Pan-Cancer Prediction of Cell-Line Drug Sensitivity Using Network-Based Methods

The development of reliable predictive models for individual cancer cell lines to identify an optimal cancer drug is a crucial step to accelerate personalized medicine, but vast differences in cancer cell lines and drug characteristics make it quite challenging to develop predictive models that result in high predictive power and explain the similarity of cell lines or drugs. Our study proposes a novel network-based methodology that breaks the problem into smaller, more interpretable problems to improve the predictive power of anti-cancer drug responses in cell lines. For the drug-sensitivity study, we used the GDSC database for 915 cell lines and 200 drugs. The theory of optimal mass transport was first used to separately cluster cell lines and drugs, using gene-expression profiles and extensive cheminformatic drug features, represented in a form of data networks. To predict cell-line specific drug responses, random forest regression modeling was separately performed for each cell-line drug cluster pair. Post-modeling biological analysis was further performed to identify potential biological correlates associated with drug responses. The network-based clustering method resulted in 30 distinct cell-line drug cluster pairs. Predictive modeling on each cell-line-drug cluster outperformed alternative computational methods in predicting drug responses. We found that among the four drugs top-ranked with respect to prediction performance, three targeted the PI3K/mTOR signaling pathway. Predictive modeling on clustered subsets of cell lines and drugs improved the prediction accuracy of cell-line specific drug responses. Post-modeling analysis identified plausible biological processes associated with drug responses.     

Human Endothelial Progenitor Cells Protect the Kidney against Ischemia-Reperfusion Injury via the NLRP3 Inflammasome in Mice

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and progression to chronic kidney disease (CKD). However, no effective therapeutic intervention has been established for ischemic AKI. Endothelial progenitor cells (EPCs) have major roles in the maintenance of vascular integrity and the repair of endothelial damage; they also serve as therapeutic agents in various kidney diseases. Thus, we examined whether EPCs have a renoprotective effect in an IRI mouse model. Mice were assigned to sham, EPC, IRI-only, and EPC-treated IRI groups. EPCs originating from human peripheral blood were cultured. The EPCs were administered 5 min before reperfusion, and all mice were killed 72 h after IRI. Blood urea nitrogen, serum creatinine, and tissue injury were significantly increased in IRI mice; EPCs significantly improved the manifestations of IRI. Apoptotic cell death and oxidative stress were significantly reduced in EPC-treated IRI mice. Administration of EPCs decreased the expression levels of NLRP3, cleaved caspase-1, p-NF-κB, and p-p38. Furthermore, the expression levels of F4/80, ICAM-1, RORγt, and IL-17RA were significantly reduced in EPC-treated IRI mice. Finally, the levels of EMT-associated factors (TGF-β, α-SMA, Snail, and Twist) were significantly reduced in EPC-treated IRI mice. This study shows that inflammasome-mediated inflammation accompanied by immune modulation and fibrosis is a potential target of EPCs as a treatment for IRI-induced AKI and the prevention of progression to CKD.     

Effect of processing parameters on compression molded PMR-15/C3K composites

The consolidation and curing history during the processing of composite materials affects the final properties of a part in various inter-related ways. In order to improve the quality of composites, these process-property relations must be understood in detail. Using a computer-controlled compression molding and data acquisition system, the processing of PMR-15/C3k composites has been investigated. The process parameters considered were the pressure, the time at which it was applied and the crosslinking temperature. Parts were tested for inter-laminar shear strength and flexural modulus, and measurements were made for void content and thickness. Full compaction strength, optimum compaction strength and void sensitivity factor have been defined.     

Lysophosphatidylserine Induces MUC5AC Production via the Feedforward Regulation of the TACE-EGFR-ERK Pathway in Airway Epithelial Cells in a Receptor-Independent Manner

Lysophosphatidylserine (LysoPS) is an amphipathic lysophospholipid that mediates a broad spectrum of inflammatory responses through a poorly characterized mechanism. Because LysoPS levels can rise in a variety of pathological conditions, we sought to investigate LysoPS’s potential role in airway epithelial cells that actively participate in lung homeostasis. Here, we report a previously unappreciated function of LysoPS in production of a mucin component, MUC5AC, in the airway epithelial cells. LysoPS stimulated lung epithelial cells to produce MUC5AC via signaling pathways involving TACE, EGFR, and ERK. Specifically, LysoPS- dependent biphasic activation of ERK resulted in TGF-α secretion and strong EGFR phosphorylation leading to MUC5AC production. Collectively, LysoPS induces the expression of MUC5AC via a feedback loop composed of proligand synthesis and its proteolysis by TACE and following autocrine EGFR activation. To our surprise, we were not able to find a role of GPCRs and TLR2, known LyoPS receptors in LysoPS-induced MUC5AC production in airway epithelial cells, suggesting a potential receptor-independent action of LysoPS during inflammation. This study provides new insight into the potential function and mechanism of LysoPS as an emerging lipid mediator in airway inflammation.     

Evaluation of physicochemical properties and fermenting qualities of apple wines added with medicinal herbs

To evaluate the possibility for development of apple wine containing medicinal herbs, we have prepared ‘Fuji’ apple (Malus domestica) wines containing pine (Pinus densiflora Siebold et Zuccarini) needle and hwanggi (Radix Astragali)/mistletoe (Viscum album). Normal apple wine was fermented rapidly, but after 40 days fermentation/maturation, the final ethanol content, pH, total acidity, and contents of sugar/organic acid showed similar levels in 3 kinds of apple wines. In other hands, the total phenols content, antocyanins content, and brightness were higher in apple-pine wine and apple-herb wine than in normal apple wine. Apple-herb wine had higher values in total phenol contents, brightness, free amino acid contents, and quenching activity for ABTS free radicals than normal apple wine, and had similar sensory evaluation values with normal apple wine. Taken together, it is supposed that hwanggi and mistletoe might provide functional components to normal apple wine and might be applied to development of functional apple wines.     

Bimodal grain structures and tensile properties of a biomedical Co-20Cr-15W-10Ni alloy with different pre-strains

The influence of pre-strain on the formation of bimodal grain structures and tensile properties of a Co-20 Cr-15 W-10 Ni alloy was investigated.The bimodal grain structures consist of fine grains(FGs;2-3 μm in diameter) and coarse grains(CGs;8-16 μm in diameter),which can be manipulated by changing the pre-strain(ε=0.3-0.7) and annealing temperatures(1000-1100℃).High pre-strain applied in the samples can intensify the plasticity heterogeneity through increasing the total dislocation density and the local volumes of high-density dislocations.This can essentially result in finer FGs,a higher FG volume fraction,and overall grain refinement in the samples after annealing.High-temperature essentially increases both the size and volume fraction of CGs,leading to an increase in the average grain size.The tensile test suggests that the bimodal grain structured samples exhibited both high strength and ductility,yield strengths of621-877 MPa and ultimate tensile strengths of1187-1367 MPa with uniform elongations of 55.0%-71.4%.The superior strength-ductility combination of the samples arises from the specific deformation mechanisms of the bimodal grain structures.The tensile properties strongly depend on the size ratio and volume fraction of FGs/CGs in addition to the average grain size in the bimodal grain structures.The grain structures can be modified via changing the pre-strain and annealing temperature.     

Glycosidase inhibitory phenolic compounds from the seed of Psoralea corylifolia

The seeds of Psoralea corylifolia were extracted into five different polar solvents: chloroform, 50% ethanol in water, ethanol, methanol and water. All extracts were evaluated for glycosidase inhibitory activity. The chloroform extract (CE) showed the lowest IC₅₀ values against α-glucosidase (82.9 μg/ml) and α-mannosidase (132 μg/ml). Chromatography of CE yielded nine phenolic compounds which were identified as isovabachalcone (1), 4′-O-methylbavachalcone (2), isobavachromene (3), corylifolin (4), bavachinin (5), psoralidin (6), neobavaisoflavone (7), corylifol A (8), and bakuchiol (9). All isolated compounds, apart from compound 5, possessed α-glucosidase inhibitory activities. Among them, compounds 6–8 exhibited potent inhibition with IC₅₀s of 13.7, 27.7 and 11.3 μM, respectively. Furthermore, compounds 2 and 6 showed α-mannosidase inhibitory activity. Mechanistic analysis of their inhibition modes against α-glucosidase showed that compounds (6 and 7) were noncompetitive, whereas compound 8 was mixed. Furthermore, the most active glycosidase inhibitors (2, 6–8) were proven to be present in the native seed in high quantities by an HPLC chromatogram.     

Synthesis and properties of click coupled graphene oxide sheets with three‐dimensional macromolecules

A facile click chemistry approach to the functionalization of three‐dimensional hyperbranched polyurethane (HPU) to graphene oxide (GO) nanosheets is presented. HPU‐functionalized GO samples of various compositions were synthesized by reacting alkyne‐functionalized HPU with azide‐functionalized GO sheets. The morphological characterization of the HPU‐functionalized GO was performed using transmission electron microscopy and its chemical characterization was carried out using Fourier transform‐infrared spectroscopy, nuclear magnetic resonance spectroscopy, and X‐ray photoelectron spectroscopy. The graphene sheet surfaces were highly functionalized, leading to improved solubility in organic solvents, and consequently, enhanced mechanical, thermal, and thermoresponsive and photothermal shape memory properties. The strategy reported herein provides a very efficient method for regulating composite properties and producing high performance materials. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43358.     

Numerical prediction of residual stresses and birefringence in injection/compression molded center‐gated disk. Part I: Basic modeling and results for injection molding

The present study attempted to numerically predict both the flow‐induced and thermally‐induced residual stresses and birefringence in injection or injection/compression molded center‐gated disks. A numerical analysis system has been developed to simulate the entire process based on a physical modeling including a nonlinear viscoelastic fluid model, stress‐optical law, a linear viscoelastic solid model, free volume theory for density relaxation phenomena and a photoviscoelasticity and so on. Part I presents physical modeling and typical numerical analysis results of residual stresses and birefringence in the injection molded center‐gated disk. Typical distribution of thermal residual stresses indicates a tensile stress in the core and a compressive stress near the surface. However, depending on the processing condition and material properties, the residual stress sometimes becomes tensile on the surface, especially when fast cooling takes place near the mold surface, preventing the shrinkage from occurring. The birefringence distribution shows a double‐hump profile across the thickness with nonzero value at the center: the nonzero birefringence is found to be thermally induced, the outer peak due to the shear flow and subsequent stress relaxation during the filling stage and the inner peak due to the additional shear flow and stress relaxation during the packing stage. The combination of the flow‐induced and thermally‐induced birefringence makes the shape of predicted birefringence distribution quite similar to the experimental one.