We have investigated the difference between adiabatic and isothermal compression of liquids by an impacting weight, as observed in the resulting change to the index of refraction. The liquids examined were sebacate, glycerol, and water. For practical reasons, sebacate is best suited for the use of a drop-weight apparatus as a metrologically traceable calibration facility for dynamic pressure. We find that its optical properties under adiabatic and isothermal compression can be converted into each other using literature values of its thermodynamic properties. Care has to be taken to avoid cavitation-like effects, an observation that might need to be taken into account for other methods of generating short pressure pulses in the hundreds-of-MPa range.
Following the clinical success of checkpoint inhibitors, cancer immunotherapy is rapidly expanding into combination treatments to enhance response rates and duration. Engagement of co-stimulatory molecules from the tumor necrosis factor receptor (TNFR) superfamily, including 4-1BB, may be a promising approach to enhance the benefits of cancer immunotherapy. Agonistic antibodies against the costimulatory receptor 4-1BB (CD137) have been shown to effectively enhance the anti-tumor activity of checkpoint inhibitors and other agents in preclinical animal models. However, the clinical development of 4-1BB agonistic antibodies has met with limited success thus far. Anti-4-1BB monoclonal antibodies have either been reported to cause significant dose-limiting hepatotoxicity or demonstrated limited efficacy as single agent therapeutics. We generated a DARPin® therapeutic candidate, MP0310 (AMG 506), which comprises domains binding to 4-1BB and fibroblast activation protein (FAP). MP0310 triggers 4-1BB activation only if bound and clustered via FAP which is abundantly expressed by cancer associated fibroblasts present in many solid tumors. In vitro functional assays indicate that MP0310 is a potent T cell co-stimulator in the presence of FAP-expressing cells. In vivo activity of tumor-targeted 4-1BB agonism was assessed in the HT-29 colon carcinoma xenograft model in PBMC humanized mice in combination with a T cell engager. Consistent with tumor targeting, MP0310 enhanced intra-tumoral CD8 T cell expansion while showing only limited systemic activity. We used a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to integrate in vitro and in vivo data to support the estimation of a minimal anticipated biological effect level (MABEL) and the relevant dose range for first in human (FIH) studies. In addition to a PK model describing the MP0310 concentrations over time in mouse and monkey, direct and indirect response models were used to describe receptor occupancy (RO), intra-tumoral CD8 T cell infiltration and peripheral CD8 count kinetics. Predictions from the combined PK and PD models using average intra-tumoral and peripheral drug concentrations (Cav) provide a MABEL dose with minimal expected systemic PD effects at 20% RO as well as the anticipated therapeutic dose range in humans. In conclusion, our PK/PD-modeling approach provides support for the selection of a safe starting dose for MP0310 (AMG506) in patients. It provides a rationale for selecting the maximum tested dose, and may help reduce the number of cancer patients receiving sub-therapeutic doses. MP0310 (AMG 506) is currently being evaluated in a Ph1 clinical study. Citation Format: Alexander Link, Laurent Juglair, Heïdi Poulet, Guy Lemaillet, Christian Reichen, Patricia Schildknecht, Ivana Tosevski, Joanna Robinson, Niina Veitonmäki, Jörg Herbst, Keith Dawson, Christof Zitt, Camila de Almeida, Rik de Greef, Victor Levitsky, Michael T. Stumpp, Hong Ji, Elmar Vom Baur. Selection of first-in-human clinical dose range for the tumor-targeted 4-1BB agonist MP0310 (AMG 506) using a pharmacokinetic/pharmacodynamics modeling approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2273.
Potato guns are popular homemade guns which work on the principle of gas combustion. They are usually constructed for recreational rather than criminal purposes. Yet some serious injuries and fatalities due to these guns are reported. As information on the internal ballistics of homemade gas combustion-powered guns is scarce, it is the aim of this work to provide an experimental model of the internal ballistics of these devices and to investigate their basic physical parameters. A gas combustion gun was constructed with a steel tube as the main component. Gas/air mixtures of acetylene, hydrogen, and ethylene were used as propellants for discharging a 46-mm caliber test projectile. Gas pressure in the combustion chamber was captured with a piezoelectric pressure sensor. Projectile velocity was measured with a ballistic speed measurement system. The maximum gas pressure, the maximum rate of pressure rise, the time parameters of the pressure curve, and the velocity and path of the projectile through the barrel as a function of time were determined according to the pressure-time curve. The maximum gas pressure was measured to be between 1.4 bar (ethylene) and 4.5 bar (acetylene). The highest maximum rate of pressure rise was determined for hydrogen at (dp/dt)max = 607 bar/s. The muzzle energy was calculated to be between 67 J (ethylene) and 204 J (acetylene). To conclude, this work provides basic information on the internal ballistics of homemade gas combustion guns. The risk of injury to the operator or bystanders is high, because accidental explosions of the gun due to the high-pressure rise during combustion of the gas/air mixture may occur.
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