. c-Met and EGFR activity was quantified based on the phenotypic profiles induced by their respective ligands, hepatocyte growth factor and EGF. The screening method was applied to a novel collection of 80 putative inhibitors of c-Met and EGFR. Compounds were identified that induced phenotypic profiles indicative of selective inhibition of c-Met, EGFR, or bispecific inhibition of both targets. In conclusion, we describe a fully scalable high-content screening platform that uses phenotypic profiling to discriminate selective and nonselective (off-target) inhibitors in a physiologically relevant 3D cell culture setting. © 2016 Society for Laboratory Automation and Screening.

Crystallization of Stretched Polyimides: A Structure-Property Study

NASA Technical Reports Server (NTRS)

Hinkley, Jeffrey A.; Dezern, James F.

2002-01-01

A simple rotational isomeric state model was used to detect the degree to which polyimide repeat units might align to give an extended crystal. It was found experimentally that the hallmarks of stretch-crystallization were more likely to occur in materials whose molecules could readily give extended, aligned conformations. A proposed screening criterion was 84% accurate in selecting crystallizing molecules.

Syphilis Screening and Diagnosis Among Men Who Have Sex With Men, 2008-2014, 20 U.S. Cities.

PubMed

An, Qian; Wejnert, Cyprian; Bernstein, Kyle; Paz-Bailey, Gabriela

2017-07-01

Annual screening for syphilis is indicated for all sexually active men who have sex with men (MSM). Using National HIV Behavioral Surveillance data from 2008, 2011, and 2014, we assessed trends in self-reported syphilis testing and diagnoses in the past 12 months among MSM. We calculated percentages of syphilis screening and diagnosis by selected characteristics for each year. Trends were assessed using Poisson regression models with generalized estimation equations. Analysis of syphilis diagnosis was limited to participants who reported syphilis screening. Analysis included data from 28,295 sexually active MSM. Overall, 49% of MSM interviewed in 2014 reported syphilis screening, a significant increase from 40% in 2011 and 38% in 2008. In 2014, syphilis screening was most commonly reported by MSM who were aged 25-29 years (56%), HIV positive (68%), and had >10 sexual partners in the past 12 months (65%). The largest increases in syphilis screening between 2008 and 2014 were among MSM aged 30-39 years (37%-52%) and MSM who reported >10 sex partners (48%-65%). Among MSM who reported syphilis screening, the diagnoses of syphilis increased from 9% in 2008 to 11% in 2014. Increases in syphilis diagnosis were observed among MSM who were aged 25-29 years (6%-10%), black (9%-14%), HIV positive (15%-21%), and reported >10 sexual partners (11%-17%). Although syphilis screening among MSM increased during 2008-2014, less than half of MSM reported recent syphilis screening in 2014. Given continued increases in syphilis among MSM, innovative interventions are needed to improve compliance with screening recommendations.

Immobilized OBOC combinatorial bead array to facilitate multiplicative screening.

PubMed

Xiao, Wenwu; Bononi, Fernanda C; Townsend, Jared; Li, Yuanpei; Liu, Ruiwu; Lam, Kit S

2013-07-01

One-bead-one-compound (OBOC) combinatorial library screening has been broadly utilized for the last two decades to identify small molecules, peptides or peptidomimetics targeting variable screening probes such as cell surface receptors, bacteria, protein kinases, phosphatases, proteases etc. In previous screening methods, library beads were suspended in solution and screened against one single probe. Only the positive beads were tracked and isolated for additional screens and finally selected for chemical decoding. During this process, the remaining negative beads were not tracked and discarded. Here we report a novel bead immobilization method such that a bead library array can be conveniently prepared and screened in its entirety, sequentially many times with a series of distinct probes. This method not only allows us to increase the screening efficiency but also permits us to determine the binding profile of each and every library bead against a large number of target receptors. As proof of concept, we serially screened a random OBOC disulfide containing cyclic heptapeptide library with three water soluble dyes as model probes: malachite green, bromocresol purple and indigo carmine. This multiplicative screening approach resulted in a rapid determination of the binding profile of each and every bead respective to each of the three dyes. Beads that interacted with malachite green only, bromocresol purple only, or both indigo carmine and bromocresol purple were isolated, and their peptide sequences were determined with microsequencer. Ultimately, the novel OBOC multiplicative screening approach could play a key role in the enhancement of existing on-bead assays such as whole cell binding, bacteria binding, protein binding, posttranslational modifications etc. with increased efficiency, capacity, and specificity.

Managing problem employees: a model program and practical guide.

PubMed

Miller, Laurence

2010-01-01

This article presents a model program for managing problem employees that includes a description ofthe basic types of problem employees and employee problems, as well as practical recommendations for. (1) selection and screening, (2) education and training, (3) coaching and counseling, (4) discipline, (5) psychological fitness-for-duty evaluations, (6) mental health services, (7) termination, and (8) leadership and administrative strategies. Throughout, the emphasis on balancing the need for order and productivity in the workplace with fairness and concern for employee health and well-being.

45 CFR 1151.33 - Employment criteria.

Code of Federal Regulations, 2013 CFR

2013-10-01

... HUMANITIES NATIONAL ENDOWMENT FOR THE ARTS NONDISCRIMINATION ON THE BASIS OF HANDICAP Discrimination... or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as used by the...

45 CFR 1151.33 - Employment criteria.

Code of Federal Regulations, 2014 CFR

2014-10-01

... HUMANITIES NATIONAL ENDOWMENT FOR THE ARTS NONDISCRIMINATION ON THE BASIS OF HANDICAP Discrimination... or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as used by the...

45 CFR 1151.33 - Employment criteria.

Code of Federal Regulations, 2012 CFR

2012-10-01

... HUMANITIES NATIONAL ENDOWMENT FOR THE ARTS NONDISCRIMINATION ON THE BASIS OF HANDICAP Discrimination... or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as used by the...

Transitioning NWChem to the Next Generation of Manycore Machines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bylaska, Eric J.; Apra, E; Kowalski, Karol

The NorthWest chemistry (NWChem) modeling software is a popular molecular chemistry simulation software that was designed from the start to work on massively parallel processing supercomputers [1-3]. It contains an umbrella of modules that today includes self-consistent eld (SCF), second order Møller-Plesset perturbation theory (MP2), coupled cluster (CC), multiconguration self-consistent eld (MCSCF), selected conguration interaction (CI), tensor contraction engine (TCE) many body methods, density functional theory (DFT), time-dependent density functional theory (TDDFT), real-time time-dependent density functional theory, pseudopotential plane-wave density functional theory (PSPW), band structure (BAND), ab initio molecular dynamics (AIMD), Car-Parrinello molecular dynamics (MD), classical MD, hybrid quantum mechanicsmore » molecular mechanics (QM/MM), hybrid ab initio molecular dynamics molecular mechanics (AIMD/MM), gauge independent atomic orbital nuclear magnetic resonance (GIAO NMR), conductor like screening solvation model (COSMO), conductor-like screening solvation model based on density (COSMO-SMD), and reference interaction site model (RISM) solvation models, free energy simulations, reaction path optimization, parallel in time, among other capabilities [4]. Moreover, new capabilities continue to be added with each new release.« less

Electronic screen use and mental well-being of 10-12-year-old children.

PubMed

Yang, Fei; Helgason, Asgeir R; Sigfusdottir, Inga Dora; Kristjansson, Alfgeir Logi

2013-06-01

Today's children spend a great deal of time viewing electronic screen material, but the consequences of such behaviors, if any, are unknown. This study sought to identify (i) the magnitude of total daily electronic screen time and (ii) the relations between electronic screen use and mental well-being indicators, in a sample of 10-12-year-old children. We analysed cross-sectional, population-based data of 10-12-year-old children from the 2007 Youth in Iceland school survey (n = 10,829, response rate: 81.7%, boys: 50.5%). Logistic regression models with odds ratios and 95% confidence intervals were conducted to assess the odds of each selected mental well-being indicator, depending on the number of daily hours spent on each electronic screen-based activity. All analyses were conducted separately for boys and girls and adjusted for family structure. The prevalence of self-reported screen use of 4 hours per day or more ranges from 2.8% to 6.6% among boys and from 1.0% to 3.8% among girls. All five screen-based activities were significantly associated with all seven well-being indicators (P < 0.001) with symptoms being more common with increased time spent on screen use. This study is the first of its kind to demonstrate a dose-response relationship between electronic screen use and mental well-being in 10-12-year-old children. Further research is needed to assess the validity and potential implications of these findings.

Small median tumor diameter at cure threshold (<20 mm) among aggressive non-small cell lung cancers in male smokers predicts both chest X-ray and CT screening outcomes in a novel simulation framework.

PubMed

Goldwasser, Deborah L; Kimmel, Marek

2013-01-01

The effectiveness of population-wide lung cancer screening strategies depends on the underlying natural course of lung cancer. We evaluate the expected stage distribution in the Mayo CT screening study under an existing simulation model of non-small cell lung cancer (NSCLC) progression calibrated to the Mayo lung project (MLP). Within a likelihood framework, we evaluate whether the probability of 5-year NSCLC survival conditional on tumor diameter at detection depends significantly on screening detection modality, namely chest X-ray and computed tomography. We describe a novel simulation framework in which tumor progression depends on cellular proliferation and mutation within a stem cell compartment of the tumor. We fit this model to randomized trial data from the MLP and produce estimates of the median radiologic size at the cure threshold. We examine the goodness of model fit with respect to radiologic tumor size and 5-year NSCLC survival among incident cancers in both the MLP and Mayo CT studies. An existing model of NSCLC progression under-predicts the number of advanced-stage incident NSCLCs among males in the Mayo CT study (p-value = 0.004). The probability of 5-year NSCLC survival conditional on tumor diameter depends significantly on detection modality (p-value = 0.0312). In our new model, selected solution sets having a median tumor diameter of 16.2-22.1 mm at cure threshold among aggressive NSCLCs predict both MLP and Mayo CT outcomes. We conclude that the median lung tumor diameter at cure threshold among aggressive NSCLCs in male smokers may be small (<20 mm). Copyright © 2012 UICC.

Predicting School Performance with the Early Screening Inventory.

ERIC Educational Resources Information Center

Meisels, Samuel J.; And Others

1984-01-01

Proposes criteria for defining and selecting preschool developmental screening instruments and describes the Early Screening Inventory (ESI), a developmental screening instrument designed to satisfy these criteria. Presents results of several studies demonstrating that the ESI predicts school performance with moderate to excellent accuracy through…

The establishment of insulin resistance model in FL83B and L6 cell

NASA Astrophysics Data System (ADS)

Liu, Lanlan; Han, Jizhong; Li, Haoran; Liu, Mengmeng; Zeng, Bin

2017-10-01

The insulin resistance models of mouse liver epithelial and rat myoblasts cells were induced by three kinds of inducers: dexamethasone, high insulin and high glucose. The purpose is to select the optimal insulin resistance model, to provide a simple and reliable TR cell model for the study of the pathogenesis of TR and the improvement of TR drugs and functional foods. The MTT method is used for toxicity screening of three compounds, selecting security and suitable concentration. We performed a Glucose oxidase peroxidase (GOD-POD) method involving FL83B and L6 cell with dexamethasone, high insulin and high glucose-induced insulin resistance. Results suggested that FL83B cells with dexamethasone-induced (0.25uM) were established insulin resistance and L6 cells with high-glucose (30mM) and dexamethasone-induced (0.25uM) were established insulin resistance.

Molecular diversity management strategies for building and enhancement of diverse and focused lead discovery compound screening collections.

PubMed

Schuffenhauer, A; Popov, M; Schopfer, U; Acklin, P; Stanek, J; Jacoby, E

2004-12-01

This publication describes processes for the selection of chemical compounds for the building of a high-throughput screening (HTS) collection for drug discovery, using the currently implemented process in the Discovery Technologies Unit of the Novartis Institute for Biomedical Research, Basel Switzerland as reference. More generally, the currently existing compound acquisition models and practices are discussed. Our informatics, chemistry and biology-driven compound selection consists of two steps: 1) The individual compounds are filtered and grouped into three priority classes on the basis of their individual structural properties. Substructure filters are used to eliminate or penalize compounds based on unwanted structural properties. The similarity of the structures to reference ligands of the main proven druggable target families is computed, and drug-similar compounds are prioritized for the following diversity analysis. 2) The compounds are compared to the archive compounds and a diversity analysis is performed. This is done separately for the prioritized, regular and penalized compounds with increasingly stringent dissimilarity criterion. The process includes collecting vendor catalogues and monitoring the availability of samples together with the selection and purchase decision points. The development of a corporate vendor catalogue database is described. In addition to the selection methods on a per single molecule basis, selection criteria for scaffold and combinatorial chemistry projects in collaboration with compound vendors are discussed.

Evaluation of control measures for bovine viral diarrhea implemented in Nemuro District, Hokkaido, Japan, using a scenario tree model

PubMed Central

ISODA, Norikazu; ASANO, Akihiro; ICHIJO, Michiru; WAKAMORI, Shiho; OHNO, Hiroshi; SATO, Kazuhiko; OKAMOTO, Hirokazu; NAKAO, Shigeru; KATO, Hajime; SAITO, Kazuma; ITO, Naoki; USUI, Akira; TAKAYAMA, Hiroaki; SAKODA, Yoshihiro

2017-01-01

A scenario tree model was developed to propose efficient bovine viral diarrhea (BVD) control measures. The model used field data in eastern Hokkaido where the risk of BVDV infection in cattle has been reduced by an eradication program including mass vaccination, individual tests prior to communal pasture grazing, herd screening tests using bulk milk, and outbreak investigations of newly infected herds. These four activities were then used as hypothesized control measures in the simulation. In each simulation, the numbers of cattle infected persistently and transiently with BVDV detected by clinical manifestations and diagnosis tests and of missed by all of the diagnosis tests were calculated, and the numbers were used as indicators to be compared for the efficacy of the control measures. The model outputs indicated that the adoption of mass vaccination decreased the number of missed BVD cattle, although it did not increase the number of detected BVD cattle. Under implementation of mass vaccination, the efficacy of individual tests on selected 20% of the young and adult cattle was equal to that of the herd screening test performed in all the herds. When the virus prevalence or the number of sensitive animals becomes low, the efficacy of herd screening test was superior to one of individual tests. Considering the model outputs together, the scenario tree model developed in the present study was useful to compare the efficacy of the control measures for BVD. PMID:28539533

Evaluation of control measures for bovine viral diarrhea implemented in Nemuro District, Hokkaido, Japan, using a scenario tree model.

PubMed

Isoda, Norikazu; Asano, Akihiro; Ichijo, Michiru; Wakamori, Shiho; Ohno, Hiroshi; Sato, Kazuhiko; Okamoto, Hirokazu; Nakao, Shigeru; Kato, Hajime; Saito, Kazuma; Ito, Naoki; Usui, Akira; Takayama, Hiroaki; Sakoda, Yoshihiro

2017-07-07

A scenario tree model was developed to propose efficient bovine viral diarrhea (BVD) control measures. The model used field data in eastern Hokkaido where the risk of BVDV infection in cattle has been reduced by an eradication program including mass vaccination, individual tests prior to communal pasture grazing, herd screening tests using bulk milk, and outbreak investigations of newly infected herds. These four activities were then used as hypothesized control measures in the simulation. In each simulation, the numbers of cattle infected persistently and transiently with BVDV detected by clinical manifestations and diagnosis tests and of missed by all of the diagnosis tests were calculated, and the numbers were used as indicators to be compared for the efficacy of the control measures. The model outputs indicated that the adoption of mass vaccination decreased the number of missed BVD cattle, although it did not increase the number of detected BVD cattle. Under implementation of mass vaccination, the efficacy of individual tests on selected 20% of the young and adult cattle was equal to that of the herd screening test performed in all the herds. When the virus prevalence or the number of sensitive animals becomes low, the efficacy of herd screening test was superior to one of individual tests. Considering the model outputs together, the scenario tree model developed in the present study was useful to compare the efficacy of the control measures for BVD.

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening.

PubMed

Millard, Marie; Yakavets, Ilya; Zorin, Vladimir; Kulmukhamedova, Aigul; Marchal, Sophie; Bezdetnaya, Lina

2017-01-01

The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS) model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM) components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs) play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a better comprehension of the interactions between NPs and tumor components that affect tumor drug delivery. MCTS is particularly suitable for the high-throughput screening of new nanodrugs.

Active-learning strategies in computer-assisted drug discovery.

PubMed

Reker, Daniel; Schneider, Gisbert

2015-04-01

High-throughput compound screening is time and resource consuming, and considerable effort is invested into screening compound libraries, profiling, and selecting the most promising candidates for further testing. Active-learning methods assist the selection process by focusing on areas of chemical space that have the greatest chance of success while considering structural novelty. The core feature of these algorithms is their ability to adapt the structure-activity landscapes through feedback. Instead of full-deck screening, only focused subsets of compounds are tested, and the experimental readout is used to refine molecule selection for subsequent screening cycles. Once implemented, these techniques have the potential to reduce costs and save precious materials. Here, we provide a comprehensive overview of the various computational active-learning approaches and outline their potential for drug discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Simultaneous Identification of Potential Pathogenicity Factors of Mycoplasma agalactiae in the Natural Ovine Host by Negative Selection

PubMed Central

Hegde, Shivanand; Hegde, Shrilakshmi; Zimmermann, Martina; Flöck, Martina; Spergser, Joachim; Rosengarten, Renate

2015-01-01

Mycoplasmas possess complex pathogenicity determinants that are largely unknown at the molecular level. Mycoplasma agalactiae serves as a useful model to study the molecular basis of mycoplasma pathogenicity. The generation and in vivo screening of a transposon mutant library of M. agalactiae were employed to unravel its host colonization factors. Tn4001mod mutants were sequenced using a novel sequencing method, and functionally heterogeneous pools containing 15 to 19 selected mutants were screened simultaneously through two successive cycles of sheep intramammary infections. A PCR-based negative selection method was employed to identify mutants that failed to colonize the udders and draining lymph nodes in the animals. A total of 14 different mutants found to be absent from ≥95% of samples were identified and subsequently verified via a second round of stringent confirmatory screening where 100% absence was considered attenuation. Using this criterion, seven mutants with insertions in genes MAG1050, MAG2540, MAG3390, uhpT, eutD, adhT, and MAG4460 were not recovered from any of the infected animals. Among the attenuated mutants, many contain disruptions in hypothetical genes, implying their previously unknown role in M. agalactiae pathogenicity. These data indicate the putative role of functionally different genes, including hypothetical ones, in the pathogenesis of M. agalactiae. Defining the precise functions of the identified genes is anticipated to increase our understanding of M. agalactiae infections and to develop successful intervention strategies against it. PMID:25916984

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Wenjun; Ercan, Dalia; Chen, Liang

2010-01-12

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potentmore » against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.« less

Prediction of success in FAA air traffic control field training as a function of selection and screening test performance.

DOT National Transportation Integrated Search

1989-05-01

This study compared correlations between Office of Personnel Management (OPM) selection test scores for Air Traffic Control Specialists (ATCSs) and scores from the FAA Academy's second-stage screening program with measures of field training performan...

Identifiability in N-mixture models: a large-scale screening test with bird data.

PubMed

Kéry, Marc

2018-02-01

Binomial N-mixture models have proven very useful in ecology, conservation, and monitoring: they allow estimation and modeling of abundance separately from detection probability using simple counts. Recently, doubts about parameter identifiability have been voiced. I conducted a large-scale screening test with 137 bird data sets from 2,037 sites. I found virtually no identifiability problems for Poisson and zero-inflated Poisson (ZIP) binomial N-mixture models, but negative-binomial (NB) models had problems in 25% of all data sets. The corresponding multinomial N-mixture models had no problems. Parameter estimates under Poisson and ZIP binomial and multinomial N-mixture models were extremely similar. Identifiability problems became a little more frequent with smaller sample sizes (267 and 50 sites), but were unaffected by whether the models did or did not include covariates. Hence, binomial N-mixture model parameters with Poisson and ZIP mixtures typically appeared identifiable. In contrast, NB mixtures were often unidentifiable, which is worrying since these were often selected by Akaike's information criterion. Identifiability of binomial N-mixture models should always be checked. If problems are found, simpler models, integrated models that combine different observation models or the use of external information via informative priors or penalized likelihoods, may help. © 2017 by the Ecological Society of America.

A rapid quantification method for the screening indicator for β-thalassemia with near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Chen, Jiemei; Peng, Lijun; Han, Yun; Yao, Lijun; Zhang, Jing; Pan, Tao

2018-03-01

Near-infrared (NIR) spectroscopy combined with chemometrics was applied to rapidly analyse haemoglobin A2 (HbA2) for β-thalassemia screening in human haemolysate samples. The relative content indicator HbA2 was indirectly quantified by simultaneous analysis of two absolute content indicators (Hb and Hb • HbA2). According to the comprehensive prediction effect of the multiple partitioning of calibration and prediction sets, the parameters were optimized to achieve modelling stability, and the preferred models were validated using the samples not involved in modelling. Savitzky-Golay smoothing was firstly used for the spectral pretreatment. The absorbance optimization partial least squares (AO-PLS) was used to eliminate high-absorption wave-bands appropriately. The equidistant combination PLS (EC-PLS) was further used to optimize wavelength models. The selected optimal models were I = 856 nm, N = 16, G = 1 and F = 6 for Hb and I = 988 nm, N = 12, G = 2 and F = 5 for Hb • HbA2. Through independent validation, the root-mean-square errors and correlation coefficients for prediction (RMSEP, RP) were 3.50 g L- 1 and 0.977 for Hb and 0.38 g L- 1 and 0.917 for Hb • HbA2, respectively. The predicted values of relative percentage HbA2 were further calculated, and the calculated RMSEP and RP were 0.31% and 0.965, respectively. The sensitivity and specificity for β-thalassemia both reached 100%. Therefore, the prediction of HbA2 achieved high accuracy for distinguishing β-thalassemia. The local optimal models for single parameter and the optimal equivalent model sets were proposed, providing more models to match possible constraints in practical applications. The NIR analysis method for the screening indicator of β-thalassemia was successfully established. The proposed method was rapid, simple and promising for thalassemia screening in a large population.

Comparative analyses of structural features and scaffold diversity for purchasable compound libraries.

PubMed

Shang, Jun; Sun, Huiyong; Liu, Hui; Chen, Fu; Tian, Sheng; Pan, Peichen; Li, Dan; Kong, Dexin; Hou, Tingjun

2017-04-21

Large purchasable screening libraries of small molecules afforded by commercial vendors are indispensable sources for virtual screening (VS). Selecting an optimal screening library for a specific VS campaign is quite important to improve the success rates and avoid wasting resources in later experimental phases. Analysis of the structural features and molecular diversity for different screening libraries can provide valuable information to the decision making process when selecting screening libraries for VS. In this study, the structural features and scaffold diversity of eleven purchasable screening libraries and Traditional Chinese Medicine Compound Database (TCMCD) were analyzed and compared. Their scaffold diversity represented by the Murcko frameworks and Level 1 scaffolds was characterized by the scaffold counts and cumulative scaffold frequency plots, and visualized by Tree Maps and SAR Maps. The analysis demonstrates that, based on the standardized subsets with similar molecular weight distributions, Chembridge, ChemicalBlock, Mucle, TCMCD and VitasM are more structurally diverse than the others. Compared with all purchasable screening libraries, TCMCD has the highest structural complexity indeed but more conservative molecular scaffolds. Moreover, we found that some representative scaffolds were important components of drug candidates against different drug targets, such as kinases and guanosine-binding protein coupled receptors, and therefore the molecules containing pharmacologically important scaffolds found in screening libraries might be potential inhibitors against the relevant targets. This study may provide valuable perspective on which purchasable compound libraries are better for you to screen. Graphical abstract Selecting diverse compound libraries with scaffold analyses.

Enrichment assessment of multiple virtual screening strategies for Toll-like receptor 8 agonists based on a maximal unbiased benchmarking data set.

PubMed

Pei, Fen; Jin, Hongwei; Zhou, Xin; Xia, Jie; Sun, Lidan; Liu, Zhenming; Zhang, Liangren

2015-11-01

Toll-like receptor 8 agonists, which activate adaptive immune responses by inducing robust production of T-helper 1-polarizing cytokines, are promising candidates for vaccine adjuvants. As the binding site of toll-like receptor 8 is large and highly flexible, virtual screening by individual method has inevitable limitations; thus, a comprehensive comparison of different methods may provide insights into seeking effective strategy for the discovery of novel toll-like receptor 8 agonists. In this study, the performance of knowledge-based pharmacophore, shape-based 3D screening, and combined strategies was assessed against a maximum unbiased benchmarking data set containing 13 actives and 1302 decoys specialized for toll-like receptor 8 agonists. Prior structure-activity relationship knowledge was involved in knowledge-based pharmacophore generation, and a set of antagonists was innovatively used to verify the selectivity of the selected knowledge-based pharmacophore. The benchmarking data set was generated from our recently developed 'mubd-decoymaker' protocol. The enrichment assessment demonstrated a considerable performance through our selected three-layer virtual screening strategy: knowledge-based pharmacophore (Phar1) screening, shape-based 3D similarity search (Q4_combo), and then a Gold docking screening. This virtual screening strategy could be further employed to perform large-scale database screening and to discover novel toll-like receptor 8 agonists. © 2015 John Wiley & Sons A/S.

Selective enzymatic hydrolysis of chlorogenic acid lactones in a model system and in a coffee extract. Application to reduction of coffee bitterness.

PubMed

Kraehenbuehl, Karin; Page-Zoerkler, Nicole; Mauroux, Olivier; Gartenmann, Karin; Blank, Imre; Bel-Rhlid, Rachid

2017-03-01

Chlorogenic acid lactones have been identified as key contributors to coffee bitterness. These compounds are formed during roasting by dehydration and cyclization of their precursors, the chlorogenic acids (CGAs). In the present study, we investigated an approach to decompose these lactones in a selective way without affecting the positive coffee attributes developed during roasting. A model system composed of (3-caffeoylquinic acid lactone (3-CQAL), 4- caffeoyl quinic acid lactone (4-CQAL), and 4-feruloylquinic acid lactone (4-FQAL)) was used for the screening of enzymes before treatment of the coffee extracts. Hog liver esterase (HLE) hydrolyzed chlorogenic acid lactones (CQALs, FQALs) selectively, while chlorogenate esterase hydrolyzed all chlorogenic acids (CQAs, FQAs) and their corresponding lactones (CQALs, FQALs) in a non-selective way. Enzymatically treated coffee samples were evaluated for their bitterness by a trained sensory panel and were found significantly less bitter than the untreated samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

An automated process for building reliable and optimal in vitro/in vivo correlation models based on Monte Carlo simulations.

PubMed

Sutton, Steven C; Hu, Mingxiu

2006-05-05

Many mathematical models have been proposed for establishing an in vitro/in vivo correlation (IVIVC). The traditional IVIVC model building process consists of 5 steps: deconvolution, model fitting, convolution, prediction error evaluation, and cross-validation. This is a time-consuming process and typically a few models at most are tested for any given data set. The objectives of this work were to (1) propose a statistical tool to screen models for further development of an IVIVC, (2) evaluate the performance of each model under different circumstances, and (3) investigate the effectiveness of common statistical model selection criteria for choosing IVIVC models. A computer program was developed to explore which model(s) would be most likely to work well with a random variation from the original formulation. The process used Monte Carlo simulation techniques to build IVIVC models. Data-based model selection criteria (Akaike Information Criteria [AIC], R2) and the probability of passing the Food and Drug Administration "prediction error" requirement was calculated. To illustrate this approach, several real data sets representing a broad range of release profiles are used to illustrate the process and to demonstrate the advantages of this automated process over the traditional approach. The Hixson-Crowell and Weibull models were often preferred over the linear. When evaluating whether a Level A IVIVC model was possible, the model selection criteria AIC generally selected the best model. We believe that the approach we proposed may be a rapid tool to determine which IVIVC model (if any) is the most applicable.

Beachfront screening for skin cancer in Texas Gulf coast surfers.

PubMed

Dozier, S; Wagner, R F; Black, S A; Terracina, J

1997-01-01

Skin cancer screening programs may attract the "worried well," while those at greatest risk for skin cancer are less likely to attend. Our purpose was to compare the results of skin cancer screening examinations between persons participating in the 1992 American Academy of Dermatology-sponsored free skin cancer screening and surfers participating in a free beachfront skin cancer screening held in conjunction with a regional surfing competition. The hypothesis was that screening an at-risk population (ie, surfers) would be more productive in terms of incidence of clinically diagnosed malignant skin lesions. Surfers were significantly younger and predominantly male. The incidence of basal cell carcinoma was significantly greater in the surfing population than in the self-selected population with similar ages. This study indicates that directed skin cancer screening of an at-risk population was more productive in finding skin cancer than screening of a self-selected population. Future efforts to identify individuals with skin cancer should be broadened to include high-risk populations such as daytime outdoor athletes and high-risk occupational groups, since they may not be reached by current screening efforts.

Amphibian (Xenopus sp.) iodothyronine deiodinase ...

EPA Pesticide Factsheets

The U.S. EPA-MED amphibian thyroid group is currently screening chemicals for inhibition of human iodothyronine deiodinase activity as components of the thyroid system important in human development. Amphibians are a bellwether taxonomic group to gauge toxicity of chemicals in the environment. Amphibian thyroid function is not only important in development but also metamorphosis. Xenopus sp. have been used extensively as model organisms and are well characterized genetically. We propose to screen a list of chemicals (selected from the human DIO screening results) to test for inhibition of Xenopus deiodinases. Large quantities of the enzymes will be produced using an adenovirus system. Our preliminary results show that there may be catalytic differences between human and Xenopus deiodinases. The Twin Ports Early Career Scientists is a new group formed within the Duluth-Superior scientific community. This presentation will provide a basic introduction to my research and our mission at EPA, and help to establish networking and collaboration relationships across disciplines and institutions.

Explosives Detection: Exploitation of the Physical Signatures

NASA Astrophysics Data System (ADS)

Atkinson, David

2010-10-01

Explosives based terrorism is an ongoing threat that is evolving with respect to implementation, configuration and materials used. There are a variety of devices designed to detect explosive devices, however, each technology has limitations and operational constraints. A full understanding of the signatures available for detection coupled with the array of detection choices can be used to develop a conceptual model of an explosives screening operation. Physics based sensors provide a robust approach to explosives detection, typically through the identification of anomalies, and are currently used for screening in airports around the world. The next generation of detectors for explosives detection will need to be more sensitive and selective, as well as integrate seamlessly with devices focused on chemical signatures. An appreciation for the details of the physical signature exploitation in cluttered environments with time, space, and privacy constraints is necessary for effective explosives screening of people, luggage, cargo, and vehicles.

Screening of nerve agent degradation products by MALDI-TOFMS.

PubMed

Shu, You-Ren; Su, An-Kai; Liu, Ju-Tsung; Lin, Cheng-Huang

2006-07-01

A novel method for the rapid screening of degradation products derived from nerve agents by matrix-assisted laser desorption ionization time-of-flight mass spectrometry is described. Five standard products were selected as model compounds, including isopropyl methylphosphonic acid (IMPA), pinacolyl methylphosphonic acid (PMPA), ethyl methylphosphonic acid (EMPA), isobutyl methylphosphonic acid (i-BuMPA), and cyclohexyl methylphosphonic acid (CHMPA), which are degradation products of Sarin (GB), Soman (GD), VX, Russian VX (RVX), and GF, respectively. For comparison, CHCA (alpha-cyano-4-hydroxycinnamic acid) and DCCA (7-(diethylamino)coumarin-3-carboxylic acid) were used as the MALDI-matrix when the third harmonic generation (355 nm) of a Nd:YAG laser and a hydrogen Raman laser (multifrequency laser) were used, respectively. The method permitted the five nerve agent degradation products to be screened rapidly and successfully, suggesting that it has the potential for use as a routine monitoring tool.

Chromatin Landscapes of Retroviral and Transposon Integration Profiles

PubMed Central

Badhai, Jitendra; Rust, Alistair G.; Rad, Roland; Hilkens, John; Berns, Anton; van Lohuizen, Maarten; Wessels, Lodewyk F. A.; de Ridder, Jeroen

2014-01-01

The ability of retroviruses and transposons to insert their genetic material into host DNA makes them widely used tools in molecular biology, cancer research and gene therapy. However, these systems have biases that may strongly affect research outcomes. To address this issue, we generated very large datasets consisting of to unselected integrations in the mouse genome for the Sleeping Beauty (SB) and piggyBac (PB) transposons, and the Mouse Mammary Tumor Virus (MMTV). We analyzed (epi)genomic features to generate bias maps at both local and genome-wide scales. MMTV showed a remarkably uniform distribution of integrations across the genome. More distinct preferences were observed for the two transposons, with PB showing remarkable resemblance to bias profiles of the Murine Leukemia Virus. Furthermore, we present a model where target site selection is directed at multiple scales. At a large scale, target site selection is similar across systems, and defined by domain-oriented features, namely expression of proximal genes, proximity to CpG islands and to genic features, chromatin compaction and replication timing. Notable differences between the systems are mainly observed at smaller scales, and are directed by a diverse range of features. To study the effect of these biases on integration sites occupied under selective pressure, we turned to insertional mutagenesis (IM) screens. In IM screens, putative cancer genes are identified by finding frequently targeted genomic regions, or Common Integration Sites (CISs). Within three recently completed IM screens, we identified 7%–33% putative false positive CISs, which are likely not the result of the oncogenic selection process. Moreover, results indicate that PB, compared to SB, is more suited to tag oncogenes. PMID:24721906

14 CFR 1251.202 - Employment criteria.

Code of Federal Regulations, 2011 CFR

2011-01-01

... HANDICAP Employment Practices § 1251.202 Employment criteria. (a) A recipient may not make use of any employment test or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as used by...

14 CFR 1251.202 - Employment criteria.

Code of Federal Regulations, 2013 CFR

2013-01-01

... HANDICAP Employment Practices § 1251.202 Employment criteria. (a) A recipient may not make use of any employment test or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as used by...

14 CFR 1251.202 - Employment criteria.

Code of Federal Regulations, 2010 CFR

2010-01-01

... HANDICAP Employment Practices § 1251.202 Employment criteria. (a) A recipient may not make use of any employment test or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as used by...

14 CFR 1251.202 - Employment criteria.

Code of Federal Regulations, 2012 CFR

2012-01-01

... HANDICAP Employment Practices § 1251.202 Employment criteria. (a) A recipient may not make use of any employment test or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as used by...

14 CFR § 1251.202 - Employment criteria.

Code of Federal Regulations, 2014 CFR

2014-01-01

... OF HANDICAP Employment Practices § 1251.202 Employment criteria. (a) A recipient may not make use of any employment test or other selection criterion that screens out or tends to screen out handicapped persons or any class of handicapped persons unless: (1) The test score or other selection criterion, as...

Withdrawing low risk women from cervical screening programmes: mathematical modelling study

PubMed Central

Sherlaw-Johnson, C; Gallivan, S; Jenkins, D

1999-01-01

Objective To evaluate the impact of policies for removing women before the recommended age of 64 from screening programmes for cervical cancer in the United Kingdom. Design A mathematical model of the clinical course of precancerous lesions which accounts for the influence of infection with the human papillomavirus, the effects of screening on the progression of disease, and the accuracy of the testing procedures. Two policies are compared: one in which women are withdrawn from the programme if their current smear is negative and they have a recent history of regular, negative results and one in which women are withdrawn if their current smear test is negative and a simultaneous test is negative for exposure to high risk types of human papillomavirus. Setting United Kingdom cervical screening programme. Main outcome measures The incidence of invasive cervical cancer and the use of resources. Results Early withdrawal of selected women from the programme is predicted to give rise to resource savings of up to 25% for smear tests and 18% for colposcopies when withdrawal occurs from age 50, the youngest age considered in the study. An increase in the incidence of invasive cervical cancer, by up to 2 cases/100 000 women each year is predicted. Testing for human papillomavirus infection to determine which women should be withdrawn from the programme makes little difference to outcome. Conclusions This model systematically analyses the consequences of screening options using available data and the clinical course of precancerous lesions. If further audit studies confirm the model’s forecasts, a policy of early withdrawal might be considered. This would be likely to release substantial resources which could be channelled into other aspects of health care or may be more effectively used within the cervical screening programme to counteract the possible increase in cancer incidence that early withdrawal might bring. Key messagesIn the United Kingdom there is concern that the cervical screening programme uses a large amount of resources to screen postmenopausal women who are at low risk of cervical cancerThere may be advantages to withdrawing these women from the screening programme before they reach the recommended age of 64A mathematical modelling approach can be used to evaluate the effectiveness of different policies for early withdrawal from screening with or without an additional test for human papillomavirus DNAEarly withdrawal could lead to a substantial reduction in the resources devoted to screening which could be channelled more effectively into other aspects of health careEarly withdrawal is likely to increase the overall incidence of cervical cancer unless other steps are taken to compensate PMID:9933195

A strategy for screening and identifying mycotoxins in herbal medicine using ultra-performance liquid chromatography with tandem quadrupole time-of-flight mass spectrometry.

PubMed

Fang, Lian-xiang; Xiong, Ai-zhen; Wang, Rui; Ji, Shen; Yang, Li; Wang, Zheng-tao

2013-09-01

The objective of this study was to develop an effective strategy for screening and identifying mycotoxins in herbal medicine (HM). Here, Imperatae Rhizoma, a commonly used Chinese herb, was selected as a model HM. A crude drug contaminated with fungi was analyzed by comparing with uncontaminated ones. Ultra-performance LC coupled to tandem quadrupole TOF-MS (UPLC-Q-TOF-MS) with collision energy function was applied to analyze different samples from Imperatae Rhizoma. Then, MarkerLynx(TM) software was employed to screen the excess components in analytes, compared with control samples, and those selected markers were likely to be the metabolites of fungi. Furthermore, each of the accurate masses of the markers obtained from MarkerLynx(TM) was then searched in a mycotoxins/fungal metabolites database established in advance. The molecular formulas with relative mass error between the measured and theoretical mass within 5 ppm were chosen and then applied to MassFragment(TM) analysis for further confirmation of their structures. With the use of this approach, five mycotoxins that have never been reported in HM were identified in contaminated Imperatae Rhizoma. The results demonstrate the potential of UPLC-Q-TOF-MS coupled with the MarkerLynx(TM) software and MassFragment(TM) tool as an efficient and convenient method to screen and identify mycotoxins in herbal materials and aid in the quality control of HM. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Exploiting temporal collateral sensitivity in tumor clonal evolution

PubMed Central

Zhao, Boyang; Sedlak, Joseph C.; Srinivas, Raja; Creixell, Pau; Pritchard, Justin R.; Tidor, Bruce; Lauffenburger, Douglas A.; Hemann, Michael T.

2016-01-01

SUMMARY The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities; a notion that we term ‘temporal collateral sensitivity’. Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph+ acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1 targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models, and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities. PMID:26924578

Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution.

PubMed

Zhao, Boyang; Sedlak, Joseph C; Srinivas, Raja; Creixell, Pau; Pritchard, Justin R; Tidor, Bruce; Lauffenburger, Douglas A; Hemann, Michael T

2016-03-24

The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities-a notion that we term "temporal collateral sensitivity." Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph(+) acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities. Copyright © 2016 Elsevier Inc. All rights reserved.

Selection and Specification of Rear-Projection Screens.

ERIC Educational Resources Information Center

Vlahos, Petro

1961-01-01

The characteristics of the rear-projection screen are examined in detail. Numerical constants are provided that define these characteristics for practical screens and convert foot-candles to footlamberts. A procedure is given by which an optimum screen may be specified for a specific application. Contents include--(1) introduction, (2) projection…

Apparel Research Network (ARN) Apparel Order Processing Module (AOPM). Application Program for Management of Special Measurement Clothing Orders

DTIC Science & Technology

1997-09-30

Screen, abandoning changes. APPAREL ORDER PROCESSING MODULE FIELD USER MANUAL Ordering Official Screens The Ordering Official Screens are provided for...currendy selected Ordering Official will appear on the Ordering Official Information Screen. APPAREL ORDER PROCESSING MODULE FIELD USER MANUAL Ordering Official

Screening and Identification in Pediatric Primary Care

ERIC Educational Resources Information Center

Simonian, Susan J.

2006-01-01

This article reviews issues related to behavioral screening in pediatric primary care settings. Structural-organizational issues affecting the use of pediatric primary care screening are discussed. This study also reviewed selected screening instruments that have utility for use in the primary care setting. Clinical and research issues related to…

Virtual screening of compound libraries.

PubMed

Cerqueira, Nuno M F S A; Sousa, Sérgio F; Fernandes, Pedro A; Ramos, Maria João

2009-01-01

During the last decade, Virtual Screening (VS) has definitively established itself as an important part of the drug discovery and development process. VS involves the selection of likely drug candidates from large libraries of chemical structures by using computational methodologies, but the generic definition of VS encompasses many different methodologies. This chapter provides an introduction to the field by reviewing a variety of important aspects, including the different types of virtual screening methods, and the several steps required for a successful virtual screening campaign within a state-of-the-art approach, from target selection to postfilter application. This analysis is further complemented with a small collection important VS success stories.

Transformation of Human Cathelicidin LL-37 into Selective, Stable, and Potent Antimicrobial Compounds

PubMed Central

2015-01-01

This Letter reports a family of novel antimicrobial compounds obtained by combining peptide library screening with structure-based design. Library screening led to the identification of a human LL-37 peptide resistant to chymotrypsin. This d-amino-acid-containing peptide template was active against Escherichia coli but not methicillin-resistant Staphylococcus aureus (MRSA). It possesses a unique nonclassic amphipathic structure with hydrophobic defects. By repairing the hydrophobic defects, the peptide (17BIPHE2) gained activity against the ESKAPE pathogens, including Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species. In vitro, 17BIPHE2 could disrupt bacterial membranes and bind to DNA. In vivo, the peptide prevented staphylococcal biofilm formation in a mouse model of catheter-associated infection. Meanwhile, it boosted the innate immune response to further combat the infection. Because these peptides are potent, cell-selective, and stable to several proteases, they may be utilized to combat one or more ESKAPE pathogens. PMID:25061850

Materials selection for long life in low earth orbit - A critical evaluation of atomic oxygen testing with thermal atom systems

NASA Technical Reports Server (NTRS)

Koontz, S. L.; Albyn, K.; Leger, L.

1990-01-01

The use of thermal atom test methods as a materials selection and screening technique for low-earth orbit (LEO) spacecraft is critically evaluated. The chemistry and physics of thermal atom environments are compared with the LEO environment. The relative reactivities of a number of materials determined in thermal atom environments are compared with those observed in LEO and in high-quality LEO simulations. Reaction efficiencies (cu cm/atom) measured in a new type of thermal atom apparatus are one-thousandth to one ten-thousandth those observed in LEO, and many materials showing nearly identical reactivities in LEO show relative reactivities differing by as much as a factor of eight in thermal atom systems. A simple phenomenological kinetic model for the reaction of oxygen atoms with organic materials can be used to explain the differences in reactivity in different environments. Certain speciic thermal atom test environments can be used as reliable materials screening tools.

Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

PubMed Central

Huang, Xi-Ping; Karpiak, Joel; Kroeze, Wesley K.; Zhu, Hu; Chen, Xin; Moy, Sheryl S.; Saddoris, Kara A.; Nikolova, Viktoriya; Farrell, Martilias S.; Wang, Sheng; Mangano, Thomas J.; Deshpande, Deepak A.; Jiang, Alice; Penn, Raymond B.; Jin, Jian; Koller, Beverly H.; Kenakin, Terry; Shoichet, Brian K.; Roth, Bryan L.

2016-01-01

At least 120 non-olfactory G protein-coupled receptors in the human genome are ”orphans” for which endogenous ligands are unknown, and many have no selective ligands, hindering elucidation of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Yeast-based screens against GPR68 identified the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. Over 3000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators many of which were confirmed in functional assays. One potent GPR68 modulator—ogerin– suppressed recall in fear conditioning in wild-type, but not in GPR68 knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs. PMID:26550826

Feasibility of two active case finding approaches for detection of tuberculosis in Bandung City, Indonesia.

PubMed

McAllister, S; Wiem Lestari, B; Sujatmiko, B; Siregar, A; Sihaloho, E D; Fathania, D; Dewi, N F; Koesoemadinata, R C; Hill, P C; Alisjahbana, B

2017-09-21

Setting: A community health clinic catchment area in the eastern part of Bandung City, Indonesia. Objective: To evaluate the feasibility of two different screening interventions using community health workers (CHWs) in detecting tuberculosis (TB) cases. Design: This was a feasibility study of 1) house-to-house TB symptom screening of five randomly selected 'neighbourhoods' in the catchment area, and 2) selected screening of household contacts of TB index patients and their neighbouring households. Acceptability was assessed through focus group discussions with key stakeholders. Results: Of 5100 individuals screened in randomly selected neighbourhoods, 48 (0.9%) reported symptoms, of whom 38 provided sputum samples; no positive TB was found. No TB cases were found among the 88 household contacts or the 423 neighbourhood contacts. With training, regular support and supervision from research staff and local community health centre staff, CHWs were able to undertake screening effectively, and almost all householders were willing to participate. Conclusion: The use of CHWs for TB screening could be integrated into routine practice relatively easily in Indonesia. The effectiveness of this would need further exploration, particularly with the use of improved diagnostics such as chest X-ray and sputum culture.

Feasibility of two active case finding approaches for detection of tuberculosis in Bandung City, Indonesia

PubMed Central

Wiem Lestari, B.; Sujatmiko, B.; Siregar, A.; Sihaloho, E. D.; Fathania, D.; Dewi, N. F.; Koesoemadinata, R. C.; Hill, P. C.; Alisjahbana, B.

2017-01-01

Setting: A community health clinic catchment area in the eastern part of Bandung City, Indonesia. Objective: To evaluate the feasibility of two different screening interventions using community health workers (CHWs) in detecting tuberculosis (TB) cases. Design: This was a feasibility study of 1) house-to-house TB symptom screening of five randomly selected ‘neighbourhoods’ in the catchment area, and 2) selected screening of household contacts of TB index patients and their neighbouring households. Acceptability was assessed through focus group discussions with key stakeholders. Results: Of 5100 individuals screened in randomly selected neighbourhoods, 48 (0.9%) reported symptoms, of whom 38 provided sputum samples; no positive TB was found. No TB cases were found among the 88 household contacts or the 423 neighbourhood contacts. With training, regular support and supervision from research staff and local community health centre staff, CHWs were able to undertake screening effectively, and almost all householders were willing to participate. Conclusion: The use of CHWs for TB screening could be integrated into routine practice relatively easily in Indonesia. The effectiveness of this would need further exploration, particularly with the use of improved diagnostics such as chest X-ray and sputum culture. PMID:29226096

Pyridoxylamine reactivity kinetics as an amine based nucleophile for screening electrophilic dermal sensitizers

PubMed Central

Chipinda, Itai; Mbiya, Wilbes; Adigun, Risikat Ajibola; Morakinyo, Moshood K.; Law, Brandon F.; Simoyi, Reuben H.; Siegel, Paul D.

2015-01-01

Chemical allergens bind directly, or after metabolic or abiotic activation, to endogenous proteins to become allergenic. Assessment of this initial binding has been suggested as a target for development of assays to screen chemicals for their allergenic potential. Recently we reported a nitrobenzenethiol (NBT) based method for screening thiol reactive skin sensitizers, however, amine selective sensitizers are not detected by this assay. In the present study we describe an amine (pyridoxylamine (PDA)) based kinetic assay to complement the NBT assay for identification of amine-selective and non-selective skin sensitizers. UV-Vis spectrophotometry and fluorescence were used to measure PDA reactivity for 57 chemicals including anhydrides, aldehydes, and quinones where reaction rates ranged from 116 to 6.2 × 10−6 M−1 s−1 for extreme to weak sensitizers, respectively. No reactivity towards PDA was observed with the thiol-selective sensitizers, non-sensitizers and prohaptens. The PDA rate constants correlated significantly with their respective murine local lymph node assay (LLNA) threshold EC3 values (R2 = 0.76). The use of PDA serves as a simple, inexpensive amine based method that shows promise as a preliminary screening tool for electrophilic, amine-selective skin sensitizers. PMID:24333919

Effective virtual screening protocol for CYP2C9 ligands using a screening site constructed from flurbiprofen and S-warfarin pockets

NASA Astrophysics Data System (ADS)

Polgár, Tímea; Menyhárd, Dóra K.; Keserű, György M.

2007-09-01

An effective virtual screening protocol was developed against an extended active site of CYP2C9, which was derived from X-ray structures complexed with flubiprofen and S-warfarin. Virtual screening has been effectively supported by our structure-based pharmacophore model. Importance of hot residues identified by mutation data and structural analysis was first estimated in an enrichment study. Key role of Arg108 and Phe114 in ligand binding was also underlined. Our screening protocol successfully identified 76% of known CYP2C9 ligands in the top 1% of the ranked database resulting 76-fold enrichment relative to random situation. Relevance of the protocol was further confirmed in selectivity studies, when 89% of CYP2C9 ligands were retrieved from a mixture of CYP2C9 and CYP2C8 ligands, while only 22% of CYP2C8 ligands were found applying the structure-based pharmacophore constraints. Moderate discrimination of CYP2C9 ligands from CYP2C18 and CYP2C19 ligands could also be achieved extending the application domain of our virtual screening protocol for the entire CYP2C family. Our findings further demonstrate the existence of an active site comprising of at least two binding pockets and strengthens the need of involvement of protein flexibility in virtual screening.

Studies of asymmetric styrene cyclopropanation with a rhodium(II) metallopeptide catalyst developed with a high-throughput screen.

PubMed

Sambasivan, Ramya; Ball, Zachary T

2013-09-01

Dirhodium metallopeptides have been developed as selective catalysts for asymmetric cyclopropanation reactions. A selective ligand sequence has been identified by screening on-bead metallopeptide libraries in a 96-well plate format. Efficient ligand synthesis and screening allows a 200-member library to be created and assayed in less than three weeks. These metallopeptides catalyze efficient cyclopropanation of aryldiazoacetates, providing asymmetric access to cyclopropane products in high diastereoselectivity. © 2013 Wiley Periodicals, Inc.

High-Throughput Screening to Identify Regulators of Meiosis-Specific Gene Expression in Saccharomyces cerevisiae.

PubMed

Kassir, Yona

2017-01-01

Meiosis and gamete formation are processes that are essential for sexual reproduction in all eukaryotic organisms. Multiple intracellular and extracellular signals feed into pathways that converge on transcription factors that induce the expression of meiosis-specific genes. Once triggered the meiosis-specific gene expression program proceeds in a cascade that drives progress through the events of meiosis and gamete formation. Meiosis-specific gene expression is tightly controlled by a balance of positive and negative regulatory factors that respond to a plethora of signaling pathways. The budding yeast Saccharomyces cerevisiae has proven to be an outstanding model for the dissection of gametogenesis owing to the sophisticated genetic manipulations that can be performed with the cells. It is possible to use a variety selection and screening methods to identify genes and their functions. High-throughput screening technology has been developed to allow an array of all viable yeast gene deletion mutants to be screened for phenotypes and for regulators of gene expression. This chapter describes a protocol that has been used to screen a library of homozygous diploid yeast deletion strains to identify regulators of the meiosis-specific IME1 gene.

A microfluidic array for high-content screening at whole-organism resolution

NASA Astrophysics Data System (ADS)

Migliozzi, D.; Cornaglia, M.; Mouchiroud, L.; Auwerx, J.; Gijs, M. A. M.

2018-02-01

A main step for the development and the validation of medical drugs is the screening on whole organisms, which gives the systemic information that is missing when using cellular models. Among the organisms of choice, Caenorhabditis elegansis a soil worm which catches the interest of researchers who study systemic physiopathology (e.g. metabolic and neurodegenerative diseases) because: (1) its large genetic homology with humans supports translational analysis; (2) worms are much easier to handle and grow in large amounts compared to rodents, for which (3) the costs and (4) the ethical concerns are substantial.C. elegansis therefore well suited for large screens, dose-response analysis and target-discovery involving an entire organism. We have developed and tested a microfluidic array for high-content screening, enabling the selection of small populations of its first larval stage in many separated chambers divided into channels for multiplexed screens. With automated protocols for feeding, drug administration and image acquisition, our chip enables the study of the nematodes throughout their entire lifespan. By using a paralyzing agent and a mitochondrial-stress inducer as case studies, we have demonstrated large field-of-view motility analysis, and worm-segmentation/signal-detection for mode-of-action quantification with genetically-encoded fluorescence reporters.

Development and application of a DNA microarray-based yeast two-hybrid system

PubMed Central

Suter, Bernhard; Fontaine, Jean-Fred; Yildirimman, Reha; Raskó, Tamás; Schaefer, Martin H.; Rasche, Axel; Porras, Pablo; Vázquez-Álvarez, Blanca M.; Russ, Jenny; Rau, Kirstin; Foulle, Raphaele; Zenkner, Martina; Saar, Kathrin; Herwig, Ralf; Andrade-Navarro, Miguel A.; Wanker, Erich E.

2013-01-01

The yeast two-hybrid (Y2H) system is the most widely applied methodology for systematic protein–protein interaction (PPI) screening and the generation of comprehensive interaction networks. We developed a novel Y2H interaction screening procedure using DNA microarrays for high-throughput quantitative PPI detection. Applying a global pooling and selection scheme to a large collection of human open reading frames, proof-of-principle Y2H interaction screens were performed for the human neurodegenerative disease proteins huntingtin and ataxin-1. Using systematic controls for unspecific Y2H results and quantitative benchmarking, we identified and scored a large number of known and novel partner proteins for both huntingtin and ataxin-1. Moreover, we show that this parallelized screening procedure and the global inspection of Y2H interaction data are uniquely suited to define specific PPI patterns and their alteration by disease-causing mutations in huntingtin and ataxin-1. This approach takes advantage of the specificity and flexibility of DNA microarrays and of the existence of solid-related statistical methods for the analysis of DNA microarray data, and allows a quantitative approach toward interaction screens in human and in model organisms. PMID:23275563

Liquid Acquisition Device Design Sensitivity Study

NASA Technical Reports Server (NTRS)

VanDyke, M. K.; Hastings, L. J.

2012-01-01

In-space propulsion often necessitates the use of a capillary liquid acquisition device (LAD) to assure that gas-free liquid propellant is available to support engine restarts in microgravity. If a capillary screen-channel device is chosen, then the designer must determine the appropriate combination screen mesh and channel geometry. A screen mesh selection which results in the smallest LAD width when compared to any other screen candidate (for a constant length) is desirable; however, no best screen exists for all LAD design requirements. Flow rate, percent fill, and acceleration are the most influential drivers for determining screen widths. Increased flow rates and reduced percent fills increase the through-the-screen flow pressure losses, which drive the LAD to increased widths regardless of screen choice. Similarly, increased acceleration levels and corresponding liquid head pressures drive the screen mesh selection toward a higher bubble point (liquid retention capability). After ruling out some screens on the basis of acceleration requirements alone, candidates can be identified by examining screens with small flow-loss-to-bubble point ratios for a given condition (i.e., comparing screens at certain flow rates and fill levels). Within the same flow rate and fill level, the screen constants inertia resistance coefficient, void fraction, screen pore or opening diameter, and bubble point can become the driving forces in identifying the smaller flow-loss-to-bubble point ratios.

Using logistic regression modeling to predict sexual recidivism: the Minnesota Sex Offender Screening Tool-3 (MnSOST-3).

PubMed

Duwe, Grant; Freske, Pamela J

2012-08-01

This study presents the results from efforts to revise the Minnesota Sex Offender Screening Tool-Revised (MnSOST-R), one of the most widely used sex offender risk-assessment tools. The updated instrument, the MnSOST-3, contains nine individual items, six of which are new. The population for this study consisted of the cross-validation sample for the MnSOST-R (N = 220) and a contemporary sample of 2,315 sex offenders released from Minnesota prisons between 2003 and 2006. To score and select items for the MnSOST-3, we used predicted probabilities generated from a multiple logistic regression model. We used bootstrap resampling to not only refine our selection of predictors but also internally validate the model. The results indicate the MnSOST-3 has a relatively high level of predictive discrimination, as evidenced by an apparent AUC of .821 and an optimism-corrected AUC of .796. The findings show the MnSOST-3 is well calibrated with actual recidivism rates for all but the highest risk offenders. Although estimating a penalized maximum likelihood model did not improve the overall calibration, the results suggest the MnSOST-3 may still be useful in helping identify high-risk offenders whose sexual recidivism risk exceeds 50%. Results from an interrater reliability assessment indicate the instrument, which is scored in a Microsoft Excel application, has an adequate degree of consistency across raters (ICC = .83 for both consistency and absolute agreement).

The Analysis of Fourth Grade Primary Students' Reader Self-Perceptions in Terms of Gender and Preschool Educational Background

ERIC Educational Resources Information Center

Sagirli, Muhittin; Okur, Burçin

2017-01-01

The aim of this study was to analyse perceptions of fourth grade primary school students on their reading ability. In study, screening model was used as a quantitative research method. The sample of this research was selected by convenience sampling. The sample consisted of 556 fourth grade students who received education in 8 public schools in…

Domestic violence screening in a military setting: provider screening and attitudes.

PubMed

Lutgendorf, Monica; Busch, Jeanne; Magann, Everett F; Morrison, John C

2010-06-01

Domestic violence is an important healthcare problem, and it appears more prevalent in military patient populations although no one has demonstrated the cause behind this phenomenon. The purpose of this observational study was to assess data regarding domestic violence screening from practitioners at one military training center. This study used an anonymous questionnaire for physicians, nurses and nurse midwives, which surveyed current methods, attitudes toward screening, and barriers for such assessment. Fifty-seven surveys were distributed, and 26 were returned for a response rate of 45.6%. Only about a third (38.5%) of the practitioners screened all obstetric patients while the remainder screened selected patients for domestic violence. Even less (19%) screened gynecology patients routinely, whereas 69% reported they screened selected women with chronic or somatic complaints. A history of prior abuse in the respondents led practitioners to try to identify such patients within their practice. Lack of education or training was the most common barrier to universal screening followed by time constraints and frustration about not being able to address adequately the problem when noted. These results emphasized the importance of an educational program to increase domestic violence awareness and routine screening.

Detecting Coevolution in and among Protein Domains

PubMed Central

Yeang, Chen-Hsiang; Haussler, David

2007-01-01

Correlated changes of nucleic or amino acids have provided strong information about the structures and interactions of molecules. Despite the rich literature in coevolutionary sequence analysis, previous methods often have to trade off between generality, simplicity, phylogenetic information, and specific knowledge about interactions. Furthermore, despite the evidence of coevolution in selected protein families, a comprehensive screening of coevolution among all protein domains is still lacking. We propose an augmented continuous-time Markov process model for sequence coevolution. The model can handle different types of interactions, incorporate phylogenetic information and sequence substitution, has only one extra free parameter, and requires no knowledge about interaction rules. We employ this model to large-scale screenings on the entire protein domain database (Pfam). Strikingly, with 0.1 trillion tests executed, the majority of the inferred coevolving protein domains are functionally related, and the coevolving amino acid residues are spatially coupled. Moreover, many of the coevolving positions are located at functionally important sites of proteins/protein complexes, such as the subunit linkers of superoxide dismutase, the tRNA binding sites of ribosomes, the DNA binding region of RNA polymerase, and the active and ligand binding sites of various enzymes. The results suggest sequence coevolution manifests structural and functional constraints of proteins. The intricate relations between sequence coevolution and various selective constraints are worth pursuing at a deeper level. PMID:17983264

Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneol synthase-a potential target to reduce Fusarium head blight disease.

PubMed

Bresso, E; Leroux, V; Urban, M; Hammond-Kosack, K E; Maigret, B; Martins, N F

2016-07-01

Fusarium head blight (FHB) is one of the most destructive diseases of wheat and other cereals worldwide. During infection, the Fusarium fungi produce mycotoxins that represent a high risk to human and animal health. Developing small-molecule inhibitors to specifically reduce mycotoxin levels would be highly beneficial since current treatments unspecifically target the Fusarium pathogen. Culmorin possesses a well-known important synergistically virulence role among mycotoxins, and longiborneol synthase appears to be a key enzyme for its synthesis, thus making longiborneol synthase a particularly interesting target. This study aims to discover potent and less toxic agrochemicals against FHB. These compounds would hamper culmorin synthesis by inhibiting longiborneol synthase. In order to select starting molecules for further investigation, we have conducted a structure-based virtual screening investigation. A longiborneol synthase structural model is first built using homology modeling, followed by molecular dynamics simulations that provided the required input for a protein-ligand ensemble docking procedure. From this strategy, the three most interesting compounds (hits) were selected among the 25 top-ranked docked compounds from a library of 15,000 drug-like compounds. These putative inhibitors of longiborneol synthase provide a sound starting point for further studies involving molecular modeling coupled to biochemical experiments. This process could eventually lead to the development of novel approaches to reduce mycotoxin contamination in harvested grain.

Dual genetic selection of synthetic riboswitches in Escherichia coli.

PubMed

Nomura, Yoko; Yokobayashi, Yohei

2014-01-01

This chapter describes a genetic selection strategy to engineer synthetic riboswitches that can chemically regulate gene expression in Escherichia coli. Riboswitch libraries are constructed by randomizing the nucleotides that potentially comprise an expression platform and fused to the hybrid selection/screening marker tetA-gfpuv. Iterative ON and OFF selections are performed under appropriate conditions that favor the survival or the growth of the cells harboring the desired riboswitches. After the selection, rapid screening of individual riboswitch clones is performed by measuring GFPuv fluorescence without subcloning. This optimized dual genetic selection strategy can be used to rapidly develop synthetic riboswitches without detailed computational design or structural knowledge.

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

PubMed

Sandham, David A; Arnold, Nicola; Aschauer, Heinrich; Bala, Kamlesh; Barker, Lucy; Brown, Lyndon; Brown, Zarin; Budd, David; Cox, Brian; Docx, Cerys; Dubois, Gerald; Duggan, Nicholas; England, Karen; Everatt, Brian; Furegati, Marcus; Hall, Edward; Kalthoff, Frank; King, Anna; Leblanc, Catherine J; Manini, Jodie; Meingassner, Josef; Profit, Rachael; Schmidt, Alfred; Simmons, Jennifer; Sohal, Bindi; Stringer, Rowan; Thomas, Matthew; Turner, Katharine L; Walker, Christoph; Watson, Simon J; Westwick, John; Willis, Jennifer; Williams, Gareth; Wilson, Caroline

2013-11-01

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of Education Based on Health Belief Model on the Behavior of Breast Cancer Screening in Women.

PubMed

Masoudiyekta, Leila; Rezaei-Bayatiyani, Hojat; Dashtbozorgi, Bahman; Gheibizadeh, Mahin; Malehi, Amal Saki; Moradi, Mehrnaz

2018-01-01

The purpose of this study was to determine the effect of education based on health belief model (HBM) on the behavior of breast cancer screening (bCS) in women. This quasi-experimental study was conducted on 226 women who were selected with cluster sampling method from those referred to Dezful health centers. Data collection tool was a researcher-made questionnaire. Demographic questionnaire bCS- scale, and the Knowledge about questionnaire, all given before and 3 months after the intervention. According to the findings of the study, there was a significant relationship between women's performance and variables of knowledge, perceived sensitivity, perceived benefits, perceived barriers, self-efficacy, and cues to action. Poor knowledge of women indicates a crucial need for formal educational programs to sensitize women regarding the importance of bCS. These educational programs should consider factors affecting bCS behaviors.

Phage display for the discovery of hydroxyapatite-associated peptides.

PubMed

Jin, Hyo-Eon; Chung, Woo-Jae; Lee, Seung-Wuk

2013-01-01

In nature, proteins play a critical role in the biomineralization process. Understanding how different peptide or protein sequences selectively interact with the target crystal is of great importance. Identifying such protein structures is one of the critical steps in verifying the molecular mechanisms of biomineralization. One of the promising ways to obtain such information for a particular crystal surface is to screen combinatorial peptide libraries in a high-throughput manner. Among the many combinatorial library screening procedures, phage display is a powerful method to isolate such proteins and peptides. In this chapter, we will describe our established methods to perform phage display with inorganic crystal surfaces. Specifically, we will use hydroxyapatite as a model system for discovery of apatite-associated proteins in bone or tooth biomineralization studies. This model approach can be generalized to other desired crystal surfaces using the same experimental design principles with a little modification of the procedures. © 2013 Elsevier Inc. All rights reserved.

Screening of extremotolerant fungi for the bioremediation of hydrocarbon contaminated sites

NASA Astrophysics Data System (ADS)

Poyntner, Caroline; Blasi, Barbara; Prenafeta, Francesc; Sterflinger, Katja

2015-04-01

Bioremediation can be used to treat contaminated sites, by taking advantage of microorganisms which have the potential to degrade a wide range of contaminants. While research has been focused mainly on bacteria, the knowledge on other microorganisms, especially fungal communities, is still limited. However, the use of fungi may have advantages compared to bacteria. Extremophile fungi like the black yeasts can withstand high levels of environmental stress (e.g. range of pH, water availability and temperature, presence of toxic chemicals). Therefore they might be applicable in situations, where bacterial communities show limited performance. In order to identify fungi which are good candidates for bioremediation application, a selection of 163 fungal strains, mostly from the group of the black yeasts, was tested for their capability to degrade three different pollutants: hexadecane, toluene, and polychlorinated biphenyl 126, which were used as model compounds for aliphatic hydrocarbons, aromatic hydrocarbons and polychlorinated biphenyls. These chemicals are frequently found in sites contaminated by oil, gas and coal. The screening was based on a two-step selection approach. As a first step, a high throughput method was developed to screen the relatively large amount of fungal strains regarding their tolerance to the contaminants. A microtiter plate based method was developed for monitoring fungal growth in the presence of the selected contaminants photometrically with a Tecan reader. Twenty five strains out of 163, being species of the genera Cladophilaophora, Scedosporium and Exophiala, showed the ability to grow on at least 2 hydrocarbons, and are therefore the most promising candidates for further tests. In a second step, degradation of the contaminants was investigated in more detail for a subset of the screened fungi. This was done by closing the carbon balance in sealed liquid cultures in which the selected pollutant was introduce as the sole source of carbon and energy. Substrate depletion and CO2 accumulation in the headspace were monitored chromatographically. In the course of these experiments, two strains showed a good capacity to grow on toluene. In summary, the presented screening method can be used to identify potential candidates for the fungal degradation of contaminants. Further research is necessary to investigate the potential use of the identified fungal strains for remediation purposes.

Identification and Characterization of Strychnine-Binding Peptides Using Phage-Display Screening.

PubMed

Zhang, Fang; Wang, Min; Qiu, Zheng; Wang, Xiao-Meng; Xu, Chun-Lei; Zhang, Xia

2017-01-01

In drug development, phage display is a high-throughput method for identifying the specific cellular targets of drugs. However, insoluble small chemicals remain intractable to this technique because of the difficulty of presenting molecules to phages without occupying or destroying the limited functional groups. In the present study, we selected Strychnine (Stry) as a model compounda and sought to develope an alternative in vitro biopanning strategy against insoluble suspension. A phage library displaying random sequences of fifteen peptides was employed to screen for interactions between Stry and its cellular selective binding peptides, which are of great value to have a complete understanding of the mechanism of Stry for its antitumor activity. After four rounds of biopanning, a selection of 100 binding clones was randomly picked and subjected to modified proliferation and diffusion assays to evaluate the binding affinity of the clones. Finally, eleven clones were identified as positive binders. The corresponding peptides were synthesized and detected for their binding activities using surface plasmon resonance imaging (SPRi). Our study provides a feasible scheme for confirming the interaction of chemical compounds and cellular binding peptides. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design of a general-purpose European compound screening library for EU-OPENSCREEN.

PubMed

Horvath, Dragos; Lisurek, Michael; Rupp, Bernd; Kühne, Ronald; Specker, Edgar; von Kries, Jens; Rognan, Didier; Andersson, C David; Almqvist, Fredrik; Elofsson, Mikael; Enqvist, Per-Anders; Gustavsson, Anna-Lena; Remez, Nikita; Mestres, Jordi; Marcou, Gilles; Varnek, Alexander; Hibert, Marcel; Quintana, Jordi; Frank, Ronald

2014-10-01

This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target- or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

QSAR modeling of cumulative environmental end-points for the prioritization of hazardous chemicals.

PubMed

Gramatica, Paola; Papa, Ester; Sangion, Alessandro

2018-01-24

The hazard of chemicals in the environment is inherently related to the molecular structure and derives simultaneously from various chemical properties/activities/reactivities. Models based on Quantitative Structure Activity Relationships (QSARs) are useful to screen, rank and prioritize chemicals that may have an adverse impact on humans and the environment. This paper reviews a selection of QSAR models (based on theoretical molecular descriptors) developed for cumulative multivariate endpoints, which were derived by mathematical combination of multiple effects and properties. The cumulative end-points provide an integrated holistic point of view to address environmentally relevant properties of chemicals.

Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model.

PubMed

Everts, Maaike; Cihlar, Tomas; Bostwick, J Robert; Whitley, Richard J

2017-01-06

Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure. Together, these steps could result in accelerated timelines for bringing antiviral therapies to market so they can treat emerging infections and reduce human suffering.

Pharmacophore based approach to design inhibitors in crustaceans: an insight into the molt inhibition response to the receptor guanylyl cyclase.

PubMed

Shrivastava, Sajal; Princy, S Adline

2014-04-01

The first set of competitive inhibitors of molt inhibiting hormone (MIH) has been developed using the effective approaches such as Hip-Hop, virtual screening and manual alterations. Moreover, the conserved residues at 71 and 72 positions in the molt inhibiting hormone is known to be significant for selective inhibition of ecdysteroidogenesis; thus, the information from mutation and solution structure were used to generate common pharmacophore features. The geometry of the final six-feature pharmacophore was also found to be consistent with the homology-modeled MIH structures from various other decapod crustaceans. The Hypo-1, comprising six features hypothesis was carefully selected as a best pharmacophore model for virtual screening created on the basis of rank score and cluster processes. The hypothesis was validated and the database was virtually screened using this 3D query and the compounds were then manually altered to enhance the fit value. The hits obtained were further filtered for drug-likeness, which is expressed as physicochemical properties that contribute to favorable ADME/Tox profiles to eliminate the molecules exhibit toxicity and poor pharmacokinetics. In conclusion, the higher fit values of CI-1 (4.6), CI-4 (4.9) and CI-7 (4.2) in conjunction with better pharmacokinetic profile made these molecules practically helpful tool to increase production by accelerating molt in crustaceans. The use of feeding sub-therapeutic dosages of these growth enhancers can be very effectively implemented and certainly turn out to be a vital part of emerging nutritional strategies for economically important crustacean livestock.

The MORPHEUS II protein crystallization screen

PubMed Central

Gorrec, Fabrice

2015-01-01

High-quality macromolecular crystals are a prerequisite for the process of protein structure determination by X-ray diffraction. Unfortunately, the relative yield of diffraction-quality crystals from crystallization experiments is often very low. In this context, innovative crystallization screen formulations are continuously being developed. In the past, MORPHEUS, a screen in which each condition integrates a mix of additives selected from the Protein Data Bank, a cryoprotectant and a buffer system, was developed. Here, MORPHEUS II, a follow-up to the original 96-condition initial screen, is described. Reagents were selected to yield crystals when none might be observed in traditional initial screens. Besides, the screen includes heavy atoms for experimental phasing and small polyols to ensure the cryoprotection of crystals. The suitability of the resulting novel conditions is shown by the crystallization of a broad variety of protein samples and their efficiency is compared with commercially available conditions. PMID:26144227

Screening of ground water samples for volatile organic compounds using a portable gas chromatograph

USGS Publications Warehouse

Buchmiller, R.C.

1989-01-01

A portable gas chromatograph was used to screen 32 ground water samples for volatile organic compounds. Seven screened samples were positive; four of the seven samples had volatile organic substances identified by second-column confirmation. Four of the seven positive, screened samples also tested positive in laboratory analyses of duplicate samples. No volatile organic compounds were detected in laboratory analyses of samples that headspace screening indicated to be negative. Samples that contained volatile organic compounds, as identified by laboratory analysis, and that contained a volatile organic compound present in a standard of selected compounds were correctly identified by using the portable gas chromatography. Comparisons of screened-sample data with laboratory data indicate the ability to detect selected volatile organic compounds at concentrations of about 1 microgram per liter in the headspace of water samples by use of a portable gas chromatography. -Author

The MORPHEUS II protein crystallization screen.

PubMed

Gorrec, Fabrice

2015-07-01

High-quality macromolecular crystals are a prerequisite for the process of protein structure determination by X-ray diffraction. Unfortunately, the relative yield of diffraction-quality crystals from crystallization experiments is often very low. In this context, innovative crystallization screen formulations are continuously being developed. In the past, MORPHEUS, a screen in which each condition integrates a mix of additives selected from the Protein Data Bank, a cryoprotectant and a buffer system, was developed. Here, MORPHEUS II, a follow-up to the original 96-condition initial screen, is described. Reagents were selected to yield crystals when none might be observed in traditional initial screens. Besides, the screen includes heavy atoms for experimental phasing and small polyols to ensure the cryoprotection of crystals. The suitability of the resulting novel conditions is shown by the crystallization of a broad variety of protein samples and their efficiency is compared with commercially available conditions.

Optimization and design of ibuprofen-loaded nanostructured lipid carriers using a hybrid-design approach for ocular drug delivery

NASA Astrophysics Data System (ADS)

Rathod, Vishal

The objective of the present project was to develop the Ibuprofen-loaded Nanostructured Lipid Carrier (IBU-NLCs) for topical ocular delivery based on substantial pre-formulation screening of the components and understanding the interplay between the formulation and process variables. The BCS Class II drug: Ibuprofen was selected as the model drug for the current study. IBU-NLCs were prepared by melt emulsification and ultrasonication technique. Extensive pre-formulation studies were performed to screen the lipid components (solid and liquid) based on drug's solubility and affinity as well as components compatibility. The results from DSC & XRD assisted in selecting the most suitable ratio to be utilized for future studies. DynasanRTM 114 was selected as the solid lipid & MiglyolRTM 840 was selected as the liquid lipid based on preliminary lipid screening. The ratio of 6:4 was predicted to be the best based on its crystallinity index and the thermal events. As there are many variables involved for further optimization of the formulation, a single design approach is not always adequate. A hybrid-design approach was applied by employing the Plackett Burman design (PBD) for preliminary screening of 7 critical variables, followed by Box-Behnken design (BBD), a sub-type of response surface methodology (RSM) design using 2 relatively significant variables from the former design and incorporating Surfactant/Co-surfactant ratio as the third variable. Comparatively, KolliphorRTM HS15 demonstrated lower Mean Particle Size (PS) & Polydispersity Index (PDI) and KolliphorRTM P188 resulted in Zeta Potential (ZP) < -20 mV during the surfactant screening & stability studies. Hence, Surfactant/Cosurfactant ratio was employed as the third variable to understand its synergistic effect on the response variables. We selected PS, PDI, and ZP as critical response variables in the PBD since they significantly influence the stability & performance of NLCs. Formulations prepared using BBD were further characterized and evaluated concerning PS, PDI, ZP and Entrapment Efficiency (EE) to identify the multi-factor interactions between selected formulation variables. In vitro release studies were performed using Spectra/por dialysis membrane on Franz diffusion cell and Phosphate Saline buffer (7.4 pH) as the medium. Samples for assay, EE, Loading Capacity (LC), Solubility studies & in-vitro release were filtered using Amicon 50K and analyzed via UPLC system (Waters) at a detection wavelength of 220 nm. Significant variables were selected through PBD, and the third variable was incorporated based on surfactant screening & stability studies for the next design. Assay of the BBD based formulations was found to be within 95-104% of the theoretically calculated values. Further studies were investigated for PS, PDI, ZP & EE. PS was found to be in the range of 103-194 nm with PDI ranging from 0.118 to 0.265. The ZP and EE were observed to be in the range of -22.2 to -11 mV & 90 to 98.7 % respectively. Drug release of 30% was observed from the optimized formulation in the first 6 hr of in-vitro studies, and the drug release showed a sustained release of ibuprofen thereafter over several hours. These values also confirm that the production method, and all other selected variables, effectively promoted the incorporation of ibuprofen in NLC. Quality by Design (QbD) approach was successfully implemented in developing a robust ophthalmic formulation with superior physicochemical and morphometric properties. NLCs as the nanocarrier demonstrated promising perspective for topical delivery of poorly water-soluble drugs.

Development and application of a screening model for simulating regional ground-water flow in the St. Croix River basin, Minnesota and Wisconsin

USGS Publications Warehouse

Feinstein, Daniel T.; Buchwald, Cheryl A.; Dunning, Charles P.; Hunt, Randall J.

2006-01-01

A series of databases and an accompanying screening model were constructed by the U.S. Geological Survey, in cooperation with the National Park Service, to better understand the regional ground-water-flow system and its relation to stream drainage in the St. Croix River Basin. The St. Croix River and its tributaries drain about 8,000 square miles in northeastern Minnesota and northwestern Wisconsin. The databases contain information for the entire St. Croix River Basin pertaining to well logs, lithology, thickness of lithologic groups, ground-water levels, streamflow, and well pumpage. Maps and generalized cross sections created from the compiled data show the lithologic groups, extending from the water table to the crystalline bedrock, through which ground water flows. These lithologic groups are: fine-grained unconsolidated deposits; coarse-grained unconsolidated deposits; sandstone bedrock; carbonate bedrock; and other bedrock lithologies including shale, siltstone, conglomerate, and igneous intrusions. The steady-state screening model treats the ground-water-flow system as a single layer with transmissivity zones that reflect the distribution of lithologic groups, and with recharge zones that correspond to general areas of high or low evapotranspiration. The model includes representation of second- and higher-order streams and municipal and other high-capacity production wells. The analytic-element model code GFLOW was used to simulate the regional ground-water flow, the water-table surface across the St. Croix River Basin, and base-flow contributions from ground water to streams. In addition, the model routes tributary base flow through the stream network to the St. Croix River. The parameter-estimation inverse model UCODE was linked to the GFLOW model to select the combination of parameter values best able to match over 5,000 water-level measurements and base-flow estimates at 22 streamflow-gaging stations. Results from the calibrated screening model show ground-water contributing areas for selected stream reaches within the basin. The delineation of these areas is useful to water-resource managers concerned with protection of fisheries and other resources. The model results also identify the areas of the basin where ground-water travel time from the water table to streams and wells is relatively short (less than 50 years). Ninety percent of the simulated ground-water pathlines require travel times between 3 and 260 years. The median pathline distance traversed and the median pathline velocity were 1.7 mi and 177 ft/y, respectively. It is important to recognize the limitations of this screening model. Heterogeneities in subsurface properties and in recharge rates are considered only at a very broad scale (miles to tens of miles). No account is taken of vertical variations in properties or pumping rates, and no provision is made to account for stacked ground-water-flow systems that have different flow patterns at different depths. Small-scale (hundreds to thousands of feet) flow systems associated with minor water bodies are neglected, and as a result, the model is not useful for simulating typical site-specific problems. Despite its limitations, the model serves as a framework for understanding the regional pattern of ground-water flow and as a starting point for a generation of more targeted and detailed ground-water models that would be needed to address emerging water-supply and water-quality concerns in the St. Croix River Basin.

Fourier transform infrared spectroscopy for the prediction of fatty acid profiles in Mucor fungi grown in media with different carbon sources.

PubMed

Shapaval, Volha; Afseth, Nils Kristian; Vogt, Gjermund; Kohler, Achim

2014-09-11

Fungal production of polyunsaturated fatty acids (PUFAs) is a highly potential approach in biotechnology. Currently the main focus is directed towards screening of hundreds strains in order to select of few potential ones. Thus, a reliable method for screening a high number of strains within a short period of time is needed. Here, we present a novel method for screening of PUFA-producing fungi by high-throughput microcultivation and FTIR spectroscopy. In the study selected Mucor fungi were grown in media with different carbon sources and fatty acid profiles were predicted on the basis of the obtained spectral data. FTIR spectra were calibrated against fatty acid analysis by GC-FD. The calibration models were cross-validated and correlation coefficients (R2) from 0.71 to 0.78 with RMSECV (root mean squared error) from 2.86% to 6.96% (percentage of total fat) were obtained. The FTIR results show a strong correlation to the results obtained by GC analysis, where high total contents of unsaturated fatty acids (both PUFA and MUFA) were achieved for Mucor plumbeus VI02019 cultivated in canola, olive and sunflower oil and Mucor hiemalis VI01993 cultivated in canola and olive oil.

Cognitive Change Questionnaire as a method for cognitive impairment screening

PubMed Central

Damin, Antonio Eduardo; Nitrini, Ricardo; Brucki, Sonia Maria Dozzi

2015-01-01

The Cognitive Change Questionnaire (CCQ) was created as an effective measure of cognitive change that is easy to use and suitable for application in Brazil. Objective To evaluate whether the CCQ can accurately distinguish normal subjects from individuals with Mild Cognitive Impairment (MCI) and/or early stage dementia and to develop a briefer questionnaire, based on the original 22-item CCQ (CCQ22), that contains fewer questions. Methods A total of 123 individuals were evaluated: 42 healthy controls, 40 patients with MCI and 41 with mild dementia. The evaluation was performed using cognitive tests based on individual performance and on questionnaires administered to informants. The CCQ22 was created based on a selection of questions that experts deemed useful in screening for early stage dementia. Results The CCQ22 showed good accuracy for distinguishing between the groups. Statistical models selected the eight questions with the greatest power to discriminate between the groups. The AUC ROC corresponding to the final version of the 8-item CCQ (CCQ8), demonstrated good accuracy in differentiating between groups, good correlation with the final diagnosis (r=0.861) and adequate internal consistency (Cronbach's α=0.876). Conclusion The CCQ8 can be used to accurately differentiate between normal subjects and individuals with cognitive impairment, constituting a brief and appropriate instrument for cognitive screening. PMID:29213967

Application of plug-plug technique to ACE experiments for discovery of peptides binding to a larger target protein: a model study of calmodulin-binding fragments selected from a digested mixture of reduced BSA.

PubMed

Saito, Kazuki; Nakato, Mamiko; Mizuguchi, Takaaki; Wada, Shinji; Uchimura, Hiromasa; Kataoka, Hiroshi; Yokoyama, Shigeyuki; Hirota, Hiroshi; Kiso, Yoshiaki

2014-03-01

To discover peptide ligands that bind to a target protein with a higher molecular mass, a concise screening methodology has been established, by applying a "plug-plug" technique to ACE experiments. Exploratory experiments using three mixed peptides, mastoparan-X, β-endorphin, and oxytocin, as candidates for calmodulin-binding ligands, revealed that the technique not only reduces the consumption of the protein sample, but also increases the flexibility of the experimental conditions, by allowing the use of MS detection in the ACE experiments. With the plug-plug technique, the ACE-MS screening methodology successfully selected calmodulin-binding peptides from a random library with diverse constituents, such as protease digests of BSA. Three peptides with Kd values between 8-147 μM for calmodulin were obtained from a Glu-C endoprotease digest of reduced BSA, although the digest showed more than 70 peaks in its ACE-MS electropherogram. The method established here will be quite useful for the screening of peptide ligands, which have only low affinities due to their flexible chain structures but could potentially provide primary information for designing inhibitors against the target protein. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate.

PubMed

Cui, Jihong; Hollmén, Maija; Li, Lina; Chen, Yong; Proulx, Steven T; Reker, Daniel; Schneider, Gisbert; Detmar, Michael

2017-01-03

Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24- phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents.

Screening of Probiotic Candidates in Human Oral Bacteria for the Prevention of Dental Disease

PubMed Central

Terai, Tomohiko; Okumura, Takekazu; Imai, Susumu; Nakao, Masumi; Yamaji, Kazuaki; Ito, Masahiko; Nagata, Tsuyoshi; Kaneko, Kimiyuki; Miyazaki, Kouji; Okada, Ayako; Nomura, Yoshiaki; Hanada, Nobuhiro

2015-01-01

The oral cavity in healthy subjects has a well-balanced microbiota that consists of more than 700 species. However, a disturbance of this balance, with an increase of harmful microbes and a decrease of beneficial microbes, causes oral disorders such as periodontal disease or dental caries. Nowadays, probiotics are expected to confer oral health benefits by modulating the oral microbiota. This study screened new probiotic candidates with potential oral health benefits and no harmful effects on the oral cavity. We screened 14 lactobacillus strains and 36 streptococcus strains out of 896 oral isolates derived from healthy subjects. These bacteria did not produce volatile sulfur compounds or water-insoluble glucan, had higher antibacterial activity against periodontal bacteria, and had higher adherence activity to oral epithelial cells or salivary-coated hydroxyapatite in vitro. We then evaluated the risk of primary cariogenicity and infective endocarditis of the selected oral isolates. As a result, Lactobacillus crispatus YIT 12319, Lactobacillus fermentum YIT 12320, Lactobacillus gasseri YIT 12321, and Streptococcus mitis YIT 12322 were selected because they showed no cariogenic potential in an artificial mouth system and a lower risk of experimental infective endocarditis in a rat model. These candidates are expected as new probiotics with potential oral health benefits and no adverse effects on general health. PMID:26053410

Microfluidic high-throughput selection of microalgal strains with superior photosynthetic productivity using competitive phototaxis

PubMed Central

Kim, Jaoon Young Hwan; Kwak, Ho Seok; Sung, Young Joon; Choi, Hong Il; Hong, Min Eui; Lim, Hyun Seok; Lee, Jae-Hyeok; Lee, Sang Yup; Sim, Sang Jun

2016-01-01

Microalgae possess great potential as a source of sustainable energy, but the intrinsic inefficiency of photosynthesis is a major challenge to realize this potential. Photosynthetic organisms evolved phototaxis to find optimal light condition for photosynthesis. Here we report a microfluidic screening using competitive phototaxis of the model alga, Chlamydomonas reinhardtii, for rapid isolation of strains with improved photosynthetic efficiencies. We demonstrated strong relationship between phototaxis and photosynthetic efficiency by quantitative analysis of phototactic response at the single-cell level using a microfluidic system. Based on this positive relationship, we enriched the strains with improved photosynthetic efficiency by isolating cells showing fast phototactic responses from a mixture of 10,000 mutants, thereby greatly improving selection efficiency over 8 fold. Among 147 strains isolated after screening, 94.6% showed improved photoautotrophic growth over the parental strain. Two mutants showed much improved performances with up to 1.9- and 8.1-fold increases in photoautotrophic cell growth and lipid production, respectively, a substantial improvement over previous approaches. We identified candidate genes that might be responsible for fast phototactic response and improved photosynthesis, which can be useful target for further strain engineering. Our approach provides a powerful screening tool for rapid improvement of microalgal strains to enhance photosynthetic productivity. PMID:26852806

Identification of Compounds That Prolong Type I Interferon Signaling as Potential Vaccine Adjuvants.

PubMed

Shukla, Nikunj M; Arimoto, Kei-Ichiro; Yao, Shiyin; Fan, Jun-Bao; Zhang, Yue; Sato-Kaneko, Fumi; Lao, Fitzgerald S; Hosoya, Tadashi; Messer, Karen; Pu, Minya; Cottam, Howard B; Carson, Dennis A; Hayashi, Tomoko; Zhang, Dong-Er; Corr, Maripat

2018-05-01

Vaccines are reliant on adjuvants to enhance the immune stimulus, and type I interferons (IFNs) have been shown to be beneficial in augmenting this response. We were interested in identifying compounds that would sustain activation of an endogenous type I IFN response as a co-adjuvant. We began with generation of a human monocytic THP-1 cell line with an IFN-stimulated response element (ISRE)-β-lactamase reporter construct for high-throughput screening. Pilot studies were performed to optimize the parameters and conditions for this cell-based Förster resonance energy transfer (FRET) reporter assay for sustaining an IFN-α-induced ISRE activation signal. These conditions were confirmed in an initial pilot screen, followed by the main screen for evaluating prolongation of an IFN-α-induced ISRE activation signal at 16 h. Hit compounds were identified using a structure enrichment strategy based on chemoinformatic clustering and a naïve "Top X" approach. A select list of confirmed hits was then evaluated for toxicity and the ability to sustain IFN activity by gene and protein expression. Finally, for proof of concept, a panel of compounds was used to immunize mice as co-adjuvant with a model antigen and an IFN-inducing Toll-like receptor 4 agonist, lipopolysaccharide, as an adjuvant. Selected compounds significantly augmented antigen-specific immunoglobulin responses.

Screening of Probiotic Candidates in Human Oral Bacteria for the Prevention of Dental Disease.

PubMed

Terai, Tomohiko; Okumura, Takekazu; Imai, Susumu; Nakao, Masumi; Yamaji, Kazuaki; Ito, Masahiko; Nagata, Tsuyoshi; Kaneko, Kimiyuki; Miyazaki, Kouji; Okada, Ayako; Nomura, Yoshiaki; Hanada, Nobuhiro

2015-01-01

The oral cavity in healthy subjects has a well-balanced microbiota that consists of more than 700 species. However, a disturbance of this balance, with an increase of harmful microbes and a decrease of beneficial microbes, causes oral disorders such as periodontal disease or dental caries. Nowadays, probiotics are expected to confer oral health benefits by modulating the oral microbiota. This study screened new probiotic candidates with potential oral health benefits and no harmful effects on the oral cavity. We screened 14 lactobacillus strains and 36 streptococcus strains out of 896 oral isolates derived from healthy subjects. These bacteria did not produce volatile sulfur compounds or water-insoluble glucan, had higher antibacterial activity against periodontal bacteria, and had higher adherence activity to oral epithelial cells or salivary-coated hydroxyapatite in vitro. We then evaluated the risk of primary cariogenicity and infective endocarditis of the selected oral isolates. As a result, Lactobacillus crispatus YIT 12319, Lactobacillus fermentum YIT 12320, Lactobacillus gasseri YIT 12321, and Streptococcus mitis YIT 12322 were selected because they showed no cariogenic potential in an artificial mouth system and a lower risk of experimental infective endocarditis in a rat model. These candidates are expected as new probiotics with potential oral health benefits and no adverse effects on general health.

Serum factors and clinical characteristics associated with serum E-Screen activity

PubMed Central

Wang, Jue; Trentham-Dietz, Amy; Hemming, Jocelyn D. C.; Hedman, Curtis J.; Sprague, Brian L.

2013-01-01

Background The E-Screen bioassay can measure the mitogenicity of human serum and thus may be useful as a biomarker in epidemiologic studies of breast cancer. While the assay’s MCF-7 cells are known to proliferate in response to estrogen, the specific determinants of variation in E-Screen activity in human serum samples are poorly understood. We sought to identify serum molecules and patient characteristics associated with serum E-Screen activity among postmenopausal women. Methods Postmenopausal women (N=219) aged 55–70 with no history of postmenopausal hormone use or breast cancer completed a questionnaire and provided a blood sample. Serum was analyzed for E-Screen activity and a variety of molecules including sex hormones, growth factors, and environmental chemicals. Stepwise selection procedures were used to identify correlates of E-Screen activity. Results Serum samples from all women had detectable E-Screen activity, with a median estradiol equivalents value of 0.027 ng/mL and interquartile range of 0.018–0.036 ng/mL. In the final multivariable-adjusted model, serum E-Screen activity was positively associated with serum estradiol, estrone, IGFBP-3, and testosterone levels (p<0.05), as well as body mass index (p=0.03). Serum E-Screen activity was lower among women with higher SHBG (p<0.0001) and progesterone levels (p=0.03). Conclusion Serum E-Screen activity varies according to levels of endogenous estrogens and other serum molecules. Obesity appears to confer additional serum mitogenicity beyond its impact on the measured hormones and growth factors. Impact By capturing mitogenicity due to a variety of patient and serum factors, the E-Screen may provide advantages for use as a biomarker in breast cancer studies. PMID:23588007

Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation.

PubMed

Nelson, Heidi D; Pappas, Miranda; Cantor, Amy; Griffin, Jessica; Daeges, Monica; Humphrey, Linda

2016-02-16

In 2009, the U.S. Preventive Services Task Force recommended biennial mammography screening for women aged 50 to 74 years and selective screening for those aged 40 to 49 years. To review studies of screening in average-risk women with mammography, magnetic resonance imaging, or ultrasonography that reported on false-positive results, overdiagnosis, anxiety, pain, and radiation exposure. MEDLINE and Cochrane databases through December 2014. English-language systematic reviews, randomized trials, and observational studies of screening. Investigators extracted and confirmed data from studies and dual-rated study quality. Discrepancies were resolved through consensus. Based on 2 studies of U.S. data, 10-year cumulative rates of false-positive mammography results and biopsies were higher with annual than biennial screening (61% vs. 42% and 7% vs. 5%, respectively) and for women aged 40 to 49 years, those with dense breasts, and those using combination hormone therapy. Twenty-nine studies using different methods reported overdiagnosis rates of 0% to 54%; rates from randomized trials were 11% to 22%. Women with false-positive results reported more anxiety, distress, and breast cancer-specific worry, although results varied across 80 observational studies. Thirty-nine observational studies indicated that some women reported pain during mammography (1% to 77%); of these, 11% to 46% declined future screening. Models estimated 2 to 11 screening-related deaths from radiation-induced cancer per 100,000 women using digital mammography, depending on age and screening interval. Five observational studies of tomosynthesis and mammography indicated increased biopsies but reduced recalls compared with mammography alone. Studies of overdiagnosis were highly heterogeneous, and estimates varied depending on the analytic approach. Studies of anxiety and pain used different outcome measures. Radiation exposure was based on models. False-positive results are common and are higher for annual screening, younger women, and women with dense breasts. Although overdiagnosis, anxiety, pain, and radiation exposure may cause harm, their effects on individual women are difficult to estimate and vary widely. Agency for Healthcare Research and Quality.

CRISPR-UMI: single-cell lineage tracing of pooled CRISPR-Cas9 screens.

PubMed

Michlits, Georg; Hubmann, Maria; Wu, Szu-Hsien; Vainorius, Gintautas; Budusan, Elena; Zhuk, Sergei; Burkard, Thomas R; Novatchkova, Maria; Aichinger, Martin; Lu, Yiqing; Reece-Hoyes, John; Nitsch, Roberto; Schramek, Daniel; Hoepfner, Dominic; Elling, Ulrich

2017-12-01

Pooled CRISPR screens are a powerful tool for assessments of gene function. However, conventional analysis is based exclusively on the relative abundance of integrated single guide RNAs (sgRNAs) between populations, which does not discern distinct phenotypes and editing outcomes generated by identical sgRNAs. Here we present CRISPR-UMI, a single-cell lineage-tracing methodology for pooled screening to account for cell heterogeneity. We generated complex sgRNA libraries with unique molecular identifiers (UMIs) that allowed for screening of clonally expanded, individually tagged cells. A proof-of-principle CRISPR-UMI negative-selection screen provided increased sensitivity and robustness compared with conventional analysis by accounting for underlying cellular and editing-outcome heterogeneity and detection of outlier clones. Furthermore, a CRISPR-UMI positive-selection screen uncovered new roadblocks in reprogramming mouse embryonic fibroblasts as pluripotent stem cells, distinguishing reprogramming frequency and speed (i.e., effect size and probability). CRISPR-UMI boosts the predictive power, sensitivity, and information content of pooled CRISPR screens.

A Modeling Study of the Spatial Structure of Electric Fields Generated by Electrified Clouds with Screening Layers

NASA Astrophysics Data System (ADS)

Biagi, C. J.; Cummins, K. L.

2015-12-01

The growing possibility of inexpensive airborne observations of electric fields using one or more small UAVs increases the importance of understanding what can be determined about cloud electrification and associated electric fields outside cloud boundaries. If important information can be inferred from carefully selected flight paths outside of a cloud, then the aircraft and its instrumentation will be much cheaper to develop and much safer to operate. These facts have led us to revisit this long-standing topic using quasi-static, finite-element modeling inside and outside arbitrarily shaped clouds with a variety of internal charge distributions. In particular, we examine the effect of screening layers on electric fields outside of electrified clouds by comparing modeling results for charged clouds having electrical conductivities that are both equal to and lower than the surrounding clear air. The comparisons indicate that the spatial structure of the electric field is approximately the same regardless of the difference in the conductivities between the cloud and clear air and the formation of a screening layer, even for altitude-dependent electrical conductivities. This result is consistent with the numerical modeling results reported by Driscoll et al [1992]. The similarity of the spatial structure of the electric field outside of clouds with and without a screening layer suggests that "bulk" properties related to cloud electrification might be determined using measurements of the electric field at multiple locations in space outside the cloud, particularly at altitude. Finally, for this somewhat simplified model, the reduction in electric field magnitude outside the cloud due to the presence of a screening layer exhibits a simple dependence on the difference in conductivity between the cloud and clear air. These results are particularly relevant for studying clouds that are not producing lightning, such as developing thunderstorms and decaying anvils associated with mature storm systems.Driscoll K.T., R.J. Blakeslee, M.E. Baginski, 1992, A modeling study of the time-averaged electric currents in the vicinity of isolated thunderstorms, J. Geophys. Res., 97, D11, pp 11535-11551.

Quantitative assessment model for gastric cancer screening

PubMed Central

Chen, Kun; Yu, Wei-Ping; Song, Liang; Zhu, Yi-Min

2005-01-01

AIM: To set up a mathematic model for gastric cancer screening and to evaluate its function in mass screening for gastric cancer. METHODS: A case control study was carried on in 66 patients and 198 normal people, then the risk and protective factors of gastric cancer were determined, including heavy manual work, foods such as small yellow-fin tuna, dried small shrimps, squills, crabs, mothers suffering from gastric diseases, spouse alive, use of refrigerators and hot food, etc. According to some principles and methods of probability and fuzzy mathematics, a quantitative assessment model was established as follows: first, we selected some factors significant in statistics, and calculated weight coefficient for each one by two different methods; second, population space was divided into gastric cancer fuzzy subset and non gastric cancer fuzzy subset, then a mathematic model for each subset was established, we got a mathematic expression of attribute degree (AD). RESULTS: Based on the data of 63 patients and 693 normal people, AD of each subject was calculated. Considering the sensitivity and specificity, the thresholds of AD values calculated were configured with 0.20 and 0.17, respectively. According to these thresholds, the sensitivity and specificity of the quantitative model were about 69% and 63%. Moreover, statistical test showed that the identification outcomes of these two different calculation methods were identical (P>0.05). CONCLUSION: The validity of this method is satisfactory. It is convenient, feasible, economic and can be used to determine individual and population risks of gastric cancer. PMID:15655813

Elaborate ligand-based modeling coupled with QSAR analysis and in silico screening reveal new potent acetylcholinesterase inhibitors.

PubMed

Abuhamdah, Sawsan; Habash, Maha; Taha, Mutasem O

2013-12-01

Inhibition of the enzyme acetylcholinesterase (AChE) has been shown to alleviate neurodegenerative diseases prompting several attempts to discover and optimize new AChE inhibitors. In this direction, we explored the pharmacophoric space of 85 AChE inhibitors to identify high quality pharmacophores. Subsequently, we implemented genetic algorithm-based quantitative structure-activity relationship (QSAR) modeling to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation among training compounds (r2(68)=0.94, F-statistic=125.8, r2 LOO=0.92, r2 PRESS against 17 external test inhibitors = 0.84). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within AChE binding pocket. The successful pharmacophores were comparable with crystallographically resolved AChE binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute list of compounds. Twenty-four low micromolar AChE inhibitors were identified. The most potent gave IC50 value of 1.0 μM.

Application of queuing model in Dubai's busiest megaplex

NASA Astrophysics Data System (ADS)

Bhagchandani, Maneesha; Bajpai, Priti

2013-09-01

This paper provides a study and analysis of the extremely busy booking counters at the Megaplex in Dubai using the queuing model and simulation. Dubai is an emirate in UAE with a multicultural population. Majority of the population in Dubai is foreign born. Cinema is one of the major forms of entertainment. There are more than 13 megaplexes each with a number of screens ranging from 3 to 22. They screen movies in English, Arabic, Hindi and other languages. It has been observed that during the weekends megaplexes attract a large number of crowd resulting in long queues at the booking counters. One of the busiest megaplex was selected for the study. Queuing theory satisfies the model when tested in real time situation. The concepts of arrival rate, service rate, utilization rate, waiting time in the system, average number of people in the queue, using Little's Theorem and M/M/s queuing model along with simulation software have been used to suggest an empirical solution. The aim of the paper is twofold-To assess the present situation at the Megaplex and give recommendations to optimize the use of booking counters.

Sequence determinants of improved CRISPR sgRNA design.

PubMed

Xu, Han; Xiao, Tengfei; Chen, Chen-Hao; Li, Wei; Meyer, Clifford A; Wu, Qiu; Wu, Di; Cong, Le; Zhang, Feng; Liu, Jun S; Brown, Myles; Liu, X Shirley

2015-08-01

The CRISPR/Cas9 system has revolutionized mammalian somatic cell genetics. Genome-wide functional screens using CRISPR/Cas9-mediated knockout or dCas9 fusion-mediated inhibition/activation (CRISPRi/a) are powerful techniques for discovering phenotype-associated gene function. We systematically assessed the DNA sequence features that contribute to single guide RNA (sgRNA) efficiency in CRISPR-based screens. Leveraging the information from multiple designs, we derived a new sequence model for predicting sgRNA efficiency in CRISPR/Cas9 knockout experiments. Our model confirmed known features and suggested new features including a preference for cytosine at the cleavage site. The model was experimentally validated for sgRNA-mediated mutation rate and protein knockout efficiency. Tested on independent data sets, the model achieved significant results in both positive and negative selection conditions and outperformed existing models. We also found that the sequence preference for CRISPRi/a is substantially different from that for CRISPR/Cas9 knockout and propose a new model for predicting sgRNA efficiency in CRISPRi/a experiments. These results facilitate the genome-wide design of improved sgRNA for both knockout and CRISPRi/a studies. © 2015 Xu et al.; Published by Cold Spring Harbor Laboratory Press.

Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer's Disease by Vitamin E and Selenium Trial (PREADViSE).

PubMed

Kryscio, Richard J; Abner, Erin L; Caban-Holt, Allison; Lovell, Mark; Goodman, Phyllis; Darke, Amy K; Yee, Monica; Crowley, John; Schmitt, Frederick A

2017-05-01

Oxidative stress is an established dementia pathway, but it is unknown if the use of antioxidant supplements can prevent dementia. To determine if antioxidant supplements (vitamin E or selenium) used alone or in combination can prevent dementia in asymptomatic older men. The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADViSE) trial began as a double-blind randomized clinical trial in May 2002, which transformed into a cohort study from September 2009 to May 2015. The PREADViSE trial was ancillary to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized clinical trial of the same antioxidant supplements for preventing prostate cancer, which closed in 2009 owing to findings from a futility analysis. The PREADViSE trial recruited 7540 men, of whom 3786 continued into the cohort study. Participants were at least 60 years old at study entry and were enrolled at 130 SELECT sites, and Cox proportional hazards models were used in a modified intent-to-treat analysis to compare hazard rates among the study arms. Participants were randomized to vitamin E, selenium, vitamin E and selenium, or placebo. While taking study supplements, enrolled men visited their SELECT site and were evaluated for dementia using a 2-stage screen. During the cohort study, men were contacted by telephone and assessed using an enhanced 2-stage cognitive screen. In both phases, men were encouraged to visit their physician if the screen results indicated possible cognitive impairment. Dementia case ascertainment relied on a consensus review of the cognitive screens and medical records for men with suspected dementia who visited their physician for an evaluation or by review of all available information, including a functional assessment screen. The mean (SD) baseline age of the 7540 participants was 67.5 (5.3) years, with 3936 (52.2%) reporting a college education or better, 754 (10.0%) reporting black race, and 505 (6.7%) reporting Hispanic ethnicity. Dementia incidence (325 of 7338 men [4.4%]) was not different among the 4 study arms. A Cox model, which adjusted incidence for participant demographic information and baseline self-reported comorbidities, yielded hazard ratios of 0.88 (95% CI, 0.64-1.20) for vitamin E, 0.83 (0.60-1.13) for selenium, and 1.00 (0.75-1.35) for the combination compared with placebo. Neither supplement prevented dementia. To our knowledge, this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men.

Assessment of global and local region-based bilateral mammographic feature asymmetry to predict short-term breast cancer risk

NASA Astrophysics Data System (ADS)

Li, Yane; Fan, Ming; Cheng, Hu; Zhang, Peng; Zheng, Bin; Li, Lihua

2018-01-01

This study aims to develop and test a new imaging marker-based short-term breast cancer risk prediction model. An age-matched dataset of 566 screening mammography cases was used. All ‘prior’ images acquired in the two screening series were negative, while in the ‘current’ screening images, 283 cases were positive for cancer and 283 cases remained negative. For each case, two bilateral cranio-caudal view mammograms acquired from the ‘prior’ negative screenings were selected and processed by a computer-aided image processing scheme, which segmented the entire breast area into nine strip-based local regions, extracted the element regions using difference of Gaussian filters, and computed both global- and local-based bilateral asymmetrical image features. An initial feature pool included 190 features related to the spatial distribution and structural similarity of grayscale values, as well as of the magnitude and phase responses of multidirectional Gabor filters. Next, a short-term breast cancer risk prediction model based on a generalized linear model was built using an embedded stepwise regression analysis method to select features and a leave-one-case-out cross-validation method to predict the likelihood of each woman having image-detectable cancer in the next sequential mammography screening. The area under the receiver operating characteristic curve (AUC) values significantly increased from 0.5863  ±  0.0237 to 0.6870  ±  0.0220 when the model trained by the image features extracted from the global regions and by the features extracted from both the global and the matched local regions (p  =  0.0001). The odds ratio values monotonically increased from 1.00-8.11 with a significantly increasing trend in slope (p  =  0.0028) as the model-generated risk score increased. In addition, the AUC values were 0.6555  ±  0.0437, 0.6958  ±  0.0290, and 0.7054  ±  0.0529 for the three age groups of 37-49, 50-65, and 66-87 years old, respectively. AUC values of 0.6529  ±  0.1100, 0.6820  ±  0.0353, 0.6836  ±  0.0302 and 0.8043  ±  0.1067 were yielded for the four mammography density sub-groups (BIRADS from 1-4), respectively. This study demonstrated that bilateral asymmetry features extracted from local regions combined with the global region in bilateral negative mammograms could be used as a new imaging marker to assist in the prediction of short-term breast cancer risk.

Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands.

PubMed

Rosano, Camillo; Ponassi, Marco; Santolla, Maria Francesca; Pisano, Assunta; Felli, Lamberto; Vivacqua, Adele; Maggiolini, Marcello; Lappano, Rosamaria

2016-01-01

Estrogens influence multiple physiological processes and are implicated in many diseases as well. Cellular responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as ligand-activated transcription factors. Recently, a member of the G protein-coupled receptor (GPCR) superfamily, namely GPER/GPR30, has been identified as a further mediator of estrogen signalling in different pathophysiological conditions, including cancer. Today, computational methods are commonly used in all areas of health science research. Among these methods, virtual ligand screening has become an established technique for hit discovery and optimization. The absence of an established three-dimensional structure of GPER promoted studies of structure-based drug design in order to build reliable molecular models of this receptor. Here, we discuss the results obtained through the structure-based virtual ligand screening for GPER, which allowed the identification and synthesis of different selective agonist and antagonist moieties. These compounds led significant advances in our understanding of the GPER function at the cellular, tissue, and organismal levels. In particular, selective GPER ligands were critical toward the evaluation of the role elicited by this receptor in several pathophysiological conditions, including cancer. Considering that structure-based approaches are fundamental in drug discovery, future research breakthroughs with the aid of computer-aided molecular design and chemo-bioinformatics could generate a new class of drugs that, acting through GPER, would be useful in a variety of diseases as well as in innovative anticancer strategies.

Therapeutic Potential of Shark Anti-ICOSL VNAR Domains is Exemplified in a Murine Model of Autoimmune Non-Infectious Uveitis.

PubMed

Kovaleva, Marina; Johnson, Katherine; Steven, John; Barelle, Caroline J; Porter, Andrew

2017-01-01

Induced costimulatory ligand (ICOSL) plays an important role in the activation of T cells through its interaction with the inducible costimulator, ICOS. Suppression of full T cell activation can be achieved by blocking this interaction and has been shown to be an effective means of ameliorating disease in models of autoimmunity and inflammation. In this study, we demonstrated the ability of a novel class of anti-ICOSL antigen-binding single domains derived from sharks (VNARs) to effectively reduce inflammation in a murine model of non-infectious uveitis. In initial selections, specific VNARs that recognized human ICOSL were isolated from an immunized nurse shark phage display library and lead domains were identified following their performance in a series of antigen selectivity and in vitro bioassay screens. High potency in cell-based blocking assays suggested their potential as novel binders suitable for further therapeutic development. To test this hypothesis, surrogate anti-mouse ICOSL VNAR domains were isolated from the same phage display library and the lead VNAR clone selected via screening in binding and ICOS/ICOSL blocking experiments. The VNAR domain with the highest potency in cell-based blocking of ICOS/ICOSL interaction was fused to the Fc portion of human IgG1 and was tested in vivo in a mouse model of interphotoreceptor retinoid-binding protein-induced uveitis. The anti-mICOSL VNAR Fc, injected systemically, resulted in a marked reduction of inflammation in treated mice when compared with untreated control animals. This approach inhibited disease progression to an equivalent extent to that seen for the positive corticosteroid control, cyclosporin A, reducing both clinical and histopathological scores. These results represent the first demonstration of efficacy of a VNAR binding domain in a relevant clinical model of disease and highlight the potential of VNARs for the treatment of auto-inflammatory conditions.

Microplate Bioassay for Determining Substrate Selectivity of "Candida rugosa" Lipase

ERIC Educational Resources Information Center

Wang, Shi-zhen; Fang, Bai-shan

2012-01-01

Substrate selectivity of "Candida rugosa" lipase was tested using "p"-nitrophenyl esters of increasing chain length (C[subscript 1], C[subscript 7], C[subscript 15]) using the high-throughput screening method. A fast and easy 96-well microplate bioassay was developed to help students learn and practice biotechnological specificity screen. The…

Comparing Two CBM Maze Selection Tools: Considering Scoring and Interpretive Metrics for Universal Screening

ERIC Educational Resources Information Center

Ford, Jeremy W.; Missall, Kristen N.; Hosp, John L.; Kuhle, Jennifer L.

2016-01-01

Advances in maze selection curriculum-based measurement have led to several published tools with technical information for interpretation (e.g., norms, benchmarks, cut-scores, classification accuracy) that have increased their usefulness for universal screening. A range of scoring practices have emerged for evaluating student performance on maze…

Validity and Reliability of Psychosocial Factors Related to Breast Cancer Screening.

ERIC Educational Resources Information Center

Zapka, Jane G.; And Others

1991-01-01

The construct validity of hypothesized survey items and data reduction procedures for selected psychosocial constructs frequently used in breast cancer screening research were investigated in telephone interviews with randomly selected samples of 1,184 and 903 women and a sample of 169 Hispanic clinic clients. Validity of the constructs is…

Logistics of Behavior Screenings: How and Why Do We Conduct Behavior Screenings at Our School?

ERIC Educational Resources Information Center

Oakes, Wendy Peia; Lane, Kathleen Lynne; Cox, Meredith Lucille; Messenger, Mallory

2014-01-01

In this article, the authors provide an overview of behavior screening tools available, including free and commercially available options. Next, the authors offer step-by-step procedures for (a) selecting, (b) scheduling, (c) preparing, (d) administering, and (e) scoring and interpreting behaviors screening tools. The authors conclude with…

A Critical Review of the Technical Characteristics of Current Preschool Screening Batteries

ERIC Educational Resources Information Center

Emmons, Michael R.; Alfonso, Vincent C.

2005-01-01

The current review provides a summary and evaluation of the technical characteristics of five preschool screening batteries, including the Brigance Screens, DIAL-3, ESI-R, ESP, and FirstSTEP. These norm-referenced instruments were selected on the basis of their commercial availability, description as a screening instrument, and ability to assess…

Development of a potent and selective FLT3 kinase inhibitor by systematic expansion of a non-selective fragment-screening hit.

PubMed

Nakano, Hirofumi; Hasegawa, Tsukasa; Imamura, Riyo; Saito, Nae; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo

2016-05-01

A non-selective inhibitor (1) of FMS-like tyrosine kinase-3 (FLT3) was identified by fragment screening and systematically modified to afford a potent and selective inhibitor 26. We confirmed that 26 inhibited the growth of FLT-3-activated human acute myeloid leukemia cell line MV4-11. Our design strategy enabled rapid development of a novel type of FLT3 inhibitor from the hit fragment in the absence of target-structural information. Copyright © 2016 Elsevier Ltd. All rights reserved.

Determinants of BH3 Binding Specificity for Mcl-1 versus Bcl-x[subscript L

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dutta, Sanjib; Gullá, Stefano; Chen, T. Scott

2010-06-25

Interactions among Bcl-2 family proteins are important for regulating apoptosis. Prosurvival members of the family interact with proapoptotic BH3 (Bcl-2-homology-3)-only members, inhibiting execution of cell death through the mitochondrial pathway. Structurally, this interaction is mediated by binding of the {alpha}-helical BH3 region of the proapoptotic proteins to a conserved hydrophobic groove on the prosurvival proteins. Native BH3-only proteins exhibit selectivity in binding prosurvival members, as do small molecules that block these interactions. Understanding the sequence and structural basis of interaction specificity in this family is important, as it may allow the prediction of new Bcl-2 family associations and/or the designmore » of new classes of selective inhibitors to serve as reagents or therapeutics. In this work, we used two complementary techniques - yeast surface display screening from combinatorial peptide libraries and SPOT peptide array analysis - to elucidate specificity determinants for binding to Bcl-x{sub L} versus Mcl-1, two prominent prosurvival proteins. We screened a randomized library and identified BH3 peptides that bound to either Mcl-1 or Bcl-x{sub L} selectively or to both with high affinity. The peptides competed with native ligands for binding into the conserved hydrophobic groove, as illustrated in detail by a crystal structure of a specific peptide bound to Mcl-1. Mcl-1-selective peptides from the screen were highly specific for binding Mcl-1 in preference to Bcl-x{sub L}, Bcl-2, Bcl-w, and Bfl-1, whereas Bcl-x{sub L}-selective peptides showed some cross-interaction with related proteins Bcl-2 and Bcl-w. Mutational analyses using SPOT arrays revealed the effects of 170 point mutations made in the background of a peptide derived from the BH3 region of Bim, and a simple predictive model constructed using these data explained much of the specificity observed in our Mcl-1 versus Bcl-x{sub L} binders.« less

Development of pseudo-linear gradient elution for high-throughput resin selectivity screening in RoboColumn® Format.

PubMed

Kiesewetter, André; Menstell, Peter; Peeck, Lars H; Stein, Andreas

2016-11-01

Rapid development of chromatographic processes relies on effective high-throughput screening (HTS) methods. This article describes the development of pseudo-linear gradient elution for resin selectivity screening using RoboColumns ® . It gives guidelines for the implementation of this HTS method on a Tecan Freedom EVO ® robotic platform, addressing fundamental aspects of scale down and liquid handling. The creation of a flexible script for buffer preparation and column operation plus efficient data processing provided the basis for this work. Based on the concept of discretization, linear gradient elution was transformed into multistep gradients. The impact of column size, flow rate, multistep gradient design, and fractionation scheme on separation efficiency was systematically investigated, using a ternary model protein mixture. We identified key parameters and defined optimal settings for effective column performance. For proof of concept, we examined the selectivity of several cation exchange resins using various buffer conditions. The final protocol enabled a clear differentiation of resin selectivity on miniature chromatography column (MCC) scale. Distinct differences in separation behavior of individual resins and the influence of buffer conditions could be demonstrated. Results obtained with the robotic platform were representative and consistent with data generated on a conventional chromatography system. A study on antibody monomer/high molecular weight separation comparing MCC and lab scale under higher loading conditions provided evidence of the applicability of the miniaturized approach to practically relevant feedstocks with challenging separation tasks as well as of the predictive quality for larger scale. A comparison of varying degrees of robotic method complexity with corresponding effort (analysis time and labware consumption) and output quality highlights tradeoffs to select a method appropriate for a given separation challenge or analytical constraints. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1503-1519, 2016. © 2016 American Institute of Chemical Engineers.

Determinants of BH3 binding specificity for Mcl-1 vs. Bcl-xL

PubMed Central

Dutta, Sanjib; Gullá, Stefano; Chen, T. Scott; Fire, Emiko; Grant, Robert A.; Keating, Amy E.

2010-01-01

Interactions among Bcl-2 family proteins are important for regulating apoptosis. Pro-survival members of the family interact with pro-apoptotic BH3-only members, inhibiting execution of cell death through the mitochondrial pathway. Structurally, this interaction is mediated by binding of the alpha-helical BH3 region of the pro-apoptotic proteins to a conserved hydrophobic groove on the pro-survival proteins. Native BH3-only proteins exhibit selectivity in binding pro-survival members, as do small molecules that block these interactions. Understanding the sequence and structural basis of interaction specificity in this family is important, as it may allow the prediction of new Bcl-2 family associations and/or the design of new classes of selective inhibitors to serve as reagents or therapeutics. In this work we used two complementary techniques, yeast surface display screening from combinatorial peptide libraries and SPOT peptide array analysis, to elucidate specificity determinants for binding to Bcl-xL vs. Mcl-1, two prominent pro-survival proteins. We screened a randomized library and identified BH3 peptides that bound to either Mcl-1 or Bcl-xL selectively, or to both with high affinity. The peptides competed with native ligands for binding into the conserved hydrophobic groove, as illustrated in detail by a crystal structure of a specific peptide bound to Mcl-1. Mcl-1 selective peptides from the screen were highly specific for binding Mcl-1 in preference to Bcl-xL, Bcl-2, Bcl-w and Bfl-1, whereas Bcl-xL selective peptides showed some cross-interaction with related proteins Bcl-2 and Bcl-w. Mutational analyses using SPOT arrays revealed the effects of 170 point mutations made in the background of a peptide derived from the BH3 region of Bim, and a simple predictive model constructed using these data explained much of the specificity observed in our Mcl-1 vs. Bcl-xL binders. PMID:20363230

Broadening the examination of sociocultural constructs relevant to African-American colorectal cancer screening.

PubMed

Thompson, V L Sanders; Harris, J; Clark, E M; Purnell, J; Deshpande, A D

2015-01-01

The importance of sociocultural constructs as influences on cancer attitudes and screening has been established in the literature. This paper reports on the efforts to explore alternatives to sociocultural constructs previously associated with African-American cancer screening, but with low acceptance among community members or incomplete measurement (empowerment and collectivism) and develop a measure for a recently identified construct of interest (privacy). We report preliminary psychometric data on these sociocultural scales and their associations with cancer attitudes. African-Americans (N = 1021), 50-75 years of age participated in this study. Participants were identified via a listed sample and completed a telephone survey administered via call center. Sociocultural attitudes were assessed using items identified through computerized database searches, reviewed by advisory panels, edited and tested using cognitive response strategies. Cancer screening pros and cons, cancer worry, perceived cancer risk, colorectal cancer (CRC) screening subjective norms, and perceived self-efficacy for colorectal cancer screening (CRCS) were also assessed. Confirmatory factor analyses and multivariate analyses were conducted to provide support for the validity of the constructs and to understand the associations among the selected sociocultural constructs (empowerment, collectivism, and privacy) and cancer beliefs and attitudes (CRC perceived benefits and barriers, perceived risks, subjective norms, and perceived behavioral control/self-efficacy). Consistent with the literature, the factor analytic model (RMSEA for the model was .062; 90% CI: .060-.065) provided support for the empowerment, collectivism, and privacy constructs. The modified collectivism and privacy scales had acceptable reliability. The privacy scale demonstrated the strongest associations with measures of cancer beliefs and attitudes. The implication of the findings and need for further scale development activities is discussed.

Broadening the examination of socio-cultural constructs relevant to African American colorectal cancer screening

PubMed Central

Sanders Thompson, V. L.; Harris, J.; Clark, E.M.; Purnell, J.; Deshpande, A.D.

2014-01-01

The importance of socio-cultural constructs as influences on cancer attitudes and screening has been established in the literature. This paper reports on efforts to explore alternatives to constructs previously associated with African American cancer screening, but with low acceptance among community members or incomplete measurement (empowerment and collectivism) and develop a measure for a recently identified construct of interest (privacy). We report preliminary psychometric data on these socio-cultural scales and their associations with cancer attitudes. African Americans (N=1021), 50 to 75 years of age participated in this study. Participants were identified via a listed sample and completed a telephone survey administered via call center. Socio-cultural attitudes were assessed using items identified through computerized database searches, reviewed by advisory panels, edited and tested using cognitive response strategies. Cancer screening pros and cons, cancer worry, perceived cancer risk, colorectal cancer screening subjective norms, and perceived self-efficacy for colorectal cancer screening were also assessed. Confirmatory factor analyses and multivariate analyses were conducted to provide support for the validity of the constructs and to understand the associations among the selected socio-cultural constructs (empowerment, collectivism and empowerment) and cancer beliefs and attitudes (CRC perceived benefits and barriers, perceived risks, subjective norms, and perceived behavioral control/self-efficacy). Consistent with the literature, the factor analytic model (RMSEA for the model was 0.062; 90% CI: 0.060-0.065) provided support for the empowerment, collectivism and privacy constructs. The modified collectivism and privacy scales had acceptable reliability. The privacy scale demonstrated the strongest associations with measures of cancer beliefs and attitudes. The implication of the findings and need for further scale development activities is discussed. PMID:24628025

An In Silico Method for Screening Nicotine Derivatives as Cytochrome P450 2A6 Selective Inhibitors Based on Kernel Partial Least Squares

PubMed Central

Wang, Yonghua; Li, Yan; Wang, Bin

2007-01-01

Nicotine and a variety of other drugs and toxins are metabolized by cytochrome P450 (CYP) 2A6. The aim of the present study was to build a quantitative structure-activity relationship (QSAR) model to predict the activities of nicotine analogues on CYP2A6. Kernel partial least squares (K-PLS) regression was employed with the electro-topological descriptors to build the computational models. Both the internal and external predictabilities of the models were evaluated with test sets to ensure their validity and reliability. As a comparison to K-PLS, a standard PLS algorithm was also applied on the same training and test sets. Our results show that the K-PLS produced reasonable results that outperformed the PLS model on the datasets. The obtained K-PLS model will be helpful for the design of novel nicotine-like selective CYP2A6 inhibitors.

Accurate and noninvasive embryos screening during in vitro fertilization (IVF) assisted by Raman analysis of embryos culture medium Accurate and noninvasive embryos screening during IVF

NASA Astrophysics Data System (ADS)

Shen, A. G.; Peng, J.; Zhao, Q. H.; Su, L.; Wang, X. H.; Hu, J. M.; Yang, J.

2012-04-01

In combination with morphological evaluation tests, we employ Raman spectroscopy to select higher potential reproductive embryos during in vitro fertilization (IVF) based on chemical composition of embryos culture medium. In this study, 57 Raman spectra are acquired from both higher and lower quality embryos culture medium (ECM) from 10 patients which have been preliminarily confirmed by clinical assay. Data are fit by using a linear combination model of least squares method in which 12 basis spectra represent the chemical features of ECM. The final fitting coefficients provide insight into the chemical compositions of culture medium samples and are subsequently used as criterion to evaluate the quality of embryos. The relative fitting coefficients ratios of sodium pyruvate/albumin and phenylalanine/albumin seem act as key roles in the embryo screening, attaining 85.7% accuracy in comparison with clinical pregnancy. The good results demonstrate that Raman spectroscopy therefore is an important candidate for an accurate and noninvasive screening of higher quality embryos, which potentially decrease the time-consuming clinical trials during IVF.

Approaches to virtual screening and screening library selection.

PubMed

Wildman, Scott A

2013-01-01

The ease of access to virtual screening (VS) software in recent years has resulted in a large increase in literature reports. Over 300 publications in the last year report the use of virtual screening techniques to identify new chemical matter or present the development of new virtual screening techniques. The increased use is accompanied by a corresponding increase in misuse and misinterpretation of virtual screening results. This review aims to identify many of the common difficulties associated with virtual screening and allow researchers to better assess the reliability of their virtual screening effort.

15-year followup of a population based prostate cancer screening study.

PubMed

Kjellman, Anders; Akre, Olof; Norming, Ulf; Törnblom, Magnus; Gustafsson, Ove

2009-04-01

We evaluated long-term survival in attendees and nonattendees of a 1-time screening for prostate cancer. A total of 2,400 men 55 to 70 years old in 1988 were randomly selected and invited to a screening for prostate cancer. Of the invited men 1,782 (74%) attended. Screening attendees were examined with digital rectal examination, transrectal ultrasound and prostate specific antigen analysis. When cancer was suspected, prostate biopsies were taken. A total of 65 men with prostate cancer were detected by this procedure. The entire source population comprising 27,204 men, including 618 nonattendees (26%), was followed for prostate cancer diagnosis and survival for 15 years. Incidence rate ratios were calculated using Poisson regression models. We found no effect of this screening procedure on the risk of death from prostate cancer and other causes of death (incidence rate ratio 1.10, 95% CI 0.83-1.46 and 0.98, 95% CI 0.92-1.05, respectively) when comparing all invited men with the source population. However, attending the screening program was associated with a significantly decreased risk of death from causes other than prostate cancer (vs source population incidence rate ratio 0.82, 95% CI 0.76-0.90). In contrast, the corresponding incidence rate ratio in nonattendees was 1.53 (95% CI 1.37-1.71). We found no evidence of a beneficial effect of this specific screening procedure but strong evidence of a difference in overall survival in screening attendees and nonattendees. These findings should be considered when interpreting previous and upcoming studies of the effect of screening programs.

Enhanced HTS hit selection via a local hit rate analysis.

PubMed

Posner, Bruce A; Xi, Hualin; Mills, James E J

2009-10-01

The postprocessing of high-throughput screening (HTS) results is complicated by the occurrence of false positives (inactive compounds misidentified as active by the primary screen) and false negatives (active compounds misidentified as inactive by the primary screen). An activity cutoff is frequently used to select "active" compounds from HTS data; however, this approach is insensitive to both false positives and false negatives. An alternative method that can minimize the occurrence of these artifacts will increase the efficiency of hit selection and therefore lead discovery. In this work, rather than merely using the activity of a given compound, we look at the presence and absence of activity among all compounds in its "chemical space neighborhood" to give a degree of confidence in its activity. We demonstrate that this local hit rate (LHR) analysis method outperforms hit selection based on ranking by primary screen activity values across ten diverse high throughput screens, spanning both cell-based and biochemical assay formats of varying biology and robustness. On average, the local hit rate analysis method was approximately 2.3-fold and approximately 1.3-fold more effective in identifying active compounds and active chemical series, respectively, than selection based on primary activity alone. Moreover, when applied to finding false negatives, this method was 2.3-fold better than ranking by primary activity alone. In most cases, novel hit series were identified that would have otherwise been missed. Additional uses of and observations regarding this HTS analysis approach are also discussed.

Using Intervention Mapping to Develop Health Education Components to Increase Colorectal Cancer Screening in Puerto Rico.

PubMed

Serra, Yolanda A; Colón-López, Vivian; Savas, Lara S; Vernon, Sally W; Fernández-Espada, Natalie; Vélez, Camille; Ayala, Alelí; Fernández, María E

2017-01-01

Colorectal cancer (CRC) is a leading cause of cancer-related mortality in Puerto Rico (PR). Although largely preventable through screening and treatment of precancerous polyps, CRC screening rates in PR remain low while CRC incidence and mortality continue to increase. We used intervention mapping (IM), a systematic framework using theory and evidence to plan a health promotion intervention to increase colorectal cancer screening (CRCS) among Puerto Rican adults 50 years and older who are patients of Federally Qualified Health Centers (FQHCs) in PR. To inform the development of a logic model of the problem during the needs assessment phase, we determined the CRC incidence and mortality rates in PR using recent data from the PR Cancer Registry, conducted a literature review to better understand behavioral and environmental factors influencing CRC among Hispanics in general and in Puerto Ricans, and collected new data. We conducted seven focus groups to identify community needs and resources, specific sub-behaviors related to CRCS (performance objectives) and the determinants of CRCS. We then developed matrices of change objectives that would guide the content, behavioral change method selection, and the practical applications that would be included in the program. We selected two overarching methods: entertainment education and behavioral journalism and developed practical applications, materials, and messages containing several other methods including modeling, persuasion, information, and tailoring. We developed and pretested a Tailored Interactive Multimedia Intervention, newsletter, an action plan, and supplemental print materials for patients. We also developed a patient mediated provider prompt to increase provider recommendation and improve patient provider communication. The use of IM for systematic planning produced a detailed coherent plan for the CRCS educational intervention. Guided by IM processes, steps, and tasks, we used community level information, existing literature, theory, and new data to develop health education materials that were well received by the priority population and will likely increase CRCS among FQHC patients in PR.

Monofluorophosphate is a selective inhibitor of respiratory sulfate-reducing microorganisms.

PubMed

Carlson, Hans K; Stoeva, Magdalena K; Justice, Nicholas B; Sczesnak, Andrew; Mullan, Mark R; Mosqueda, Lorraine A; Kuehl, Jennifer V; Deutschbauer, Adam M; Arkin, Adam P; Coates, John D

2015-03-17

Despite the environmental and economic cost of microbial sulfidogenesis in industrial operations, few compounds are known as selective inhibitors of respiratory sulfate reducing microorganisms (SRM), and no study has systematically and quantitatively evaluated the selectivity and potency of SRM inhibitors. Using general, high-throughput assays to quantitatively evaluate inhibitor potency and selectivity in a model sulfate-reducing microbial ecosystem as well as inhibitor specificity for the sulfate reduction pathway in a model SRM, we screened a panel of inorganic oxyanions. We identified several SRM selective inhibitors including selenate, selenite, tellurate, tellurite, nitrate, nitrite, perchlorate, chlorate, monofluorophosphate, vanadate, molydate, and tungstate. Monofluorophosphate (MFP) was not known previously as a selective SRM inhibitor, but has promising characteristics including low toxicity to eukaryotic organisms, high stability at circumneutral pH, utility as an abiotic corrosion inhibitor, and low cost. MFP remains a potent inhibitor of SRM growing by fermentation, and MFP is tolerated by nitrate and perchlorate reducing microorganisms. For SRM inhibition, MFP is synergistic with nitrite and chlorite, and could enhance the efficacy of nitrate or perchlorate treatments. Finally, MFP inhibition is multifaceted. Both inhibition of the central sulfate reduction pathway and release of cytoplasmic fluoride ion are implicated in the mechanism of MFP toxicity.

Where Have All the Interactions Gone? Estimating the Coverage of Two-Hybrid Protein Interaction Maps

PubMed Central

Huang, Hailiang; Jedynak, Bruno M; Bader, Joel S

2007-01-01

Yeast two-hybrid screens are an important method for mapping pairwise physical interactions between proteins. The fraction of interactions detected in independent screens can be very small, and an outstanding challenge is to determine the reason for the low overlap. Low overlap can arise from either a high false-discovery rate (interaction sets have low overlap because each set is contaminated by a large number of stochastic false-positive interactions) or a high false-negative rate (interaction sets have low overlap because each misses many true interactions). We extend capture–recapture theory to provide the first unified model for false-positive and false-negative rates for two-hybrid screens. Analysis of yeast, worm, and fly data indicates that 25% to 45% of the reported interactions are likely false positives. Membrane proteins have higher false-discovery rates on average, and signal transduction proteins have lower rates. The overall false-negative rate ranges from 75% for worm to 90% for fly, which arises from a roughly 50% false-negative rate due to statistical undersampling and a 55% to 85% false-negative rate due to proteins that appear to be systematically lost from the assays. Finally, statistical model selection conclusively rejects the Erdös-Rényi network model in favor of the power law model for yeast and the truncated power law for worm and fly degree distributions. Much as genome sequencing coverage estimates were essential for planning the human genome sequencing project, the coverage estimates developed here will be valuable for guiding future proteomic screens. All software and datasets are available in Datasets S1 and S2, Figures S1–S5, and Tables S1−S6, and are also available from our Web site, http://www.baderzone.org. PMID:18039026

Selecting predictors for discriminant analysis of species performance: an example from an amphibious softwater plant.

PubMed

Vanderhaeghe, F; Smolders, A J P; Roelofs, J G M; Hoffmann, M

2012-03-01

Selecting an appropriate variable subset in linear multivariate methods is an important methodological issue for ecologists. Interest often exists in obtaining general predictive capacity or in finding causal inferences from predictor variables. Because of a lack of solid knowledge on a studied phenomenon, scientists explore predictor variables in order to find the most meaningful (i.e. discriminating) ones. As an example, we modelled the response of the amphibious softwater plant Eleocharis multicaulis using canonical discriminant function analysis. We asked how variables can be selected through comparison of several methods: univariate Pearson chi-square screening, principal components analysis (PCA) and step-wise analysis, as well as combinations of some methods. We expected PCA to perform best. The selected methods were evaluated through fit and stability of the resulting discriminant functions and through correlations between these functions and the predictor variables. The chi-square subset, at P < 0.05, followed by a step-wise sub-selection, gave the best results. In contrast to expectations, PCA performed poorly, as so did step-wise analysis. The different chi-square subset methods all yielded ecologically meaningful variables, while probable noise variables were also selected by PCA and step-wise analysis. We advise against the simple use of PCA or step-wise discriminant analysis to obtain an ecologically meaningful variable subset; the former because it does not take into account the response variable, the latter because noise variables are likely to be selected. We suggest that univariate screening techniques are a worthwhile alternative for variable selection in ecology. © 2011 German Botanical Society and The Royal Botanical Society of the Netherlands.

[Comparative study of protein markers in serum and bronchoalveolar lavage fluid from patients with lung cancer by surface-enhanced laser desorption ionization time of flight mass spectrometry].

PubMed

Zhou, Ji-hong; Liu, Guang-nan; Huang, Si-ming; Zhong, Xiao-ning; Su, Hong; Zhou, Yi

2011-04-01

To detect the protein markers in serum and bronchoalveolar lavage fluid (BALF) of the patients with lung cancer by surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS) technology, and to explore if they can be used as markers for the diagnosis of lung cancer. SELDI-TOF-MS technology and protein chips weak cation exchange (WCX-2 chip) were used to detect the protein mass spectrum in serum and BALF of 35 patients with lung cancer and 18 cases of benign pulmonary diseases. The different protein markers were analyzed by Biomarker Pattern Software and the initial diagnosis models were set up. The diagnosis models were verified further by blind screen to confirm the efficacy of diagnosis. Five protein peaks in the sera of the patients with lung cancer were significantly higher (P < 0.05). The protein peak with a mass/charge ratio (M/Z) of 5639 was selected to establish the classification tree model. The sensitivity of diagnosis was 80% (28/35) and the specificity was 78% (14/18). The results verified by blind screen showed a sensitivity of 85% (17/20), a specificity of 90% (9/10), a crude accuracy (CA) of 87% (26/30) and Youden's index (γ) of 0.7. Eight protein peaks in the BALF of the patients with lung cancer were significantly higher (P < 0.05). The different protein peaks with M/Z of 7976 and 11 809 respectively were selected to establish the classification tree model. The sensitivity of diagnosis was 86% (30/35) and the specificity was 72% (13/18). The results verified by blind screen showed a sensitivity of 90% (18/20), a specificity of 90% (9/10), a CA of 90% (27/30) and γ of 0.8. There was a complementary role in combination of differential proteins in serum and BALF and the sensitivity, specificity and accuracy of diagnosis for lung cancer were 100% by parallel test. The SELDI-TOF-MS technology can screen out the differential protein markers in serum and BALF of the patients with lung cancer, which show high sensitivity and specificity as tumor markers. The differential proteins in the BALF may be more promising for clinical application.

Joint effect of unlinked genotypes: application to type 2 diabetes in the EPIC-Potsdam case-cohort study.

PubMed

Knüppel, Sven; Meidtner, Karina; Arregui, Maria; Holzhütter, Hermann-Georg; Boeing, Heiner

2015-07-01

Analyzing multiple single nucleotide polymorphisms (SNPs) is a promising approach to finding genetic effects beyond single-locus associations. We proposed the use of multilocus stepwise regression (MSR) to screen for allele combinations as a method to model joint effects, and compared the results with the often used genetic risk score (GRS), conventional stepwise selection, and the shrinkage method LASSO. In contrast to MSR, the GRS, conventional stepwise selection, and LASSO model each genotype by the risk allele doses. We reanalyzed 20 unlinked SNPs related to type 2 diabetes (T2D) in the EPIC-Potsdam case-cohort study (760 cases, 2193 noncases). No SNP-SNP interactions and no nonlinear effects were found. Two SNP combinations selected by MSR (Nagelkerke's R² = 0.050 and 0.048) included eight SNPs with mean allele combination frequency of 2%. GRS and stepwise selection selected nearly the same SNP combinations consisting of 12 and 13 SNPs (Nagelkerke's R² ranged from 0.020 to 0.029). LASSO showed similar results. The MSR method showed the best model fit measured by Nagelkerke's R² suggesting that further improvement may render this method a useful tool in genetic research. However, our comparison suggests that the GRS is a simple way to model genetic effects since it does not consider linkage, SNP-SNP interactions, and no non-linear effects. © 2015 John Wiley & Sons Ltd/University College London.

Screening bioactive quality control markers of QiShenYiQi dripping pills based on the relationship between the ultra-high performance liquid chromatography fingerprint and vascular protective activity.

PubMed

Zhuo, Limeng; Peng, Jingjing; Zhao, Yunli; Li, Dongxiang; Xie, Xiuman; Tong, Ling; Yu, Zhiguo

2017-10-01

Traditional Chinese medicine consists of complex phytochemical constituents. Selecting appropriate analytical markers of traditional Chinese medicine is a critical step in quality control. Currently, the combination of fingerprinting and efficacy evaluation is considered as a useful method for screening active ingredients in complex mixtures. This study was designed to develop an orthogonal partial least squares model for screening bioactive quality control markers of QishenYiqi dripping pills based on the fingerprint-efficacy relationship. First, the chemical fingerprints of 49 batches of QishenYiqi dripping pill samples were established by ultra-high performance liquid chromatography coupled with a photodiode array detector. Second, ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry was exploited to systematically investigate the 36 copossessing fingerprint components in QishenYiqi dripping pills. The vascular protective activity of QishenYiqi dripping pills was determined by using a cell counting kit-8 assay. Finally, fingerprint-efficacy relationship was established by orthogonal partial least squares model. The results indicated that ten components exhibited strong correlation with vascular protective activity, and these were preliminarily screened as quality control markers. The present study provided a novel idea for the study of the pharmacodynamic material basis and quality evaluation of QishenYiqi dripping pills. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clinical Decision Support Tools for Selecting Interventions for Patients with Disabling Musculoskeletal Disorders: A Scoping Review.

PubMed

Gross, Douglas P; Armijo-Olivo, Susan; Shaw, William S; Williams-Whitt, Kelly; Shaw, Nicola T; Hartvigsen, Jan; Qin, Ziling; Ha, Christine; Woodhouse, Linda J; Steenstra, Ivan A

2016-09-01

Purpose We aimed to identify and inventory clinical decision support (CDS) tools for helping front-line staff select interventions for patients with musculoskeletal (MSK) disorders. Methods We used Arksey and O'Malley's scoping review framework which progresses through five stages: (1) identifying the research question; (2) identifying relevant studies; (3) selecting studies for analysis; (4) charting the data; and (5) collating, summarizing and reporting results. We considered computer-based, and other available tools, such as algorithms, care pathways, rules and models. Since this research crosses multiple disciplines, we searched health care, computing science and business databases. Results Our search resulted in 4605 manuscripts. Titles and abstracts were screened for relevance. The reliability of the screening process was high with an average percentage of agreement of 92.3 %. Of the located articles, 123 were considered relevant. Within this literature, there were 43 CDS tools located. These were classified into 3 main areas: computer-based tools/questionnaires (n = 8, 19 %), treatment algorithms/models (n = 14, 33 %), and clinical prediction rules/classification systems (n = 21, 49 %). Each of these areas and the associated evidence are described. The state of evidentiary support for CDS tools is still preliminary and lacks external validation, head-to-head comparisons, or evidence of generalizability across different populations and settings. Conclusions CDS tools, especially those employing rapidly advancing computer technologies, are under development and of potential interest to health care providers, case management organizations and funders of care. Based on the results of this scoping review, we conclude that these tools, models and systems should be subjected to further validation before they can be recommended for large-scale implementation for managing patients with MSK disorders.

Returning negative results to individuals in a genomic screening program: lessons learned.

PubMed

Butterfield, Rita M; Evans, James P; Rini, Christine; Kuczynski, Kristine J; Waltz, Margaret; Cadigan, R Jean; Goddard, Katrina A B; Muessig, Kristin R; Henderson, Gail E

2018-06-06

In genomics, the return of negative screening results for rare, medically actionable conditions in large unselected populations with low prior risk of disease is novel and may involve important and nuanced concerns for communicating their meaning. Recruitment may result in self-selection because of participants' personal or family history, changing the characteristics of the screened population and interpretation of both positive and negative findings; prior motivations may also affect responses to results. Using data from GeneScreen, an exploratory adult screening project that targets 17 genes related to 11 medically actionable conditions, we address four questions: (1) Do participants self-select based on actual or perceived risk for one of the conditions? (2) Do participants understand negative results? (3) What are their psychosocial responses? (4) Are negative results related to changes in reported health-related behaviors? We found disproportionate enrollment of individuals at elevated prior risk for conditions being screened, and a need to improve communication about the nature of screening and meaning of negative screening results. Participants expressed no decision regret and did not report intention to change health-related behaviors. This study illuminates critical challenges to overcome if genomic screening is to benefit the general population.

Input selection and performance optimization of ANN-based streamflow forecasts in the drought-prone Murray Darling Basin region using IIS and MODWT algorithm

NASA Astrophysics Data System (ADS)

Prasad, Ramendra; Deo, Ravinesh C.; Li, Yan; Maraseni, Tek

2017-11-01

Forecasting streamflow is vital for strategically planning, utilizing and redistributing water resources. In this paper, a wavelet-hybrid artificial neural network (ANN) model integrated with iterative input selection (IIS) algorithm (IIS-W-ANN) is evaluated for its statistical preciseness in forecasting monthly streamflow, and it is then benchmarked against M5 Tree model. To develop hybrid IIS-W-ANN model, a global predictor matrix is constructed for three local hydrological sites (Richmond, Gwydir, and Darling River) in Australia's agricultural (Murray-Darling) Basin. Model inputs comprised of statistically significant lagged combination of streamflow water level, are supplemented by meteorological data (i.e., precipitation, maximum and minimum temperature, mean solar radiation, vapor pressure and evaporation) as the potential model inputs. To establish robust forecasting models, iterative input selection (IIS) algorithm is applied to screen the best data from the predictor matrix and is integrated with the non-decimated maximum overlap discrete wavelet transform (MODWT) applied on the IIS-selected variables. This resolved the frequencies contained in predictor data while constructing a wavelet-hybrid (i.e., IIS-W-ANN and IIS-W-M5 Tree) model. Forecasting ability of IIS-W-ANN is evaluated via correlation coefficient (r), Willmott's Index (WI), Nash-Sutcliffe Efficiency (ENS), root-mean-square-error (RMSE), and mean absolute error (MAE), including the percentage RMSE and MAE. While ANN models are seen to outperform M5 Tree executed for all hydrological sites, the IIS variable selector was efficient in determining the appropriate predictors, as stipulated by the better performance of the IIS coupled (ANN and M5 Tree) models relative to the models without IIS. When IIS-coupled models are integrated with MODWT, the wavelet-hybrid IIS-W-ANN and IIS-W-M5 Tree are seen to attain significantly accurate performance relative to their standalone counterparts. Importantly, IIS-W-ANN model accuracy outweighs IIS-ANN, as evidenced by a larger r and WI (by 7.5% and 3.8%, respectively) and a lower RMSE (by 21.3%). In comparison to the IIS-W-M5 Tree model, IIS-W-ANN model yielded larger values of WI = 0.936-0.979 and ENS = 0.770-0.920. Correspondingly, the errors (RMSE and MAE) ranged from 0.162-0.487 m and 0.139-0.390 m, respectively, with relative errors, RRMSE = (15.65-21.00) % and MAPE = (14.79-20.78) %. Distinct geographic signature is evident where the most and least accurately forecasted streamflow data is attained for the Gwydir and Darling River, respectively. Conclusively, this study advocates the efficacy of iterative input selection, allowing the proper screening of model predictors, and subsequently, its integration with MODWT resulting in enhanced performance of the models applied in streamflow forecasting.

Selecting the Best and Brightest: A Structured Approach to Orthopedic Resident Selection.

PubMed

Schenker, Mara L; Baldwin, Keith D; Israelite, Craig L; Levin, L Scott; Mehta, Samir; Ahn, Jaimo

2016-01-01

Resident selection is integral to the graduate medical educational process and the future of our profession. There is no consensus among residency directors as to how to systematically and consistently screen and select applicants who would perform well as residents. The purpose of this study was to introduce and assess a high volume application screening tool and semistructured interview process. This study took place in an academic orthopedic surgery department over 2 years (2013-2014). Overall, 1382 applications were screened in 7 categories, with a maximum score of 100. A total of 14 faculty reviewed applications; 218 interviews were offered; 165 applicants accepted the interview. Overall, 4 interview domains (cognitive, affective, activities, and theme), and an impression score were ranked from 1 (Exceptional) to 6 (Concern). Each room had an assigned "theme" (ethics, affective, cognitive, research, and "fit") with standardized questions. A summary score was generated of all scores to determine the preliminary rank list; the final rank list was determined after group discussion. Correlation between preliminary rank, final rank, and screening scores were assessed. The average screening score was 62.5 (range: 0-100, median = 64). The average interview score was 69.5 (range: 32.24-95.0). Final rank lists correlated most highly with initial rank (0.912, p < 0.001), impression (0.847, p < 0.001), and affective domain (0.834, p < 0.001). Cognitive domain (0.628, p < 0.001) and screening scores (0.264, p < 0.001) less highly correlated with final rank position. A systematic approach was used to screen and evaluate a large number of orthopedic surgery applicants. Our system demonstrated excellent feasibility, reliability, and predictability for the final rank list. Copyright © 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

A collaborative university model for employee wellness.

PubMed

Carter, Melondie R; Kelly, Rebecca C; Alexander, Chelley K; Holmes, Lauren M

2011-01-01

Universities are taking a more active approach in understanding and monitoring employees' modifiable health risk factors and chronic care conditions by developing strategies to encourage employees to start and sustain healthy behaviors. WellBama, the University of Alabama's signature health and wellness program, utilizes a collaborative model in partnership with select colleges and departments to implement strategies to improve employees' health status. The program provides onsite health screenings and assessments, timely health advising sessions, assistance in setting and monitoring individual health goals to promote improved health, and preventive examination referrals.

Initial development of an ablative leading edge for the space shuttle orbiter

NASA Technical Reports Server (NTRS)

Daforno, G.; Rose, L.; Graham, J.; Roy, P.

1974-01-01

A state-of-the-art preliminary design for typical wing areas is developed. Seven medium-density ablators (with/without honeycomb, flown on Apollo, Prime, X15A2) are evaluated. The screening tests include: (1) leading-edge models sequentially subjected to ascent heating, cold soak, entry heating, post-entry pressure fluctuations, and touchdown shock, and (2) virgin/charred models subjected to bondline strains. Two honeycomb reinforced 30 pcf elastomeric ablators were selected. Roughness/recession degradation of low speed aerodynamics appears acceptable. The design, including attachments, substructure and joints, is presented.

Animal models for medications development targeting alcohol abuse using selectively bred rat lines: Neurobiological and pharmacological validity

PubMed Central

Bell, Richard L.; Sable, Helen J.K.; Colombo, Giancarlo; Hyytia, Petri; Rodd, Zachary A.; Lumeng, Lawrence

2012-01-01

The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence. PMID:22841890

Integrating modelling and phenotyping approaches to identify and screen complex traits - Illustration for transpiration efficiency in cereals.

PubMed

Chenu, K; van Oosterom, E J; McLean, G; Deifel, K S; Fletcher, A; Geetika, G; Tirfessa, A; Mace, E S; Jordan, D R; Sulman, R; Hammer, G L

2018-02-21

Following advances in genetics, genomics, and phenotyping, trait selection in breeding is limited by our ability to understand interactions within the plants and with their environments, and to target traits of most relevance for the target population of environments. We propose an integrated approach that combines insights from crop modelling, physiology, genetics, and breeding to identify traits valuable for yield gain in the target population of environments, develop relevant high-throughput phenotyping platforms, and identify genetic controls and their values in production environments. This paper uses transpiration efficiency (biomass produced per unit of water used) as an example of a complex trait of interest to illustrate how the approach can guide modelling, phenotyping, and selection in a breeding program. We believe that this approach, by integrating insights from diverse disciplines, can increase the resource use efficiency of breeding programs for improving yield gains in target populations of environments.

Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives

NASA Astrophysics Data System (ADS)

Fogel, Gary B.; Cheung, Mars; Pittman, Eric; Hecht, David

2008-01-01

Modeling studies were performed on known inhibitors of the quadruple mutant Plasmodium falciparum dihydrofolate reductase (DHFR). GOLD was used to dock 32 pyrimethamine derivatives into the active site of DHFR obtained from the x-ray crystal structure 1J3K.pdb. Several scoring functions were evaluated and the Molegro Protein-Ligand Interaction Score was determined to have one of the best correlation to experimental p K i . In conjunction with Protein-Ligand Interaction scores, predicted binding modes and key protein-ligand interactions were evaluated and analyzed in order to develop criteria for selecting compounds having a greater chance of activity versus resistant strains of Plasmodium falciparum. This methodology will be used in future studies for selection of compounds for focused screening libraries.

Selective Inhibition of HER2-Positive Breast Cancer Cells by the HIV Protease Inhibitor Nelfinavir

PubMed Central

2012-01-01

Background Human epidermal growth factor receptor 2 (HER2)–positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2-positive breast cancer are needed. Methods We conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library. To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xenografts in athymic nude mouse models (n = 4–6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided. Results Pharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2-positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, difference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations. Conclusion Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients. PMID:23042933

Charge transfer optical absorption and fluorescence emission of 4-(9-acridyl)julolidine from long-range-corrected time dependent density functional theory in polarizable continuum approach.

PubMed

Kityk, A V

2014-07-15

A long-range-corrected time-dependent density functional theory (LC-TDDFT) in combination with polarizable continuum model (PCM) have been applied to study charge transfer (CT) optical absorption and fluorescence emission energies basing on parameterized LC-BLYP xc-potential. The molecule of 4-(9-acridyl)julolidine selected for this study represents typical CT donor-acceptor dye with strongly solvent dependent optical absorption and fluorescence emission spectra. The result of calculations are compared with experimental spectra reported in the literature to derive an optimal value of the model screening parameter ω. The first absorption band appears to be quite well predictable within DFT/TDDFT/PCM with the screening parameter ω to be solvent independent (ω ≈ 0.245 Bohr(-1)) whereas the fluorescence emission exhibits a strong dependence on the range separation with ω-value varying on a rising solvent polarity from about 0.225 to 0.151 Bohr(-1). Dipolar properties of the initial state participating in the electronic transition have crucial impact on the effective screening. Copyright © 2014 Elsevier B.V. All rights reserved.

High-throughput screening of PLGA thin films utilizing hydrophobic fluorescent dyes for hydrophobic drug compounds.

PubMed

Steele, Terry W J; Huang, Charlotte L; Kumar, Saranya; Widjaja, Effendi; Chiang Boey, Freddy Yin; Loo, Joachim S C; Venkatraman, Subbu S

2011-10-01

Hydrophobic, antirestenotic drugs such as paclitaxel (PCTX) and rapamycin are often incorporated into thin film coatings for local delivery using implantable medical devices and polymers such as drug-eluting stents and balloons. Selecting the optimum coating formulation through screening the release profile of these drugs in thin films is time consuming and labor intensive. We describe here a high-throughput assay utilizing three model hydrophobic fluorescent compounds: fluorescein diacetate (FDAc), coumarin-6, and rhodamine 6G that were incorporated into poly(d,l-lactide-co-glycolide) (PLGA) and PLGA-polyethylene glycol films. Raman microscopy determined the hydrophobic fluorescent dye distribution within the PLGA thin films in comparison with that of PCTX. Their subsequent release was screened in a high-throughput assay and directly compared with HPLC quantification of PCTX release. It was observed that PCTX controlled-release kinetics could be mimicked by a hydrophobic dye that had similar octanol-water partition coefficient values and homogeneous dissolution in a PLGA matrix as the drug. In particular, FDAc was found to be the optimal hydrophobic dye at modeling the burst release as well as the total amount of PCTX released over a period of 30 days. Copyright © 2011 Wiley-Liss, Inc.

Microbead-induced ocular hypertensive mouse model for screening and testing of aqueous production suppressants for glaucoma.

PubMed

Yang, Qiang; Cho, Kin-Sang; Chen, Huihui; Yu, Dekuang; Wang, Wan-Heng; Luo, Gang; Pang, Iok-Hou; Guo, Wenyi; Chen, Dong Feng

2012-06-20

To characterize the microbead-induced ocular hypertension (OHT) mouse model and investigate its potential use for preclinical screening and evaluation of ocular hypotensive agents, we tested the model's responses to major antiglaucoma drugs. Adult C57BL/6J mice were induced to develop OHT unilaterally by intracameral injection of microbeads. The effects of the most commonly used ocular hypotensive drugs, including timolol, brimonidine, brinzolamide, pilocarpine, and latanoprost, on IOP and glaucomatous neural damage were evaluated. Degeneration of retinal ganglion cells (RGCs) and optic nerve axons were quantitatively assessed using immunofluorescence labeling and histochemistry. Thickness of the ganglion cell complex (GCC) was also assessed with spectral-domain optical coherence tomography (SD-OCT). A microbead-induced OHT model promptly responded to drugs, such as timolol, brimonidine, and brinzolamide, that lower IOP through suppressing aqueous humor production and showed improved RGC and axon survival as compared to vehicle controls. Accordingly, SD-OCT detected significantly less reduction of GCC thickness in mice treated with all three aqueous production suppressants as compared to the vehicle contol-treated group. In contrast, drugs that increase aqueous outflow, such as pilocarpine and latanoprost, failed to decrease IOP in the microbead-induced OHT mice. Microbead-induced OHT mice carry dysfunctional aqueous outflow facility and therefore offer a unique model that allows selective screening of aqueous production suppressant antiglaucoma drugs or for studying the mechanisms regulating aqueous humor production. Our data set the stage for using GCC thickness assessed by SD-OCT as an imaging biomarker for noninvasive tracking of neuronal benefits of glaucoma therapy in this model.

Development of a Decision Support Model for Screening Attention-deficit Hyperactivity Disorder with Actigraph-based Measurements of Classroom Activity

PubMed Central

Kam, H.J.; Shin, Y.M.; Cho, S.M.; Kim, S.Y.; Kim, K.W.; Park, R.W.

2010-01-01

Objective Questionnaire-based ADHD screening tests may not always be objective or accurate, owing to both subjectivity and prejudice. Despite attempts to develop objective measures to characterize ADHD, no widely applicable index currently exists. The principal aim of this study was to develop a decision support model for ADHD screening by monitoring children’s school activities using a 3-axial actigraph. Methods Actigraphs were placed on the non-dominant wrists of 153 children for 3 hours, while they were at school. Children who scored high on the questionnaires were clinically examined by child psychiatrists, who then confirmed ADHD. Mean, variance, and ratios of low-level (0.5-1.0G) and high-level (1.6-3.2G) activity were extracted as activity features from 142 children (10 ADHD, 132 non-ADHD). Two decision-tree models were constructed using the C5.0 algorithm: [A] from whole hours (class + playtime) and [B] during classes. Accuracy, sensitivity, and specificity were evaluated. PPV, NPV, likelihood ratio, and AUC were also calculated for evaluation. Results [Model A] One child without ADHD was misclassified, resulting in an accuracy score of 99.30%. Sensitivity and NPV were 1.0000. Specificity and PPV were 0.992 and 0.803-0.909, respectively. [Model B] Two children without ADHD were misclassified, resulting in an accuracy score of 98.59%. Specificity and PPV were scored at 0.985 and 0.671-0.832, respectively. Conclusion The selected features were consistent with the findings of previous studies. Objective screening of latent patients with ADHD can be accomplished with a simple watch-like sensor, which is worn for just a few hours while the child attends school. The model proposed herein can be applied to a great many children without heavy cost in time and manpower cost, and would generate valuable results from a public health perspective. PMID:23616848

Choosing options for ultrasound screening in pregnancy and comparing cost effectiveness: a decision analysis approach.

PubMed

Roberts, T; Mugford, M; Piercy, J

1998-09-01

To compare the cost effectiveness of different programmes of routine antenatal ultrasound screening to detect four key fetal anomalies: serious cardiac anomalies, spina bifida, Down's syndrome and lethal anomalies, using existing evidence. Decision analysis was used based on the best data currently available, including expert opinion from the Royal College of Obstetricians and Gynaecologists, Working Party and secondary data from the literature, to predict the likely outcomes in terms of malformations detected by each screening programme. Results applicable in clinics, hospitals or GP practices delivering antenatal screening. The number of cases with a 'target' malformation correctly detected antenatally. There was substantial overlap between the cost ranges of each screening programme demonstrating considerable uncertainty about the relative economic efficiency of alternative programmes for ultrasound screening. The cheapest, but not the most effective, screening programme consisted of one second trimester ultrasound scan. The cost per target anomaly detected (cost effectiveness) for this programme was in the range 5,000 pound silver-109,000, pound silver but in any 1000 women it will also fail to detect between 3.6 and 4.7 target anomalies. The range of uncertainty in the costs did not allow selection of any one programme as a clear choice for NHS purchasers. The results suggested that the overall allocation of resources for routine ultrasound screening in the UK is not currently economically efficient, but that certain scenarios for ultrasound screening are potentially within the range of cost effectiveness reached by other, possibly competing, screening programmes. The model highlighted the weakness of available evidence and demonstrated the need for more information both about current practice and costs.

Incorporating DNA Sequencing into Current Prenatal Screening Practice for Down's Syndrome

PubMed Central

Wald, Nicholas J.; Bestwick, Jonathan P.

2013-01-01

Background Prenatal screening for Down's syndrome is performed using biochemical and ultrasound markers measured in early pregnancy such as the Integrated test using first and second trimester markers. Recently, DNA sequencing methods have been introduced on free DNA in maternal plasma, yielding a high screening performance. These methods are expensive and there is a test failure rate. We determined the screening performance of merging the Integrated test with the newer DNA techniques in a protocol that substantially reduces the cost compared with universal DNA testing and still achieves high screening performance with no test failures. Methods Published data were used to model screening performance of a protocol in which all women receive the first stage of the Integrated test at about 11 weeks of pregnancy. On the basis of this higher risk women have reflex DNA testing and lower risk women as well as those with a failed DNA test complete the Integrated test at about 15 weeks. Results The overall detection rate was 95% with a 0.1% false-positive rate if 20% of women were selected to receive DNA testing. If all women had DNA testing the detection rate would be 3 to 4 percentage points higher with a false-positive rate 30 times greater if women with failed tests were treated as positive and offered a diagnostic amniocentesis, or 3 times greater if they had a second trimester screening test (Quadruple test) and treated as positive only if this were positive. The cost per women screened would be about one-fifth, compared with universal DNA testing, if the DNA test were 20 times the cost of the Integrated test. Conclusion The proposed screening protocol achieves a high screening performance without programme test failures and at a substantially lower cost than offering all women DNA testing. PMID:23527014