•Miniature mechanical safety and arming device is proposed for actual munition firing.•Reliable arming delay performance was achieved by runaway escapement mechanism.•Compact design of the device was ...available by stainless steel wet etching process.•The device showed successful safety and arming performance under actual field tests.•The device found to be appropriate under variety of environmental conditions.
In this research, a miniature mechanical SAD (Safety and Arming Device) with arming delay was developed for actual munitions application. Reliable arming delay performance was achieved by applying a runaway escapement system that operates by a rack-and-pinion motion. The miniature mechanical SAD was fabricated using a stainless steel wet etching process that provided not only miniaturization but also a high processing yield. The miniature mechanical SAD performed successfully under the desired safety and arming conditions in lab tests and showed fine agreement with the finite element method simulation results. Field tests were performed with a grenade launcher to validate its performance under the actual firing conditions. One hundred samples that were shot 23.6 m (safety distance) and 200 m (arming distance), and every specific test criterion was met successfully. The new SAD was also found to be appropriate for safe use in artillery fuzes by conducting environmental tests under a variety of temperature, vibration, and impact conditions.
In this study, we present a multi-stage robust multi-objective optimization (MRMO) method that takes into consideration uncertainties stemming from fabrication errors. This efficient method has been ...employed to optimize an inertial setback feature (ISF) within the microelectromechanical system (MEMS) safety and arming device (SAD). Sensitivity analysis and meta-model techniques are utilized to reduce the computational dimension and cost of optimizing the objectives. The accuracy of the approximation between the global meta-model (GMM) in the method and finite element analysis (FEA) results is guaranteed through appropriate calculation samples. Two optimization algorithms, the fuzzy multi-objective particle swarm optimization (f-MOPSO) algorithm and the adaptive accelerated gravitational search algorithm (AAGSA), are performed to global optimization and local search for the fitness values sequentially to enhance the optimization performance. Robust optimal solutions are shortlisted and selected from among candidate solutions exhibiting superior performance. The effectiveness of the method is demonstrated through a comparison of the results obtained from FEA and the GMM with experimental data collected from some fabricated ISF prototypes. This method achieves the objective of reducing the burden of repetitive FEA calculations and better performance enhancement in robustness optimization.
Concepts in Oncolytic Adenovirus Therapy Mantwill, Klaus; Klein, Florian Gerhard; Wang, Dongbiao ...
International journal of molecular sciences,
10/2021, Letnik:
22, Številka:
19
Journal Article
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Oncolytic adenovirus therapy is gaining importance as a novel treatment option for the management of various cancers. Different concepts of modification within the adenovirus vector have been ...identified that define the mode of action against and the interaction with the tumour. Adenoviral vectors allow for genetic manipulations that restrict tumour specificity and also the expression of specific transgenes in order to support the anti-tumour effect. Additionally, replication of the virus and reinfection of neighbouring tumour cells amplify the therapeutic effect. Another important aspect in oncolytic adenovirus therapy is the virus induced cell death which is a process that activates the immune system against the tumour. This review describes which elements in adenovirus vectors have been identified for modification not only to utilize oncolytic adenovirus vectors into conditionally replicating adenoviruses (CRAds) that allow replication specifically in tumour cells but also to confer specific characteristics to these viruses. These advances in development resulted in clinical trials that are summarized based on the conceptual design.
We analyze a dynamic, two-country model that highlights the various trade-offs each country faces between current consumption and competing investments in its future productive and military ...capacities as it prepares for a possible conflict in the future. Our focus is on the circumstances under which the effects of current trade between the two countries on the future balance of power render trade unappealing to one of them. We find that a positive probability of future conflict induces the country with less resource wealth to “prey” on the relatively more “prudent” behavior of its larger rival, and more so as conflict becomes more likely. While a shift from autarky to trade always raises the current incomes of both countries, the smaller country realizes the relatively larger income gain from trade and also devotes a relatively larger share of its income gain towards arming. Our analysis shows that the larger country rationally chooses not to trade today when the difference in initial resource wealth is sufficiently large and is more likely to prefer autarky when the probability of future conflict is higher.
The yeast surface display system is a valuable platform for constructing cells with novel functions for various applications and high-throughput screening of protein or peptide libraries containing ...random mutations. Among the host microorganisms used for surface display, yeast is the most suitable microorganism for surface engineering owing to its eukaryotic features. In yeast, proper folding and glycosylation of expressed eukaryotic proteins can be performed. Furthermore, in this system, multiple kinds of proteins can be simultaneously displayed on the cell surface. This allows for a synergistic effect between the displayed enzymes, leading to an efficient multistep reaction. Alternatively, the ratio of the enzymes to be displayed can be controlled by the co-culture of surface-engineered yeasts displaying a single kind of enzyme. Therefore, yeast surface display systems have been applied to the construction of various whole-cell biocatalysts. Here, we describe methods for the simultaneous display of multiple kinds of proteins on the yeast cell surface.
Our goal was to develop a simpler and less expensive method of obtaining human clinical-grade WBCs using an alternative method to continuous leukapheresis. Our purpose for the WBCs is to arm them ...with rabbit anticancer antibodies for a phase I clinical trial.
Using leukocyte reduction filters (LRFs) discarded from the blood bank, we evaluated multiple variables to maximize recovery of WBCs with the lowest contamination of RBCs. Using an optimized protocol, full-scale runs according to FDA current Good Manufacturing Practice (cGMP) standards were completed with immediate filtration of blood obtained from donors participating in our study.
Forward flushing of the filter removed 85% to 95% of residual RBCs and platelets. When backward flushed with 800 mL, 95% of the WBCs recovered were contained in the first 400 mL. The number of recovered WBCs was in the range of 166–211 million/100 mL filtered blood. Subpopulations of WBCs recovered from the LRFs were in the same proportion as the donors' whole blood. Viability of recovered WBCs was 96–99%. Exogenous rabbit antibodies bound well to the recovered WBCs and were retained for at least 5 h without significant reduction. Three full scale runs of WBCs recovered from donor blood filtered through the LRF met all FDA specification of sterility, endotoxin levels, viability and stability.
Using LRFs, high quality clinical grade WBCs are readily obtained in quantities of 0.2 to 1.2 billion cells from 100 mL to 450 mL (1 unit) of whole blood.
•Recovery of WBCs was performed with leukocyte reduction filters.•Conditions for maximal recovery of viable WBCs were established.•FDA approved use of the recovered WBCs for a Phase I human clinical trial.•WBCs were armed with antibodies in preparation for a phase I cancer trial.
Antibodies and other recognition molecules direct cancer cell death by multiple types of immune cells. Therapy directed at only one target typically results in tumor regrowth because of tumor ...heterogeneity. Our goal is to direct therapy to multiple targets simultaneously. Our previous studies showed that multiple antibodies targeting mutated tumor proteins inhibited tumor growth when injected subcutaneously near the time of cancer cell implantation.
A cocktail of rabbit antibodies against B16-F10 cell surface related mutated proteins were generated. Implanted B16-F10 cells were allowed to grow to palpable size before treatment. Antibodies were administered using different routes of exposure. Free antibody was compared to antibody armed on mouse splenic white blood cells (WBCs). Binding of the antibody cocktail was determined for mouse and human WBCs.
The antibody cocktail inhibited tumor growth and prolonged survival when administered as free antibody or armed on WBCs. The antibody cocktail armed on WBCs achieved similar tumor inhibition as free antibody but at a dose 1000-fold less. Armed WBCs achieved tumor inhibition by intravenous and subcutaneous administration. The antibody cocktail bound well to human WBCs and saturation dose was defined. Binding was stable under simulated in vivo condition in human plasma at 37 °C.
Antibodies targeting multiple tumor mutated proteins inhibited tumor growth and prolonged survival. Effective antibody dose was reduced 1000-fold by arming WBCs. Rabbit antibodies saturated human WBCs using <1 mg per billion cells. A phase I trial in cancer patients using this strategy has been approved by the FDA.
•Multiple antibodies targeting multiple cell membrane mutated proteins inhibit tumor.•Administration of antibodies armed on WBCs inhibits tumor growth.•Dose of antibody reduced 1000-fold by arming WBCs instead of free antibody.•Rabbit antibodies bind well to human WBCs.
The micro-electromechanical system (MEMS) safety-and-arming (S&A) device has the features of integration and miniaturization, which is one of the important directions of weapon development. Confined ...by the fabrication process, the silicon-based devices are too fragile, and the metal-based devices are low precision. In order to solve the contradiction between high precision and high structure strength, a metal/silicon composite structure is proposed in this paper, and a hybrid fabrication process is introduced. This new method mainly consists of metal sputtering, electroplating, and (inductively−coupled-plasma) ICP etching. As the resolution of the thick dry film is limited, the process of a femtosecond laser is applied to refine the structure, and the Ni plate (a block of 1 mm × 3 mm × 0.3 mm with a cavity of ϕ 0.85 mm × 0.3 mm in the center) is fabricated on the silicon-on-insulator (SOI) wafer successfully. After the double sides are etched by ICP, the SOI wafer is immersed in a buffered-oxide-etch (BOE) etchant to remove the buried layer. The cover plate acts as the encapsulation and is bonded with the SOI wafer by the epoxy glue. Then, the temporary support beam of the device is broken by the probe, and the suspended composite structure can be fully released. The hybrid process is the integration of the silicon-based process and the metal-based process, which can combine the advantages of both high precision and a high structure strength. The process proposed here is suitable for the application of weapon miniaturization.
This article introduces a novel micro-optical electromechanical system safety and arming (S&A) device that utilizes both electrothermal and centrifugal actuators to ensure the reliability and ...efficiency of the device. The S&A device comprises a pair of V-shaped latching actuators, a pair of U-shaped latching actuators, a reverse blocking actuator, a centrifugal alignment actuator, and two sets of status monitoring units. The V- and U-shaped latching actuators serve as safety features to prevent accidental triggering, while the centrifugal alignment actuator aligns the optical fibers. The mechanical responses of the device under dual-environment loads are analyzed using a finite element model, while a theoretical model is introduced to predict the centrifugal acceleration required for alignment. The device is fabricated using deep reactive ion etching on silicon-on-insulator wafers. Experimental tests confirm the effectiveness of the safety features and the device's capability to transmit high-power optical energy. The optical efficiency ranges from 71.8% to 76.4% (1.17-1.44 dB insertion loss), and the maximum power transfer is 902 mW from an 1180 mW input.
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