Potency and pharmacokinetics of broad spectrum and isoform-specific p110 gamma and delta inhibitors in cancers

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110 and p110 catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110 structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110 and p110, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110 and p110 are evolutionarily divergent; they probably need separate strategies for drug development.

Novel PARP inhibitors sensitize human leukemic cells in an endogenous PARP activity dependent manner

Poly(ADP-ribose) polymerase (PARP) is a critical nuclear enzyme which safeguards genome stability from genotoxic insults and helps in DNA repair. Inhibition of PARP results in sustained DNA damage in cancer cells. PARP inhibitors are known to play an important role in chemotherapy as single agents in many DNA repair pathway deficient tumor cells or in combination with several other chemotherapeutic agents. In the present study, we synthesize and characterize novel pyridazine derivatives, and evaluate their potential for use as PARP inhibitors. Results show that pyridazine derivatives inhibited the PARP1 enzymatic activity at the nanomolar range and showed anti-proliferative activity in leukemic cells. Interestingly, human leukemic cell line, Nalm6, in which PARP1 and PARP2 expression as well as intrinsic PARP activity are high, showed significant sensitivity for the novel inhibitors compared to other leukemic cells. Among the inhibitors, P10 showed maximum inhibition of intrinsic PARP activity and inhibited cell proliferation in Nalm6 cells. Besides P10 also showed maximum inhibition against purified PARP1 protein, which was comparable to olaparib in our assays. Newly synthesized compounds also showed remarkable DNA trapping ability, which is a signature feature of many PARP inhibitors. Importantly, P10 also induced late S and G2/M arrest in Nalm6 cells, indicating accumulation of DNA damage. Therefore, we identify P10 as a potential PARP inhibitor, which can be developed as a chemotherapeutic agent.

Nano-hardness Techniques and Its Applications in Mechanical Property Measurements for Surface Engineering

结合纳米硬度技术测量各类薄膜和块体材料表层的纳米压痕硬度、弹性模量、断裂韧性、膜厚、微结构的弯曲变形,采用纳米划痕硬度技术测量各类薄膜和块体材料的粗糙度、临界附着力、摩擦系数、划痕横剖面.纳米硬度计是检测材料表层微米乃至几十纳米力学性能的先进仪器,可广泛应用于表面工程中的质量检测.

Structural Evolution and Property Changes in Nd_{60}Al_{10}Fe_{20}Co_{10} Bulk Metallic Glass During Crystallization

The structural evolution and property changes in Nd60Al10Fe20Co10 bulk metallic glass (BMG) upon crystallization are investigated by the ultrasonic method, x-ray diffraction, density measurement, and differential scanning calorimetry. The elastic constants and Debye temperature of the BMG are obtained as a function of annealing temperature. Anomalous changes in ultrasonic velocities, elastic constants, and density are observed between 600–750 K, corresponding to the formation of metastable phases as an intermediate product in the crystallization process. The changes in acoustic velocities, elastic constants, density, and Debye temperature of the BMG relative to its fully crystallized state are much smaller, compared with those of other known BMGs, the differences being attributed to the microstructural feature of the BMG.

Correlation between Discharging Property and Coatings Microstructure during Plasma Electrolytic Oxidation

The voltage-current properties during plasma electrolytic discharge were determined by measuring the current density and cell voltage as functions of processing time and then by mathematical transformation. Correlation between discharge I-V property and the coatings microstructure on aluminum alloy during plasma electrolfic oxidation was determined by comparing the voltage-current properties at different process stages with SEM results of the corresponding coatings. The results show that the uniform passive film corresponds to a I-V property with one critical voltage, and a compound of porous layer and shred ceramic particles corresponds to a I-Vproperty with two critical voltages. The growth regularity of PEO cermet coatings was also studied.

Further analysis of indentation loading curves: Effects of tip rounding on mechanical property measurements

The effects of indenter tip rounding on the shape of indentation loading curves have been analyzed using dimensional and finite element analysis for conical indentation in elastic-perfectly plastic solids. A method for obtaining mechanical properties from indentation loading curves is then proposed. The validity of this method is examined using finite element analysis. Finally, the method is used to determine the yield strength of several materials for which the indentation loading curves are available in the literature.

Interface Fracture Property Of Peo Ceramic Coatings On Aluminum Alloy

This paper combines the four-point bending test, SEM and finite element method to study the interface fracture property of PEO coatings on aluminum alloy. The interface failure mode of the coating on the compression side is revealed. The ceramic coating crack firstly along the 45 degrees to the interface, then the micro crack in the coating deduces the interface crack. The plastic deformation observed by SEM shows excellent adhesion property between the coating and substrate. The plastic deformation in the substrate is due to the interfacial crack extension, so the interface crack mode of PEO coatings is ductile crack. The results of FEM show that the compression strength is about 600 MPa. (C) 2008 Elsevier B.V. All rights reserved.

Integration property of a wedge-elliptic cone waverider with scramjet engine

The hypersonic waverider forebody is designed in this paper. For the present waverider, the undersurface is carved out as a stream surface of a hypersonic inviscid flow field around wedge-elliptic cone, and the upper surface is assumed to be a freestream surface. A finite-volume code is used to generate the three-dimensional flow field. The leading edge is determined by satisfying the condition that the lip is situated at the intersection line of shocks.

Experimental Research On Fatigue Property Of Steel Rubber Vibration Isolator For Offshore Jacket Platform In Cold Environment

Jacket platform is the most widely used offshore platform. Steel rubber vibration isolator and damping isolation system are often used to reduce or isolate the ice-induced and seismic-induced vibrations. The previous experimental and theoretical studies concern mostly with dynamic properties, vibration isolation schemes and vibration-reduction effectiveness analysis. In this paper, the experiments on steel rubber vibration isolator were carried out to investigate the compressive properties and fatigue properties in different low temperature conditions. The results may provide some guidelines for design of steel rubber vibration isolator for offshore platform in a cold environment, and for maintenance and replacement of steel rubber vibration isolator, and also for fatigue life assessment of the steel rubber vibration isolator. (C) 2009 Elsevier Ltd. All rights reserved.

Applying hedonic property models in the planning and evaluation of shoreline management

According to the Millennium Ecosystem Assessment’s chapter “Coastal Systems” (Agardy and Alder 2005), 40% of the world population falls within 100 km of the coast. Agardy and Alder report that population densities in coastal regions are three times those of inland regions and demographic forecasts suggest a continued rise in coastal populations. These high population levels can be partially traced to the abundance of ecosystem services provided in the coastal zone. While populations benefit from an abundance of services, population pressure also degrades existing services and leads to increased susceptibility of property and human life to natural hazards. In the face of these challenges, environmental administrators on the coast must pursue agendas which reflect the difficult balance between private and public interests. These decisions include maintaining economic prosperity and personal freedoms, protecting or enhancing the existing flow of ecosystem services to society, and mitigating potential losses from natural hazards. (PDF contains 5 pages)