Quantitative high-throughput phenotypic screening of pediatric cancer cell lines identifies multiple opportunities for drug repurposing

Drug repurposing approaches have the potential advantage of facilitating rapid and cost-effective development of new therapies. Particularly, the repurposing of drugs with known safety profiles in children could bypass or streamline toxicity studies. We employed a phenotypic screening paradigm on a panel of well-characterized cell lines derived from pediatric solid tumors against a collection of ∼3,800 compounds spanning approved drugs and investigational agents. Specifically, we employed titration-based screening where compounds were tested at multiple concentrations for their effect on cell viability. Molecular and cellular target enrichment analysis indicated that numerous agents across different therapeutic categories and modes of action had an antiproliferative effect, notably antiparasitic/protozoal drugs with non-classic antineoplastic activity. Focusing on active compounds with dosing and safety information in children according to the Children's Pharmacy Collaborative database, we identified compounds with therapeutic potential through further validation using 3D tumor spheroid models. Moreover, we show that antiparasitic agents induce cell death via apoptosis induction. This study demonstrates that our screening platform enables the identification of chemical agents with cytotoxic activity in pediatric cancer cell lines of which many have known safety/toxicity profiles in children. These agents constitute attractive candidates for efficacy studies in pre-clinical models of pediatric solid tumors

A physicochemical descriptor-based scoring scheme for effective and rapid filtering of kinase-like chemical space

<p>Abstract</p> <p>Background</p> <p>The current chemical space of known small molecules is estimated to exceed 10⁶⁰structures. Though the largest physical compound repositories contain only a few tens of millions of unique compounds, virtual screening of databases of this size is still difficult. In recent years, the application of physicochemical descriptor-based profiling, such as Lipinski's rule-of-five for drug-likeness and Oprea's criteria of lead-likeness, as early stage filters in drug discovery has gained widespread acceptance. In the current study, we outline a kinase-likeness scoring function based on known kinase inhibitors.</p> <p>Results</p> <p>The method employs a collection of 22,615 known kinase inhibitors from the ChEMBL database. A kinase-likeness score is computed using statistical analysis of nine key physicochemical descriptors for these inhibitors. Based on this score, the kinase-likeness of four publicly and commercially available databases, i.e., National Cancer Institute database (NCI), the Natural Products database (NPD), the National Institute of Health's Molecular Libraries Small Molecule Repository (MLSMR), and the World Drug Index (WDI) database, is analyzed. Three of these databases, i.e., NCI, NPD, and MLSMR are frequently used in the virtual screening of kinase inhibitors, while the fourth WDI database is for comparison since it covers a wide range of known chemical space. Based on the kinase-likeness score, a kinase-focused library is also developed and tested against three different kinase targets selected from three different branches of the human kinome tree.</p> <p>Conclusions</p> <p>Our proposed methodology is one of the first that explores how the narrow chemical space of kinase inhibitors and its relevant physicochemical information can be utilized to build kinase-focused libraries and prioritize pre-existing compound databases for screening. We have shown that focused libraries generated by filtering compounds using the kinase-likeness score have, on average, better docking scores than an equivalent number of randomly selected compounds. Beyond library design, our findings also impact the broader efforts to identify kinase inhibitors by screening pre-existing compound libraries. Currently, the NCI library is the most commonly used database for screening kinase inhibitors. Our research suggests that other libraries, such as MLSMR, are more kinase-like and should be given priority in kinase screenings.</p

Seed-hoarding of Edward's long-tailed rats Leopoldamys edwardsi in response to weevil infestation in cork oak Quer-cus variabilis

Seed hoarders show different hoarding and eating responses towards insect-infested seeds that can affect the fitness of both the seeds and insects. It remains unclear how seed hoarders adopt different strategies in eating and hoarding infested seeds with and without larvae concealed inside. Here we investigated hoarding and eating responses of Edward’s long-tailed rats Leopoldamys edwardsi (scatter hoarders) to weevil infestation of cork oak Quercus variabilis seeds within outdoor enclosures. We provided sound seeds, larvae-emerged seeds, (infested seeds where larvae have emerged) and larvae-concealed seeds (infested seeds with larvae concealed inside) to subjects independently (each seed type presented separately) and in pairwise combinations (sound and larvae-emerged seeds; sound and larvae-concealed seeds). We found that L. edwardsi removed, scatter hoarded and ate fewer larvae-emerged seeds than sound seeds. No difference was found between sound seeds and larvae-concealed seeds. These results suggest that sound and larvae-concealed seeds are more favored by L. edwardsi than larvae-emerged seeds. We posit that not only plants but also insects may benefit from the behavioral responses of hoarders to seed infestation under natural conditions [Current Zoology 57 (1): 50–55, 2011]

Data from: Weak olfaction increases seed scatter-hoarding by Siberian chipmunks: implication in shaping plant-animal interactions

Scatter-hoarding of seeds by animals plays an essential role in seed dispersal of plants and in shaping plant–animal interactions in forest ecosystems, but the function of scatter-hoarding behavior is still unclear. We hypothesize that weak olfactory cues between seeds and scatter-hoarding animals would increase scatter-hoarding. Using a rodent–plant system of Siberian chipmunks Tamias sibiricus and Korean pines Pinus koraiensis, we tested the effects on seed scatter-hoarding intensity by measuring and modifying the seed odor intensities and the abilities of the animals to detect seed odor. Siberian chipmunks seemed to scatter-hoard more seeds with weaker odor signals, and Siberian chipmunks with reduced olfactory ability scatter-hoarded more seeds, supporting our hypothesis. Our studies suggest that olfaction may have played an important role in the evolution of the strength of seed odor and scatter-hoarding behavior of animals, and in shaping plant–animal interactions

An Integrated Flood Risk Assessment Model for Cities Located in the Transitional Zone between Taihang Mountains and North China Plain: A Case Study in Shijiazhuang, Hebei, China

Cities located in the transitional zone between Taihang Mountains and North China plain run high flood risk in recent years, especially urban waterlogging risk. In this paper, we take Shijiazhuang, which is located in this transitional zone, as the study area and proposed a new flood risk assessment model for this specific geographical environment. Flood risk assessment indicator factors are established by using the digital elevation model (DEM), along with land cover, economic, population, and precipitation data. A min-max normalization method is used to normalize the indices. An analytic hierarchy process (AHP) method is used to determine the weight of each normalized index and the geographic information system (GIS) spatial analysis tool is adopted for calculating the risk map of flood disaster in Shijiazhuang. This risk map is consistent with the reports released by Hebei Provincial Water Conservancy Bureau and can provide reference for flood risk management

Oikos data-Yi

Oikos data-Y

Fate among years and species and relationship between pilferage and seed fates

Scatter-hoarding and lader-hoarding among years and species, and relationship between pilferage and seed fates