•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.
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.
•Soybean seed coat peroxidase was displayed on the cell surface of Yarrowia lipolytica to generate a whole-cell biocatalyst.•The recombinant enzyme activity was greatly increased after a series of ...culture optimization.•This biocatalyst exhibited outstanding enzyme activity and stability without obvious negative effect to the host cells.
Whole-cell biocatalysts could be used in wide-ranging applications. In this study, a new kind of whole-cell biocatalyst was successfully constructed by genetically immobilizing soybean seed coat peroxidase (SBP) on the cell surface of Yarrowia lipolytica Po1h, using a new integrative surface display expression vector (pMIZY05). The coding sequence of SBP was optimized and chemically synthesized, then inserted into pMIZY05 to generate expression plasmid pMIZY05-oEp. A DNA fragment corresponding to SBP and selection marker expression cassettes, without bacterial sequences, was released from pMIZY05-oEp by enzyme digestion and used to transform host yeast cells. A transformant (CM11) with a high recombinant SBP activity of 1571.9 U/mL was obtained, and recombinant SBP was proved to be successfully anchored on cell surface by testing the activities of different cellular fractions. After optimization of culture conditions, the recombinant SBP activity of CM11 was increased to 4187.8 U/mL. Afterwards, biochemical properties of the recombinant SBP were determined: optimum catalytic conditions were 37.5℃ at pH 3.5, and recombinant SBP exhibited high stability during thermal or acidic treatment. Recombinant activity of cell-displayed SBP was re-examined at optimum temperature and pH, which promoted an increase up to 4432.5 U/mL. To our knowledge, this represents the highest activity ever reported for heterologous expression of SBP. This study also provides a useful strategy for heterologous expression of proteins which could be toxic to intracellular content of host cells.
To solve the structural strength problem of a MEMS arming device for a fuze, a kind of arming device applied to a certain type of 40 mm grenade is designed. This paper introduces the working ...principle of the arming device; simulates the shear pin, rotary pin and locking mechanism in the device; designs a variety of different test tools for test verification; and further increases the explosion reliability and arming safety tests. The results show that the arming device improves the structural strength and can meet the action requirements of a certain type of 40 mm grenade for safety release, as well as the application requirements of explosion reliability and arming safety.
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.
Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects via systemic administration. Tumor cells often create an unfavorable ...immunosuppressive microenvironment that degrade viral structures and impede viral replication; however, recent studies have established that viruses altered via genetic modifications can serve as effective oncolytic agents to combat hostile tumor environments. Specifically, oncolytic vaccinia virus (OVV) has gained popularity owing to its safety, potential for systemic delivery, and large gene insertion capacity. This review highlights current research on the use of engineered mutated viruses and gene-armed OVVs to reverse the tumor microenvironment and enhance antitumor activity in vitro and in vivo, and provides an overview of ongoing clinical trials and combination therapies. In addition, we discuss the potential benefits and drawbacks of OVV as a cancer therapy, and explore different perspectives in this field.
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.