Non-clinical studies for oncology drug development

Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs

Experimental Study of Starvation and Flow Behavior in Grease-Lubricated EHD Contact

This paper describes an experimental study of starvation and flow behavior in grease-lubricated elastohydrodynamic contact. Rolling tests were conducted with four grease samples with different thickeners and base oils in a conventional ball-on-disk test rig. The EHL central film thickness was determined with SLIM, the Spacer Layer Imaging Method, and grease flow around the conjunction and the flow pattern on the track of the disk specimen were observed with CCD cameras. The grease track included some thickener deposited on the track and a corrugated fingerlike flow pattern outward from the center of the track. It was found that the flow pattern varied with grease type and test conditions, and that the average interval between fingers decreased with the entrainment speed. At higher speeds, inlet starvation occurred and the finger pattern was deformed and gradually ruptured. The speed of the finger-loss was higher than the speed at which starvation started. It was also found that the starvation speed was greater with greases having lower apparent viscosity at lower shear rate and higher apparent viscosity at high shear rate. This implied that the replenishment and entrainment of the greases depended on the viscosity characteristics of the greases

The role of synthetic oils in controlling hydrogen permeation of rolling/sliding contacts

Bearing steels suffer from a degradation of mechanical properties when atomic hydrogen diffuses into the steel from the contact surface. In rolling contact fatigue tests this can lead to a significant reduction in fatigue lives of the specimens as the amount of hydrogen diffused into the steel increases. To mitigate this challenge synthetic oils of different chemistry have been studied so as to identify their efficiency and mechanism of retarding or preventing hydrogen permeation. Thrust bearing type tests were conducted with three synthetic base oils. The effect of base oil chemistry on hydrogen generation and permeation in bearing steel was explored by relating the concentration of hydrogen species in specimens with changes in the surface and subsurface of the wear track and the condition of the oil

Hydrocarbon lubricants can control hydrogen embrittlement

While it is well known that during RCF tests the formation of nascent catalytic sites on the wear track can break down hydrocarbon molecules to release atomic hydrogen, the potential of the hydrogen environment in fuel cells to hydrocrack the hydrocarbon lubricant in high pressure rolling contacts has so far been ignored. Here we investigate for the first time the ability of the hydrogen environment to generate a chemical tribofilm on the wear track most likely through lubricant hydrocracking, as compared with argon and air environments. Despite the ability of the hydrogen environment to generate a notably larger amount of atomic hydrogen, the chemical tribofilm significantly prevents the formation of atomic hydrogen and its subsequent diffusion through the lattice of steel rolling element bearings. This is of great importance in the lubrication of hydrogen technology and the prevention of Hydrogen embrittlement (HE). An investigation into the prospects of high energy micro-computed-tomography (Micro-CT) as a non-destructive technique for sub-surface damage characterisation in RCF was comparatively performed alongside traditional sectioning methods

Effects of Environmental Gas and Trace Water on the Friction of DLC Sliding with Metals

This paper describes an experimental study on the friction of a-C:H diamond-like carbon (DLC) and ta-C DLC coatings in gas with different concentration of trace water. Pin-on-disk sliding experiments were conducted with DLC coated disks and aluminum pins in hydrogen, nitrogen, and argon. Trace oxygen was eliminated to less than 0.1 ppm, while water in the gas was controlled between 0 and 160 ppm. Fourier transform infrared spectroscopy (FT-IR) and laser Raman spectroscopy were used to analyze the transfer films on the metal surfaces. It was found that trace water slightly increased friction in hydrogen gas, whereas trace water caused a significant decrease in the friction coefficient in nitrogen and argon, particularly with a-C:H DLC. The low friction in hydrogen was brought about by the formation of transfer films with structured amorphous carbon, but no differences in the structure and contents of the films were found in the tests with and without trace water. In nitrogen and argon, the low friction with a-C:H DLC was achieved by the gradual formation of transfer films containing structured amorphous carbon, and FT-IR spectra showed that the films contained CH, OH, C–O–C, and C–OH bonds

WS2 nanoadditized lubricant for applications affected by hydrogen embrittlement

Hydrogen is one of the cleanest available vehicle fuels but its small atomic size allows it to diffuse readily through the lattice of solid materials, which can cause catastrophic failure in high strength steels. Metal embrittlement has been identified as a major consequence of hydrogen uptake and represents an extra challenge for lubricated tribological parts in fuel cell vehicles, hydrogen compressors, storage tanks, dispensers and wind turbines that are normally subjected to high stresses. This study has found WS2 nanoparticles as an effective additive candidate to impede the permeation of hydrogen into rolling element bearings at high temperatures and pressures. Compared to the pure polyalphaolefin (PAO) base oil, WS2 nanoadditized oil reduced the concentration of permeated hydrogen in the bearing steel and led to controlled wear and smoother tracks. These effects are attributed to the formation of a chemical tribofilm on the wear track which reduces hydrogen embrittlement and extends the life of steel through several mechanisms: (1) its continuous generation impedes formation of nascent catalytic surfaces during rubbing and thus prevents the decomposition of oil/water molecules and generation of atomic hydrogen; (2) acts as a physical barrier to hydrogen permeation through the wear track; (3) the low coefficient of diffusion of hydrogen through the tungsten compounds found in the tribofilm further reduces hydrogen permeation; (4) some of the atomic hydrogen is used up in redox reactions during the formation of the tribofilm and (5) the tribofilm reduces the total amount of water in the steel formed by the reaction of hydrogen atoms with oxides and thus extends the fatigue life. WS2 nanoadditized lubricants can lead to improved profitability and sustainability of the emerging renewable energy industry

Effect of Environmental Gas on Surface Initiated Rolling Contact Fatigue

This paper describes an exploratory study on the effects of temperature on the formation of oxide film and rolling contact fatigue life in hydrogen, argon and air. Rolling contact fatigue tests were conducted at 333 K and 363 K by using a three-ball-on-disk type apparatus. The rolling contact fatigue life in hydrogen was shorter than that in argon, and life in air was the longest. Relationship was found between fatigue life and hydrogen concentration in steel. Cross sections of the specimens show that iron oxide grew to larger grain size in the subsurface in hydrogen environment, which may have resulted in shorter fatigue life. It was also found that fatigue failure occurs on ball surface in hydrogen at 363 K

Self-lubricating Al-WS2 composites for efficient and greener tribological parts

Due to their mechanical and physical properties, aluminium alloys possess wide potential in the automotive industry, particularly in hot reciprocating applications such as pistons for diesel and petrol engines. WS2 particle-reinforced composites could bring further improvements by reducing friction and wear between moving parts. Reducing friction improves efficiency by lowering energy/fuel use, ultimately leading to lower greenhouse gas emissions, while antiwear properties can prolong component life. This study compares for the first time the tribological performance of powder metallurgy-consolidated Al composites reinforced with either IF- or 2H-WS2 particles, so as to elucidate their mechanism of action in test conditions similar to those encountered in engine applications. The composites were tested in lubricated reciprocating contacts against AISI52100 steel balls and the impact of WS2 could be seen at both 25 and 100ºC. The reduced friction and wear at ambient temperature is due to the predominantly physical mechanism of action of WS2, while the best antiwear performance is measured at elevated (standard operating engine) temperatures that promote the chemical reaction of WS2 with the aluminium matrix. The investigation focused on studying the wear tracks/scars and the tribofilms generated on the composite and ball with optical profilometry, SEM, XPS and Auger spectroscopy.<br/