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1
Li, Shan Feng, and Lei Yang. "Application of Distributed Measurement and Control System." Applied Mechanics and Materials 385-386 (August 2013): 504–9. http://dx.doi.org/10.4028/www.scientific.net/amm.385-386.504.
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Measurement and control system plays a gatekeeper and director role in industrial production. It obtains various parameters from the production site, in order to meet the needs of production, improve quality, ensure safety in production. Distributed measurement and control systems scalability, inexpensive cost and other factors have been widely used. This paper mainly discusses a distributed measurement and control system which based on STC89C52 MCU, RS485 bus, 18B20 temperature components and ADS7822 voltage acquisition components with a main control terminal and three nodes, through RS485 communications. The main control terminal has keyboard and LCD1602 displayer, which can read each node state. Each node refers to one of the measurement and control items below (temperature measurement, current or voltage measurement, switch input measurement and switch output control).
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Han, Shu Ren, Jun Wang, Ling Liang, and Xian Peng Liu. "Hardware Design of Coal Mine Safety Monitoring System Based on WSN." Advanced Materials Research 546-547 (July 2012): 1483–88. http://dx.doi.org/10.4028/www.scientific.net/amr.546-547.1483.
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In the safety production of coal mine, monitoring exact and real-time mine parameter is very important and key problem. The monitoring system of mine environment with wireless is designed, which is based on the structure of wireless sensor network (WSN).The system includes sensor node, Sink node and monitoring center. In the paper, the function structure and hardware design of sensor are introduced for the monitoring of temperature, humidity and gas concentration, and the function structure and hardware design of sink node is designed. The system has low power, rapid real-timing, stable running. Etc. This can satisfy with the requirement of WSN and suit the monitoring of bad environments. It will have wide application prospect.
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Qiang, Zilin, Yingsen Wang, Kai Song, and Zijuan Zhao. "Mine Consortium Blockchain: The Application Research of Coal Mine Safety Production Based on Blockchain." Security and Communication Networks 2021 (June 17, 2021): 1–10. http://dx.doi.org/10.1155/2021/5553874.
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To solve the problem that the safety data in the process of coal mine production are easy to be maliciously tampered with and deleted, a mine consortium blockchain data security monitoring system is proposed. The coal mine consortium blockchain includes supervision department, builds favourable centralized and decentralized production mode, and improves PBFT (Practical Byzantine Fault Tolerance) consensus mechanism to implement practical coal mine safety production. The evaluation shows that the architecture we proposed is more appropriate and efficient for the mine Internet of Things than the traditional blockchain architecture. The Hyperledger Fabric platform is used to build the mine consortium blockchain system to achieve the sensor data reliability, node consensus, safe operation automation management, and major equipment traceability.
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Liu, Hai Long, and Yan Wang. "The Application Research in the Coal Mine on Chirp-UWB Wireless Communication Technology." Advanced Materials Research 1079-1080 (December 2014): 787–90. http://dx.doi.org/10.4028/www.scientific.net/amr.1079-1080.787.
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With the rapid development of wireless network technology, according to the actual need, the computer network group network type and each node has different function, so that the computer network system has node complexity, structure complexity and various other complexities. For these reasons, the large scale computer network can be treated and researched abstractly as specific Chirp-UWB network. Therefore, to keep up with the trend of technology progress by means of computer wireless technology, aided design of wireless communication system, it is quite necessary for the implementation of computer management of production safety.
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Yang, Guang Xue, and Wei Han. "The Ammonia Leak Monitoring and Warning System Based on Wireless Sensor Network in Industrial Environments." Applied Mechanics and Materials 538 (April 2014): 348–51. http://dx.doi.org/10.4028/www.scientific.net/amm.538.348.
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In order to prevent the ammonia leak caused casualties incidents, this paper adopts ZigBee wireless technology to real-time monitoring of ammonia concentration. Equipped with MQ137 ammonia sensor in the terminal node, and the use of STM8 microcontroller collected the ammonia concentration data. The data will be transmitted to the coordinator through ZigBee. Using LabVIEW to design the monitoring interface of computer, and read concentration data through the serial port communication. When the ammonia concentration exceeds the preset value, the GSM module will send the location of leak in the form of short messages to staff. Through the reasonable arrangement of sensor nodes in ammonia production workshop, can effectively avoid the ammonia leak hurting the safety of people's life and property.
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Wyciszkiewicz, Aleksander, Krzysztof Golacki, and Waldemar Samociuk. "Hazards and their reduction in urea production for synthesis reactor by Mitsui - Toatsu technology." Scientific Journal of the Military University of Land Forces 187, no. 1 (March 1, 2018): 150–64. http://dx.doi.org/10.5604/01.3001.0011.7369.
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Industrial large-scale urea production creates a number of hazards due to equipment and machine failures as well as service errors. Failures can cause material, environmental and human losses. The work presents the assessment of safety hazards and failure effects for selected emergency scenarios of Mitsui - Toatsu's urea synthesis reactor. A fragment of the process implemented in the synthesis node was covered by HAZOP (Hazard and Operability Study), and the critical points, from the security point of view, were identified. Several emergency scenarios for various types of failures and various effects are presented. The analyzed contingency scenarios include: blocking the valve on the outflow from the reactor and leaks caused by corrosion resulting from the maintenance of improper technological parameters of the process. The work suggested the need for new security measures and modernization of the installation by using the safety function for the selected critical point. The hazards analyzed and the contingency scenarios developed are essential for risk assessment and its possible reduction.
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Schutsky, Keith, Dana Curtis, Emily K. Bongiorno, Darryll A. Barkhouse, Rhonda B. Kean, Bernhard Dietzschold, D. Craig Hooper, and Milosz Faber. "Intramuscular Inoculation of Mice with the Live-Attenuated Recombinant Rabies Virus TriGAS Results in a Transient Infection of the Draining Lymph Nodes and a Robust, Long-Lasting Protective Immune Response against Rabies." Journal of Virology 87, no. 3 (November 28, 2012): 1834–41. http://dx.doi.org/10.1128/jvi.02589-12.
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ABSTRACTA single intramuscular application of the live but not UV-inactivated recombinant rabies virus (RABV) variant TriGAS in mice induces the robust and sustained production of RABV-neutralizing antibodies that correlate with long-term protection against challenge with an otherwise lethal dose of the wild-type RABV. To obtain insight into the mechanism by which live TriGAS induces long-lasting protective immunity, quantitative PCR (qPCR) analysis of muscle tissue, draining lymph nodes, spleen, spinal cord, and brain at different times after TriGAS inoculation revealed the presence of significant copy numbers of RABV-specific RNA in muscle, lymph node, and to a lesser extent, spleen for several days postinfection. Notably, no significant amounts of RABV RNA were detected in brain or spinal cord at any time after TriGAS inoculation. Differential qPCR analysis revealed that the RABV-specific RNA detected in muscle is predominantly genomic RNA, whereas RABV RNA detected in draining lymph nodes is predominantly mRNA. Comparison of genomic RNA and mRNA obtained from isolated lymph node cells showed the highest mRNA-to-genomic-RNA ratios in B cells and dendritic cells (DCs), suggesting that these cells represent the major cell population that is infected in the lymph node. Since RABV RNA declined to undetectable levels by 14 days postinoculation of TriGAS, we speculate that a transient infection of DCs with TriGAS may be highly immunostimulatory through mechanisms that enhance antigen presentation. Our results support the superior efficacy and safety of TriGAS and advocate for its utility as a vaccine.
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Pei, Ying Na, Yong Tao Zhang, Fan Wei Meng, You Liang Yang, and Cui Hong Ma. "Design of Wireless Sensor Network Based on STM32W108." Applied Mechanics and Materials 303-306 (February 2013): 1834–37. http://dx.doi.org/10.4028/www.scientific.net/amm.303-306.1834.
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At present, cable transmission is used mostly in the coal mine safety production monitoring. Cable transmission mode has many shortcomings, for example: wiring complex, line dependence of strong, installation and maintenance cost more. Badly working conditions of coal mine underground increase the difficulty of the wiring. In order to solve the cable transmission mode existing problems and the insufficiency, this paper analysis wireless sensor node which use in the coal mine underground and the functions of its modules characteristics and performance requirements deeply .And design wireless sensor node of coal mine based on STM32W108 chip, research emphatically each function module of the working principle. It also presents the hardware platform of the overall design scheme and hardware circuit diagram and software flow chart.
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Ma, Ying, Xiao Yu Ma, and Guo Dong Wang. "Research on Coal Mine Roadway Safety Monitoring System Based on Zigbee." Applied Mechanics and Materials 88-89 (August 2011): 185–90. http://dx.doi.org/10.4028/www.scientific.net/amm.88-89.185.
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With the higher and higher demands to the safety in coal mines and the development of the enterprises themselves, the security problems in coal mines already become the most important ones. Because of many hidden dangers existing in coal mines, the accidents that make the heavy economic losses and personnel casualty occurs frequently in China coal mines. It shows that the existing safety monitoring systems in coal mines has some insufficiencies. By researching on the collection of human physiology information, the design of wireless sensor network node and wireless networking technology, the system applies ZigBee technology into the environment of coal mine roadway safety production, which realizes the detecting of daily work environment of coal mine roadway as well as the real time monitoring of the location and status of the trapped people underground when safety accident happens so as to provide accurate information for rescue.
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Ngosomwile, Ntuli, Calvin Sindato, Erick V. G. Komba, and Daniel W. Ndyetabula. "The role of Pig production and Market value chain in the occurrence of African Swine Fever in Songwe and Ruvuma regions, Tanzania." East Africa Science 3, no. 1 (March 15, 2021): 86–101. http://dx.doi.org/10.24248/easci-d-20-00004.
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Background: In recent years, the pig industry in Tanzania has faced frequent occurrence of outbreaks of African swine fever (ASF). However, there is inadequate information on the pig value chain operation in relation to occurrence of ASF. This study aimed at mapping pig value chain and assess its contribution to the occurrence and spread of ASF in Tanzania.
Methods: A cross sectional study was carried out in Songwe, Momba, Songea and Mbinga districts of Tanzania. Study districts were purposively selected based on the density of pig population, differences in production systems and history of ASF outbreaks. A total number of 484 pig producers and 28 traders were involved in the study. Random sampling was used to select pig producers. Pig traders were selected using snowball technique. Structured questionnaires were used to collect data on pig management and production practices, veterinary services, pig marketing practices and biosecurity measures using Open Data Kit (ODK) software. Semi structured interviews were conducted with key informants on perceived risk practices that are related to ASF outbreaks, challenges and recommendations on ASF prevention and control measures. Observation method was used to assess structure, facilities and practices within the pig production chain.
Results: The main actors in the pig production chain were pig producers, assemblers, wholesalers and retailers. Unknown stock source (30%), poor husbandry practice such as free ranging (5%), poor management of waste products (73%) and poor handling of feed (73%) were risk practices in the production node. Transportation nodes operated under high risk due to frequent movements and pick-ups of ≥ 30 pigs per trip.
Conclusion: The results demonstrated that different actors operate in the pig production, distribution and marketing chain. Each node operated under low biosecurity measures, and poor infrastructures that are likely to contribute to occurrence of ASF. There is need to improve good husbandry practices, marketing and infrastructures to increase production while ensuring pork safety.
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Froiz-Míguez, Iván, Paula Fraga-Lamas, José Varela-Barbeito, and Tiago M. Fernández-Caramés. "LoRaWAN and Blockchain based Safety and Health Monitoring System for Industry 4.0 Operators." Proceedings 42, no. 1 (November 14, 2019): 77. http://dx.doi.org/10.3390/ecsa-6-06577.
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The latest advances in the different Industry 4.0 technologies have enabled the automation and optimization of complex tasks of production processes thanks to their ability to monitor and track the state of physical elements like machinery, environmental sensors/actuators or industrial operators. This paper focuses on the latter and presents the design and evaluation of a system for monitoring industrial workers that provides a near real-time decentralized response system aimed at reacting and tracing events that affect operator personal safety and health. Such a monitoring system is based on the information collected from sensors encapsulated in IoT wearables that are used to measure both personal and environmental data. The communications architecture relies on LoRaWAN, an LPWAN (Low-Power Wide-Area Network) technology that offers good reliability in harsh communications environments and that provides relatively long distance communications with low-energy consumption. Specifically, each wearable sends the collected information (e.g., heart rate, altitude, external temperature, gas concentration, location) from the sensors to the nearest LoRaWAN gateway, which is transmitted to a pool of nodes where information is stored in a distributed manner. Such a decentralized system allows for providing information redundancy and guarantees its availability as long as there is an operative node. In addition, the proposed system is able to store and to process the collected data through smart contracts in a blockchain, which eliminate the need for a central backend and ensure the traceability and immutability of such data in order to share them with third parties (e.g., insurance companies or medical services).
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Shuang, Qing, Yisheng Liu, Jing Liu, and Qigang Chen. "Serviceability Assessment for Cascading Failures in Water Distribution Network under Seismic Scenario." Mathematical Problems in Engineering 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/1431457.
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The stability of water service is a hot point in industrial production, public safety, and academic research. The paper establishes a service evaluation model for the water distribution network (WDN). The serviceability is measured in three aspects: (1) the functionality of structural components under disaster environment; (2) the recognition of cascading failure process; and (3) the calculation of system reliability. The node and edge failures in WDN are interrelated under seismic excitations. The cascading failure process is provided with the balance of water supply and demand. The matrix-based system reliability (MSR) method is used to represent the system events and calculate the nonfailure probability. An example is used to illustrate the proposed method. The cascading failure processes with different node failures are simulated. The serviceability is analyzed. The critical node can be identified. The result shows that the aged network has a greater influence on the system service under seismic scenario. The maintenance could improve the antidisaster ability of WDN. Priority should be given to controlling the time between the initial failure and the first secondary failure, for taking postdisaster emergency measures within this time period can largely cut down the spread of cascade effect in the whole WDN.
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Zhu, Ying Li, and Ling Qing Xie. "Monitoring and Alarm System for Coal Mine Safety Based on Wireless Sensor Network." Advanced Materials Research 588-589 (November 2012): 1099–102. http://dx.doi.org/10.4028/www.scientific.net/amr.588-589.1099.
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In order to guarantee the safety of the coal production and effectiveness better, this paper designs a monitoring system for coal mine safety based on wireless sensor networks, and gives the hardware design of sensor nodes and the flowchart of software. For the purpose of meeting requirements of monitoring signals, CC2430 is chosen as the microprocessor. The sensor nodes can collect and transport the environment parameters of the mine including temperature, humidity and gas concentrate and so on, and send the data through the GPRS module to the remote monitoring center. The system can improve the level of monitoring production safety and reduce accident in the coal mine.
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Zhu, Lin-bo, Feng Zhu, Peng-fei Li, and Peng-bin Zhang. "Infiltration of nanocarbon suspension into the tracheal cavity during surgical treatment of papillary thyroid carcinoma: a case report." Journal of International Medical Research 48, no. 4 (April 2020): 030006052091925. http://dx.doi.org/10.1177/0300060520919251.
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Cervical lymph node metastasis in patients with differentiated thyroid cancer affects postoperative recurrence and survival. Hypoparathyroidism is caused by parathyroid gland injury during thyroidectomy. Carbon nanoparticles can trace stained lymph nodes, aiding in thorough dissection of lymph nodes in the operation area. To reduce postoperative occurrence of hypoparathyroidism, the parathyroid glands and their functions (identified by negative imaging induced by carbon nanoparticles) are retained in situ. However, the safety and adverse effects of nanocarbon suspension in thyroid surgery have rarely been evaluated. In this report, we describe a patient with thyroid cancer who had carbon secretions in the trachea caused by nanocarbon suspension when tracheal intubation was performed under general anesthesia, and the inflatable balloon surface of the tracheal tube was covered with these secretions. The patient recovered without fever, cough, phlegm production, chest pain, hoarseness, or hypocalcemia-induced convulsions. No consensus has yet been reached on the most appropriate injection site, depth, dose, or waiting time for nanocarbons in thyroid cancer surgery. We believe that nanocarbon suspension is safe for use in thyroid cancer surgery, but the most appropriate injection depth should be based on the thickness of the thyroid gland tissue to avoid deep injection into the trachea.
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Wei, Yun Kai, Yu Ming Mao, Qin Yu, and Na Li. "A Structure of Large Scale WSN Based Safety Monitoring System for Natural Gas Industry." Advanced Materials Research 512-515 (May 2012): 2482–86. http://dx.doi.org/10.4028/www.scientific.net/amr.512-515.2482.
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With the rapidly development of natural gas production, storage and transportation, the requirement for safety monitoring on natural gas industry are continuously increasing. This paper analyzes the application of WSN (wireless sensor network) in natural gas industry safety monitoring, and proposes a layered structure for large scale WSN based safety monitoring system, which can be used in collecting various kinds of safety information in natural gas industry, and sending them to surveillance center for data analyzing and early warning of abnormal situation. In the structure, we discuss the deployment of sensor nodes, sink nodes and e-sink nodes, and proposed the layered data fusion model and query model.
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Zhu, Ying Li, Wang Hui Zeng, and Ling Qing Xie. "Automatic Monitoring System for Coal Mine Safety Based on nRF24E1." Applied Mechanics and Materials 130-134 (October 2011): 158–61. http://dx.doi.org/10.4028/www.scientific.net/amm.130-134.158.
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This paper describes the design of monitoring system for coal mine safety constructed by MSP430 and nRF24E1, which has described the structure of the system, working principle, and gives the hardware design of sensor nodes and the software design. This system is used for on-line monitoring of coal mine safety with the character of simple structure, low cost, low power consumption and so on, which will improve the level of monitoring production safety and reduce accident in the coal mine.
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Zhu, Ying Li, and Ling Qing Xie. "The Application of Wireless Sensor Network in Coal Mine Monitoring." Advanced Materials Research 694-697 (May 2013): 1043–46. http://dx.doi.org/10.4028/www.scientific.net/amr.694-697.1043.
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The safe of the cola mine has become the focus of the national industrial security, the prevention and monitoring of coal mine safety have been researched in recent years. With the development of sensor technology, MEMS, wireless communications, Wireless Sensor Networks have been paid great attention in industry field and our daily life. According to the grim situation of current production safety, the article applies WSN (Wireless Sensor Network) to safety monitoring system of the coal mine. For the purpose of meeting requirements of monitoring signals, JN5139 is chosen as the microprocessor. The sensor nodes can collect and transport the environment parameters of the coal mine including temperature, humidity and gas concentrate and so on, and send the data to the remote monitoring center. The monitoring system can improve the level of monitoring production safety and reduce accident in the coal mine.
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Wu, Da, Ling Qiao Zhu, Jun Tang, Tao Jiang, Zhi Min Li, and Xiang Guang Chen. "The Development of the Remote Wireless Monitoring Device for Toxic Gases." Advanced Materials Research 846-847 (November 2013): 415–20. http://dx.doi.org/10.4028/www.scientific.net/amr.846-847.415.
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For the scene where there is a toxic gas leak, in order to detect the gas quickly and safely and make the effective solutions, the project of monitoring toxic gases in a remote wireless way and the process of the development is proposed in this paper. The device developed in this paper includes several wireless sensor network (WSN) nodes and one hand-held terminal, and the sensor module of WSN node is composed of several chemical gas sensors. The nodes will be sent to the scene by ground robots or unmanned aerial vehicles and make up the WSN monitoring system automatically, to achieve an aim of monitoring the toxic gas in real time. The experiment results show that the device can deal with the emergencies about the leak of toxic gas efficiently. And it has the advantages of low power consumption, high cost performance, self-forming network, anti-interference. Its suitable to monitor the toxic gas in various environments of industrial production and chemical scene of accident and unexpected occasions where there is a leak of toxic gas.
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Jiang, Zhi Hong, Feng Huang, Da Xi Wang, Bo Hu, and Ji Jiang Dou. "The Design and Implementation of Construction Site Safety Supervisory System Based on the Internet of Things." Applied Mechanics and Materials 241-244 (December 2012): 3190–94. http://dx.doi.org/10.4028/www.scientific.net/amm.241-244.3190.
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According to the present situation that China's construction site safety supervision of the development toward informatization, this essay put forward a kind of construction site safety supervisory system based on the internet of things through the introduction of wireless network. At first, combined with the requirements of government and industry, we have analyses the requirements of building construction site for safety supervision. Then combined with the difference between architecture construction site and industrial production safety supervision, referring to the existing industrial video safety supervision system, we put forward the structure of the construction site safety system based on the internet of things. At last, we have also analyses several problems about the contracture of network nodes which should be valued. Wireless network can be better adapted to the changing characteristics of construction site safety supervisory operation, and this will promote effectively the development of safety supervision toward the direction of informationization.
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Deja, Agnieszka, and Tygran Dzhuguryan. "Environmental Sustainable Waste Management for a City Multi-Floor Manufacturing Cluster." System Safety: Human - Technical Facility - Environment 1, no. 1 (March 1, 2019): 457–64. http://dx.doi.org/10.2478/czoto-2019-0059.
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AbstractA multi-floor manufacturing in residential districts of huge city promotes decongestion of urban traffic and satisfy the population’s demand for essential goods. City manufacturing and its supply chain entail several challenges related to the sustainable development of a large agglomeration. Environmental problems impose significant constraints on such manufacturing activities and production waste in the urban environment poses a real problem that needs to be addressed by special research. This paper discusses integrated sustainable production waste management for a city multi-floor manufacturing cluster, consisting of a group of production buildings and a supporting logistics node. In line with the theory of integrated sustainable waste management, three key components are addressed: waste management stakeholders, components of the waste management system, and the technical, environmental and legal aspects of a city multi-floor manufacturing cluster. The goal of the paper is to develop a concept for a model of environmental sustainable waste management in a city multi-floor manufacturing cluster, aimed at ensuring the system safety: human - technical facility - environment. This model can serve as a basis for the development of appropriate logistics chains for production waste management considering their hazardousness indicator. The versatility of the model will allow it to be widely used, and when its stages and working principles are embedded in the practice of city multi-floor manufacturing, proper control over the waste management process can be achieved. The application of the proposed model of integrated sustainable production waste management in the practice of the city multi-floor manufacturing clusters will contribute to the environmental sustainability of its operation.
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Song, Boming, Shen Zhang, Jia Long, and Qingsong Hu. "Fingerprinting Localization Method Based on TOA and Particle Filtering for Mines." Mathematical Problems in Engineering 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/3215978.
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Accurate target localization technology plays a very important role in ensuring mine safety production and higher production efficiency. The localization accuracy of a mine localization system is influenced by many factors. The most significant factor is the non-line of sight (NLOS) propagation error of the localization signal between the access point (AP) and the target node (Tag). In order to improve positioning accuracy, the NLOS error must be suppressed by an optimization algorithm. However, the traditional optimization algorithms are complex and exhibit poor optimization performance. To solve this problem, this paper proposes a new method for mine time of arrival (TOA) localization based on the idea of comprehensive optimization. The proposed method utilizes particle filtering to reduce the TOA data error, and the positioning results are further optimized with fingerprinting based on the Manhattan distance. This proposed method combines the advantages of particle filtering and fingerprinting localization. It reduces algorithm complexity and has better error suppression performance. The experimental results demonstrate that, as compared to the symmetric double-sided two-way ranging (SDS-TWR) method or received signal strength indication (RSSI) based fingerprinting method, the proposed method has a significantly improved localization performance, and the environment adaptability is enhanced.
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Zavala, Araceli, David Nowicki, and Jose Emmanuel Ramirez-Marquez. "Quantitative metrics to analyze supply chain resilience and associated costs." Proceedings of the Institution of Mechanical Engineers, Part O: Journal of Risk and Reliability 233, no. 2 (April 12, 2018): 186–99. http://dx.doi.org/10.1177/1748006x18766738.
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The growth of global supply chains has allowed trading partners to experience synergistic, economic expansion and increase their competitive success. At the same time, reliance on global supply chains exposes its trading partners to unforeseen disruptions. While the economic benefits are tremendous, they are not without risk as global supply chains are by their very nature susceptible to a wide array of disruptions. Methods that mitigate the effect of disruption directly contribute to the competitive success of global supply chain networks. One approach for mitigating the effects of disruption is to increase resilience. Thus, this research focuses on understanding supply chain vulnerability and how to return the supply chain to its desirable performance level after a disruptive event by reconfiguring the supply chain network. This article frames this foundational work in the context of systems theory to add to the body of resilience research by providing a time-dependent definition of supply chain resilience. This article then provides a mathematical model, based on inventory theory that operationalizes that definition. The model is presented in the context of a multi-echelon, post-production support network of a sustainment-dominated system such as those found in the aerospace, defense, utilities, and construction industries. The model demonstrates the post-disruption resilience at each supply chain network node along with the investment necessary to restore the network.
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Qin, Bo, Luyang Zhang, Heng Yin, and Yan Qin. "Multiple Feature Vectors Based Fault Classification for WSN Integrated Bearing of Rolling Mill." Journal of Control Science and Engineering 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/3041591.
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For rolling mill machines, the operation status of bearing has a close relationship with process safety and production effectiveness. Therefore, reliable fault diagnosis and classification are indispensable. Traditional methods always characterize fault feature using a single fault vector, which may fail to reveal whole fault influences caused by complex process disturbances. Besides, it may also lead to poor fault classification accuracy. To solve the above-mentioned problems, a fault extraction method is put forward to extract multiple feature vectors and then a classification model is developed. First, to collect sufficient data, a data acquisition system based on wireless sensor network is constructed to replace the traditional wired system which may bring dangers during production. Second, the measured signal is filtered by a morphological average filtering algorithm to remove process noise and then the empirical mode decomposition method is applied to extract the intrinsic mode function (IMF) which contains the fault information. On the basis of the IMFs, a time domain index (energy) and a frequency index (singular values) are proposed through Hilbert envelope analysis. From the above analysis, the energy index and the singular value matrix are used for fault classification modeling based on the enhanced extreme learning machine (ELM), which is optimized by the bat algorithm to adjust the input weights and threshold of hidden layer node. In comparison with the fault classification methods based on SVM and ELM, the experimental results show that the proposed method has higher classification accuracy and better generalization ability.
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Van Rhee, Frits, Marcelo Capra, Raymond Wong, Jessica Vermeulen, Karim Safer, Marija Todorovic, Patricia Rhoten, and Helgi Van De Velde. "Recruitment in a randomized, double-blind, placebo-controlled study to assess siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in patients with multicentric Castleman’s disease." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS8117. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps8117.
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TPS8117 Background: Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder in which dysregulated production of interleukin (IL)-6 results in lymph node enlargement and debilitating symptoms, including systemic inflammatory manifestations (eg, fever, fatigue, weight loss), autoimmune phenomena, and markedly abnormal laboratory findings (eg, anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis, increases in acute-phase proteins such as CRP, ESR, fibrinogen). There is currently no approved systemic treatment for MCD in the US or EU. Siltuximab (CNTO 328) is a chimeric mAb with high affinity for soluble IL-6. In a previous phase 1 study, high objective tumor response rate (64%) has been observed in patients with MCD (van Rhee F et al. Blood 2008;112:1008), and the long-term safety profile looks favourable (Kurzrock R et al. Blood 2011;118:3959). These results have prompted a randomized, double-blind, placebo-controlled study to definitively assess the efficacy and safety of siltuximab in combination with best supportive care (BSC) compared with BSC in patients with MCD. Methods: Eligibility includes HIV- and HHV-8-negative, symptomatic, measurable MCD patients. Patients with prior lymphoma or prior exposure to treatment targeting IL-6 or its receptor are excluded. Patients can be enrolled when receiving stable doses of corticosteroids (<1 mg/kg/d of prednisone or equivalent). Patients will be randomized in a 1:2 ratio to placebo + BSC or to 11 mg/kg siltuximab + BSC and will receive siltuximab/placebo in a 1-hour IV infusion every 3 weeks. The primary objective is to evaluate durable tumor and symptomatic response in the intent-to-treat population. Secondary objectives include additional efficacy measures, safety, patient reported outcomes, and pharmacologic assessment. Status: 67/78 patients have been randomly assigned. This is the first randomized, placebo-controlled study to be conducted in MCD. The rarity of the disease has posed unique challenges, and various enrollment strategies have been successfully implemented, with projected completion of enrollment in March 2012.
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Adeleke, Najeem, Mku T. Ityokumbul, and Michael Adewumi. "Blockage Detection and Characterization in Natural Gas Pipelines by Transient Pressure-Wave Reflection Analysis." SPE Journal 18, no. 02 (December 28, 2012): 355–65. http://dx.doi.org/10.2118/160926-pa.
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Summary Pipeline blockage is a major problem in gas production and transportation processes. Safety and economic costs of pipeline blockages are compelling the industry to design innovative means for early detection of partial blockages along pipe systems as a preventive measure. This paper presents a simple numerical model to be used for accurate blockage characterization in natural gas pipelines. The transport phenomenon is modeled with a quasi-1D set of partial differential equations for isothermal natural gas flow in pipes. The variable area formulation maintains the simplicity of a 1D formulation and yet allows for the complex geometries associated with natural gas pipeline blockages. Viscous effects are also included in the formulation of the governing equations, and a cubic equation of state is incorporated into the model to provide the quasi-compositional effect of real gases without the complexities of a fully compositional model. The generalized Newton-Raphson technique is used to solve the piece-wise finite-volume formulation iteratively as an optimization problem with pressure and velocity as perturbed variables. Reflected pressure waves observed at the pipe inlet node were analyzed for blockage characterization. It was observed that viscous losses have no effect on blockage length and location prediction accuracy, but has significant impact on the accuracy of blockage severity predictions.
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Yadav, Ashok Kumar. "Paclobutrazol Boost up for Fruit Production: A review." Research International Journal of Energy & Environmental Sciences 01, no. 01 (2020): 019–31. http://dx.doi.org/10.37179/rijees.000005.
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Paclobutrazol (PBZ), a triazole derivative, has been effectively used to induce and manipulate flowering, fruiting, and tree vigor in several perennial fruit crops. Soil application of paclobutrazol has been efefficacious in promoting lowering and increasing yield in many fruit crops. However, there are some conlicting reports on its impact on fruit quality parameters. Besides reducing gibberellins level, PBZ increases cytokinin contents, root activity and C: N ratio, whereas its inluence on nutrient uptake lacks consistency. The ability of the crops to produce fruits throughout the year is of great interest in recent years. Usually, it is applied as a soil application in the month of September-November in the case of mango. It inhibits gibberellins biosynthesis at the kaurene stage and has proved to be a reduction of vegetative growth, promising for lower initiation in shoot bud, giving early and profuse lowering, increases fruit yield and improving quality regularly in alternate bearing cultivars. The main aim of this review is to focus upon contemporary information about paclobutrazol in fruit production. The persistence of culture in orchard soil for a long time and its half-life varies with soil type and climatic conditions, which may severely affect the development of subsequent crops and moved rapidly between the shoot tips and basal nodes both in the acropetal and basipetal directions and persisted for several months. The potential of PBZ to contaminate groundwater at optimum concentrations is low however the risk of its exposure to aquatic life is high. PBZ is considered moderately hazardous for human beings with remote chance of being genotoxic and carcinogenic. In view of the above, optimized use of the PBZ to derive maximum beneit with the least undesirable impact on food and environmental safety aspects are suggested.
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Tessanne, K., J. Yao, K. Cornetta, M. Westhusin, T. Spencer, and C. Long. "434 REPLICATION COMPETENT LENTIVIRUS (RCL) ANALYSIS IN RECIPIENT ANIMALS OF TRANSGENIC EMBRYOS PRODUCED BY LENTIVIRAL TRANSFER." Reproduction, Fertility and Development 22, no. 1 (2010): 374. http://dx.doi.org/10.1071/rdv22n1ab434.
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Lentiviral vectors have become a useful tool for gene therapies and the expression of small hairpin (sh)RNAs to target genes both in vitro and in vivo. This is due primarily to their ability to integrate transgenes into both dividing and nondividing cells, as well as the lack of silencing in the germ cell line. However, the retroviral basis for these recombinant, replication-incompetent viruses has prompted investigation into their safety for use in therapeutics and transgenic animal production. Concerns are that recombination with wild-type viruses or endogenous retroviral elements may allow the integrated provirus genome to become replication competent. In order to investigate this, transgenic embryos produced by lentiviral-mediated gene transfer were transferred into recipient animals. The lentiviral plasmids used in this experiment contained a self-inactivating 3′ untranslated region as well as a green fluorescent protein (GFP) reporter gene (Miyoshi et al. 1998 J.Virol. 72, 8150-8157). Recombinant lentivirus was produced through cotransfection of HEK293T cells with the lentiviral transfer plasmid as well as a packaging plasmid and a plasmid encoding the vesicular stomatitis virus glycoprotein (VSV-G), which was used to pseudotype viral particles. Two methods were used for production of transgenic embryos. The first was lentiviral transduction of bovine fetal fibroblasts followed by somatic cell nuclear transfer. The second was incubation of IVP hatched ovine blastocysts in culture medium containing infectious recombinant lentiviral particles. Recipients were then sacrificed and analyzed for the presence of replication competent lentivirus (RCL). Tissues collected from each recipient included blood, lung, lymph node, kidney, liver, mammary gland, ovary, skeletal muscle, spleen, and uterus. In addition, when available, fetal and placental samples were collected. Analyses for RCL included a serum ELISA test for presence of the p24 HIV antigen as well as real-time quantitative PCR (qRT-PCR) on genomic DNA for the presence of VSV-G. To date, a total of 13 recipients including both sheep and cattle have been analyzed. All animals had p24 titers below the level of detection for the assay (<12.5 pg mL-1). Additionally, the tissues mentioned above have been analyzed by qRT-PCR for 6 of the 13 recipients so far, and all have been negative for VSV-G as determined by comparison with positive and negative control samples. Additional collections and analysis are ongoing. A lack of detection of RCL in these animals will build confidence in the use of lentiviral vectors in transgenic animal production and will lend support for their safety in both animal and human therapies.
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Schmidt, Manuel, Javier de Christobal, Nicole Hagner, Astrid Sander, Alberto Marco, Sven A. Koenig-Merediz, and Burghardt Wittig. "Potent Phosphorodiester-Based DNA Immunomodulators (dSLIM) Exhibit Enhanced Safety Compared to Phosphorothioate-Based Oligonucleotides." Blood 106, no. 11 (November 16, 2005): 3915. http://dx.doi.org/10.1182/blood.v106.11.3915.3915.
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Abstract Linear, single-stranded oligonucleotides (ODN) with non-methylated cytosine-guanine (CpG) motifs are immunomodulatory since they resemble bacterial DNA and serve as “danger signals”. These CpG-ODNs promote predominately a TH1-response, with secretion of IL-12 and IFN-γ, and B-cell, natural killer (NK)-cell and dendritic cell (DC) activation and have a broad potential as therapeutic agents, i.e. for cancer gene therapy and for the treatment of allergic diseases. Distinct groups of CpG-ODNs were characterized differing in structure and function: one group promotes B-cell proliferation, monocyte stimulation and secretion of IgM and IL-6; another activates plasmacytoid DC to produce IFN-α/-β and thus γδT-cells and NK-cells to express CD69 and secrete IFN-γ. And a third group exhibits combined properties of stimulating IL-6 and IgM secretion from B cells as well as IFN-α production from pDCs. Phosphorothioate (PS) modifications, usually introduced to enhance stability, result in several side-effects, like prolongation of the blood clotting time, non-specific binding to various proteins and acute toxicities in primates. In addition, a recent publication showed severe side-effect like significant organ enlargements and morphological changes in mice [Heikenwalder et al., Nat Med. 10:187, 2004]. We generated short covalently-closed dumbbell-like structures (dSLIM) to stabilize the DNA without the otherwise necessary PS-modification. Moreover, the covalently closed constructs do not signal for apoptosis, as high intracellular concentrations of open DNA ends would do. These dSLIM molecules are stable in serum and during long-term storage regarding both DNA integrity and biological function. Their broad activity, like increasing surface expression of CD80/B7.1, CD40, HLA-DR/MHC-II and CD54/ICAM-1 and enhancing production of a wide range of cytokines (IL-6, IFN-α, IFN-γ, IL-12, IL-2), was strictly dependent on molecule structure and size. Increasing or decreasing of stem size lead to reduced potency of the dumbbell-shaped dSLIM molecule. This was observed for a decreased size of the loops as well. But the most intriguing result was the significantly reduced toxicity of dSLIM compared to PS-ODN: After repeated injection of dSLIM or PS-ODN, respectively, into mice the mice receiving PS-ODN developed enlargement of liver, spleen and lymph nodes whereas dSLIM did not induce such changes. In addition, damage of liver and spleen - such as necrotic hepatocytes or hyperplasia - was observed in PS-ODN treated but not in dSLIM treated mice. Nevertheless, both dSLIM and PS-ODN induced a comparable IL-12 production in these mice in vivo. The significant differences of side-effect were true for PS-ODN and dSLIM molecules with various nucleotide sequences. In conclusion, we present the new class of potent immunomodulators (dSLIM) with significantly reduced side-effects.
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Maxwell, Gavin, and Cameron MacKay. "Application of a Systems Biology Approach to Skin Allergy Risk Assessment." Alternatives to Laboratory Animals 36, no. 5 (November 2008): 521–56. http://dx.doi.org/10.1177/026119290803600510.
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We have developed an in silico model of the induction of skin sensitisation, in order to characterise and quantify the contribution of each pathway to the overall biological process. This analysis has been used to guide our research on skin sensitisation and in vitro test development programmes, and provides a theoretical rationale for the interpretation and integration of non-animal predictive data for risk assessment (RA) purposes. The in vivo mouse Local Lymph Node Assay (LLNA) is now in widespread use for the evaluation of skin sensitisation potential and potency. Recent changes in European Union (EU) legislation (i.e. the 7th Amendment to the EU Cosmetics Directive) have made the development of non-animal approaches to provide the data for skin sensitisation RA a key business need. Several in vitro predictive assays have already been developed for the prediction of skin sensitisation. However, these are based on the determination of a small number of pathways within the overall biological process, and our understanding of the relative contribution of these individual pathways to skin sensitisation induction is limited. To address this knowledge gap, a “systems biology” approach has been used to construct a computer-based mathematical model of the induction of skin sensitisation, in collaboration with Entelos, Inc. The biological mechanisms underlying the induction phase of skin sensitisation are represented by nonlinear ordinary differential equations and defined by using information from over 500 published papers. By using the model, we have identified knowledge gaps for future investigative research, and key factors that have a major influence on the induction of skin sensitisation (e.g. TNF-α production in the epidermis). The relative contribution of each of these key pathways has been assessed by determining their contributions to the overall process (e.g. sensitiser-specific T-cell proliferation in the draining lymph node). This information provides a biologically-relevant rationale for the interpretation and potential integration of diverse types of non-animal predictive data. Consequently, the Skin Sensitisation Physiolab® (SSP) platform represents one approach to integration that is likely to prove an invaluable tool for hazard evaluation in a new framework for consumer safety RA.
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Qi, Yan Jun. "Research on Mine Monitoring Technology Based on Internet of Things." Applied Mechanics and Materials 321-324 (June 2013): 767–70. http://dx.doi.org/10.4028/www.scientific.net/amm.321-324.767.
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In order to find out the status of unmanned area and staff position in mine, the important content for intelligent mine is the detection and location of personnel underground. Analyze the architecture of location system and location principle based on Internet of Things (IoTs) along with ZigBee wireless networks and pyroelectric sensor technology. In the meantime, Install test wireless network nodes and achieve measurement data. The results show that this technique is suitable for the worse physical conditions in mine, lower in cost, higher accuracy in location and detection. The scheme can greatly improve the level of coal mine safety production and reduce the occurrence of catastrophes and casualties.
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Zabłudowski, Łukasz, Beata Marciniak, Damian Ledziński, and Mirosław Maszewski. "Reliability in Low Emission Wireless Measurement Networks." Solid State Phenomena 237 (August 2015): 107–11. http://dx.doi.org/10.4028/www.scientific.net/ssp.237.107.
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Wireless sensor networks called WSN’s increasingly find their wide application in various distributed measurement systems. Currently, many manufacturers focus on implementation of these devices in energy meters. In addition these devices are increasingly being considered as a system that do not carry big financial effort to be implement as a measuring systems of key safety parameters in production environments. Such environments are becoming an important element to ensure reliable transmission between measuring devices broadcasting. Another challenge in the systems under consideration is to provide low emissivity in the network. The low emissivity provides less interference between operating devices. This premise has an important effect on networks with large numbers of nodes.
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Alexandrova, Elena, Maria Poltavtseva, and Anastasia Yarmak. "Application of hierarchic authentication to isogenies of elliptic curves for providing safety of data routing in the systems of analysis of digital production traffic." SHS Web of Conferences 44 (2018): 00007. http://dx.doi.org/10.1051/shsconf/20184400007.
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The article discusses the peculiarities of the process of information routing in the course of acquisition and processing big data of digital production, including systems of traffic analysis. Such a specific features variability of physical nodes-processors with the retention of functional stringency of order of information processing is distinguished. Inordertoprovidesafetyofthedescribedprocessofinformationprocessingand possibility of restoration of a chain of processing every fragment of data, the authors offer a protocol of hierarchic authentication developed thereby on isogenies of elliptic curves. The work includes algorithms of shaping parameters, generation of keys, generation and checking signature. The evaluation of signature stability again basic types of attacks has been performed. A solution offered by the authors can be used both in traditional and, in future, in quantum systems. A simulation of corresponding signature dimensions has been performed in the work.
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Zhang, Shihong, Karan Kohli, R. Graeme Black, Brian Hayes, Cassandra Miller, Mari Maeda-Whitaker, Brett Schroeder, et al. "139 Establishment of canine CAR T cells treatment model for solid tumor immunotherapy development." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A152—A153. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0139.
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BackgroundChimeric antigen receptor (CAR) T cell therapy has transformed therapy for hematological malignancies but has not yet been established as standard of care for any solid tumors. One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant, immunocompetent animal models. In this study, we sought to establish CAR T cells for naturally occurring canine sarcomas in client owned animals as a model for human CAR T cell therapy.MethodsArchived FFPE, freshly isolated canine solid tumor samples as well as tumor lines were tested for B7H3 expression by immunohistochemistry (IHC) and flow cytometry analysis. We designed CARs using the scFv from the human B7H3-specific antibody MGA271 and confirmed the cross-reactivity to canine B7H3 (construct information see figure 1A). A truncated EGFR (tEGFR) was included in the construct to allow for IHC and flow cytometry testing for the presence of CAR T cells. Killing efficiency was evaluated using 3D tumor spheroid killing assays to monitor dynamics. Safety of the CAR products following lymphodepletion was confirmed in two healthy dogs (figure 1B).ResultsCanine solid tumors were confirmed to be B7H3 positive in almost all cases. Using the GALV-pseudotyped retrovirus system, transduction was efficient with up to 70% CAR+ cells. Post-transduction expansion was over 100 folds. B7H3 CAR transduced canine T cells were able to eliminate B7H3+ canine tumor spheroids effectively (figure 2). Safety of the CAR T cells (dose: 1 × 109/m2) were confirmed in both healthy animals following cyclophosphamide lymphodepletion. After week 6, cetuximab was given to the subjects to deplete EGFR+ cells. Subject 2 experienced fever after CAR T cell administration. Both dogs showed elevated serum ALP and ALT levels and returned to normal (figure 3). No other treatment-related adverse events were observed. Information of the CAR T cell products can be found in table 1.Abstract 139 Figure 1Construct information and safety trial design(A) Four 2nd generation CAR constructs were generated. Two B7H3 CARs were candidates for the treatment, and two HER2 CARs served as controls, as they have been shown to kill canine cancer cells. The CARs are consisted of a single chain variable fragment (scFv, either B7H3-specific MGA271 or HER2-specific FRP5), a short hinge, a transmembrane domain (tm), a canine costimulatory signaling domain (either canine CD28 or 4-1BB) and canine CD3? signaling domain. Truncated EGFR is added in the construct for CAR+ T cell detection and facilitate the depletion of CAR T cells in vivo as a safety measure. (B) Blood from the subjects were drawn 3 weeks prior to the treatment for CAR T cell production. Cyclophosphamide (Cy, 400 mg/m2) and Fludarabine (Flu, 10 mg/m2) were given to the subjects for 2 days for lymphodepletion. CAR T cells (1 × 109/m2) and cetuximab (200 mg/m2) were given to the subjects as indicated. Blood, lymph node (LN) and bone marrow (BM) aspirates were collected for CAR T cell homing and persistence analysisAbstract 139 Figure 2Killing of canine OSA spheroids by canine CAR T ce(A) Scheme of tumor cell spheroid forming and killing. The loss of GFP can be measured for cytotoxicity readout (B) FRP5 and MGA271 CAR T cells can effectively kill canine cancer spheroids. Experiments were done in triplicates and error bars indicate SDAbstract 139 Figure 3Dynamics of peripheral lymphocytes, serum ALP and Current treatment regimen effectively decreased peripheral lymphocytes number after cyclophosphamide and fludarabine administration (D-4 and D-3) and increased serum ALP and ALT level after CAR T cell infusion (D0). Dashed line in both graphs show the upper limit of ALP and ALT levels, which are both 68U/LAbstract 139 Table 1Infused CAR T cell product informationBoth subjects are adult male beagle mixConclusionsWe demonstrated that, similar to human cancers, B7H3 is a target in canine solid tumors. We successfully generated canine B7H3 specific CAR T cell products that are highly efficient at killing canine 3D tumor spheroids using a production protocol that closely models human CAR T cell production procedure and confirmed the safety in vivo. We plan to test and optimize various approaches to enhance CAR T cell efficacy for solid tumor treatment both in vitro and in canine sarcoma patients.Ethics ApprovalThe study was approved by Fred Hutchinson Cancer Research Center‘s Institutional Animal Care and Use Committee (IACUC), approval number PROTO201900860
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Dorr, Paul M., Daniel A. Tadesse, Bayleyegn Molla Zewde, Pamela Fry, Siddhartha Thakur, and Wondwossen A. Gebreyes. "Longitudinal Study of Salmonella Dispersion and the Role of Environmental Contamination in Commercial Swine Production Systems." Applied and Environmental Microbiology 75, no. 6 (January 9, 2009): 1478–86. http://dx.doi.org/10.1128/aem.01632-08.
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ABSTRACT This study investigated the roles of various environmental sources, such as truck-washing systems, waste-processing lagoons, and other sources, as potential contributors to the exposure and dissemination of Salmonella in commercial swine production systems. Four cohorts of nursery age swine herds which originated from distinct farm flows were selected. In addition, cross-sectional sampling of four truck wash stations selected based on the types of disinfectants and sources of water used for sanitizing trucks were tested. Salmonella isolates were recovered from pigs (feces, cecal contents, and mesenteric lymph nodes) and environmental sources (barn floor, lagoon, barn flush, trucks, and holding pens). Antimicrobial susceptibility testing and genotyping were conducted using Kirby-Bauer disk diffusion and amplified fragment length polymorphism, respectively. Salmonella prevalence significantly increased with age from late nursery to slaughter for all of the cohorts (P = 0.007). In two of three instances, all three pig holding pens (lairage) sampled at processing were Salmonella positive. The predominant antibiotypes for all sources included ACSSuT (51.8%), SSuT (16.8%), T (6%), and pansusceptible (7.4%). For the isolates obtained at the farms, the ACSSuT phenotype was 5.6 times more likely to be found in the animals than in the environment (95% confidence interval, 4.4 to 7.2 times). Serogroup B was the most common serogroup (79%), followed by serogroup E (10.4%). Despite the fact that the four production flows were independent, 1 of the 11 genotypic clusters (cluster A1) was commonly detected in any type of sample regardless of its origin. Five of the genotypic clusters (clusters A3, A4, A5, A6, and A7) contained isolates that originated from trucks and lairage swabs and also from cecal contents and/or mesenteric lymph nodes. More interestingly, genotypic clusters A3, A4, and A6 (but not clusters A5 and A7) were not detected on the farms. They originated from the trucks and lairage swabs and then were identified from the cecal contents and/or mesenteric lymph nodes. These findings underscore the significance of various environmental factors, including inadequate truck-washing systems, and emphasize the role of lairage contamination by Salmonella that has food safety significance.
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Sonpavde, Guru, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen E. Gschwend, Michiel Simon Van Der Heijden, Nathalie Garzon, et al. "A phase 3 randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± BMS-986205 in cisplatin-eligible muscle invasive bladder cancer (MIBC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS4587. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps4587.
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TPS4587 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible MIBC, the recommended tx regimen is cisplatin-based NAC prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, suggesting that the PD-1/PD-L1 axis is a valid therapeutic target. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. BMS-986205, a selective, potent, once-daily oral IDO1 inhibitor that works early in the IDO1 pathway to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + BMS-986205 in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± BMS-986205 followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + BMS-986205 (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320.
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Sonpavde, Guru, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen Gschwend, Michiel Simon Van Der Heijden, Audrey Richiero, et al. "A phase III randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± linrodostat mesylate, followed by adjuvant postsurgical NIVO ± linrodostat, in cisplatin-eligible muscle invasive bladder cancer (MIBC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS5091. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps5091.
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TPS5091 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible, muscle invasive BC (MIBC), the recommended tx is cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, supporting the therapeutic pursuit of the PD-1/PD-L1 axis. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. Linrodostat mesylate, a selective, potent, once-daily oral IDO1 inhibitor that works to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + linrodostat in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± linrodostat followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + linrodostat (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320 .
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Depypere, Lieven P., Niccolò Daddi, Michael R. Gooseman, Hasan F. Batirel, and Alessandro Brunelli. "The impact of coronavirus disease 2019 on the practice of thoracic oncology surgery: a survey of members of the European Society of Thoracic Surgeons (ESTS)." European Journal of Cardio-Thoracic Surgery 58, no. 4 (August 30, 2020): 752–62. http://dx.doi.org/10.1093/ejcts/ezaa284.
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Abstract OBJECTIVES There is widespread acknowledgement that coronavirus disease 2019 (COVID-19) has disrupted surgical services. The European Society of Thoracic Surgeons (ESTS) sent out a survey to assess what impact the COVID-19 pandemic has had on the practice of thoracic oncology surgery. METHODS All ESTS members were invited (13–20 April 2020) to complete an online questionnaire of 26 questions, designed by the ESTS learning affairs committee. RESULTS The response rate was 23.0% and the completeness rate was 91.2%. The number of treated COVID-positive cases per hospital varied from fewer than 20 cases (30.6%) to more than 200 cases (22.7%) per hospital. Most hospitals (89.1%) postponed surgical procedures. All hospitals performed patient screening with a nasopharyngeal swab, but only 6.7% routinely tested health care workers. A total of 20% of respondents reported that multidisciplinary meetings were completely cancelled and 66%, that multidisciplinary decisions were not different from normal practice. Trends were recognized in prioritizing surgical patients based on age (younger than 70), type of surgery (lobectomy or less), size of tumour (T1–2) and lymph node involvement (N1). Sixty-three percent of respondents reported that surgeons were involved in daily care of COVID-19-positive patients. Fifty-three percent mentioned that full personal protective equipment was available to them when treating a COVID-19-positive patient. CONCLUSIONS The COVID-19 pandemic has created issues for the safety of health care workers, and surgeons have been forced to change their routine practice. However, there was no consensus about surgical priorities in lung cancer patients, demonstrating the need for the production of specific guidelines.
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Tukhvatulin, Amir, Alina Dzharullaeva, Alina Erokhova, Anastasia Zemskaya, Maxim Balyasin, Tatiana Ozharovskaia, Olga Zubkova, et al. "Adjuvantation of an Influenza Hemagglutinin Antigen with TLR4 and NOD2 Agonists Encapsulated in Poly(D,L-Lactide-Co-Glycolide) Nanoparticles Enhances Immunogenicity and Protection against Lethal Influenza Virus Infection in Mice." Vaccines 8, no. 3 (September 10, 2020): 519. http://dx.doi.org/10.3390/vaccines8030519.
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Along with their excellent safety profiles, subunit vaccines are typically characterized by much weaker immunogenicity and protection efficacy compared to whole-pathogen vaccines. Here, we present an approach aimed at bridging this disadvantage that is based on synergistic collaboration between pattern-recognition receptors (PRRs) belonging to different families. We prepared a model subunit vaccine formulation using an influenza hemagglutinin antigen incorporated into poly-(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles adjuvanted with monophosphoryl lipid A (TLR4 agonist) and muramyl dipeptide (NOD2 agonist). The efficacy studies were conducted in comparison to control vaccine formulations containing individual PRR agonists. We show that the complex adjuvant based on TLR4 and NOD2 agonists potentiates proinflammatory cell responses (measured by activity of transcription factors and cytokine production both in vitro and in vivo) and enhances the phagocytosis of vaccine particles up to comparable levels of influenza virus uptake. Finally, mice immunized with vaccine nanoparticles containing both PRR agonists exhibited enhanced humoral (IgG, hemagglutination-inhibition antibody titers) and cellular (percentage of proliferating CD4+ T-cells, production of IFNɣ) immunity, leading to increased resistance to lethal influenza challenge. These results support the idea that complex adjuvants stimulating different PRRs may present a better alternative to individual PAMP-based adjuvants and could further narrow the gap between the efficacy of subunit versus whole-pathogen vaccines.
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Evseev, D. G., V. N. Filippov, G. I. Petrov, Yu N. Shebeko, and S. V. Bespalko. "ON A NESSECITY OF A CREATION OF A UNITED TECHNICAL POLICY IN THE AREA OF A FIRE SAFETY ENSURING OF A TRANSPORTATION OF HAZARDOUS GOODS ON RUSSIAN RAILWAYS." Pozharovzryvobezopasnost/Fire and Explosion Safety 27, no. 9 (October 19, 2018): 26–34. http://dx.doi.org/10.18322/pvb.2018.27.09.26-34.
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Introduction. The work is devoted to the results of many years of research to ensure the fire and explosion safety of tanks for liquefied petroleum gases, conducted by the Moscow state University of Railways (MIIT), together with other organizations.Methods. On the basis of statistical data, the main scenarios of emergency situations were determined.Experimental and theoretical studies of the behavior of tanks under emergency conditions associated with dynamic and thermal effects were carried out. Numerous experiments were carried out both on full-scale samples and on models using the theory of similarity. The results of the ex¬periments are used both for verification of theoretical models and for specification of parameters of the calculation schemes.The mathematical models developed in the framework of theoretical research were implemented in the form of a package of computer programs and used later to select the parameters of the means of protection.Results. In terms of protection against thermal effects, the following were proposed: safety valves, fire-retardant coatings, upgraded versions of control, drain and safety valves using design solutions adopted in nuclear engineering. In particular, the use of fire-resistant coatings SGKprovides an increase of 2.5-3.5 times the time of the accident-free stay of the tank in the fire.A new layout of the drain-filling pipes is recommended, which significantly reduces the proba¬bility of breakage of the elements of the drain-filling fittings. The design of safety arcs and nodes for connection of arc elements with the shell is proposed.Conclusion. On the basis of the whole complex of the conducted researches the family of tanks for the transportation of liquefied hydrocarbon gases was developed, the production of which was carried out at the enterprises of Russia, Ukraine, Japan, Poland.However, there is a problem of contradictions in the regulatory documentation on the issues of fire and explosion safety of tanks, which requires the formation of a unified technical policy in this area.
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Prudencio, Tomas M., Luther M. Swift, Devon Guerrelli, Blake Cooper, Marissa Reilly, Nina Ciccarelli, Jiansong Sheng, Rafael Jaimes, and Nikki Gillum Posnack. "Bisphenol S and Bisphenol F Are Less Disruptive to Cardiac Electrophysiology, as Compared With Bisphenol A." Toxicological Sciences 183, no. 1 (July 8, 2021): 214–26. http://dx.doi.org/10.1093/toxsci/kfab083.
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Abstract Bisphenol A (BPA) is a high-production volume chemical used to manufacture consumer and medical-grade plastic products. Due to its ubiquity, the general population can incur daily environmental exposure to BPA, whereas heightened exposure has been reported in intensive care patients and industrial workers. Due to health concerns, structural analogs are being explored as replacements for BPA. This study aimed to examine the direct effects of BPA on cardiac electrophysiology compared with recently developed alternatives, including BPS (bisphenol S) and BPF (bisphenol F). Whole-cell voltage-clamp recordings were performed on cell lines transfected to express the voltage-gated sodium channel (Nav1.5), L-type voltage-gated calcium channel (Cav1.2), or the rapidly activating delayed rectifier potassium channel (hERG). Cardiac electrophysiology parameters were measured using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and intact, whole rat heart preparations. BPA was the most potent inhibitor of fast/peak (INa-P) and late (INa-L) sodium channel (IC50 = 55.3, 23.6 µM, respectively), L-type calcium channel (IC50 = 30.8 µM), and hERG channel current (IC50 = 127 µM). Inhibitory effects on L-type calcium channels were supported by microelectrode array recordings, which revealed a shortening of the extracellular field potential (akin to QT interval). BPA and BPF exposures slowed atrioventricular (AV) conduction and increased AV node refractoriness in isolated rat heart preparations, in a dose-dependent manner (BPA: +9.2% 0.001 µM, +95.7% 100 µM; BPF: +20.7% 100 µM). BPS did not alter any of the cardiac electrophysiology parameters tested. Results of this study demonstrate that BPA and BPF exert an immediate inhibitory effect on cardiac ion channels, whereas BPS is markedly less potent. Additional studies are necessary to fully elucidate the safety profile of bisphenol analogs on the heart.
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Liashenko, Vasilii, and Vsevolod Franchuk. "Improving the efficiency and safety of hardening filling mixtures pipeline transport to deep mines." Izvestiya vysshikh uchebnykh zavedenii. Gornyi zhurnal, no. 1 (February 17, 2021): 15–26. http://dx.doi.org/10.21440/0536-1028-2021-1-15-26.
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Relevance. Extraction of mineral raw materials has a negative impact on the natural environment. This effect is neutralized through technologies for mineral extraction using various options for development systems with worked-out spaces filling with hardening filling mixtures of various composition and strength. However, their application is complicated by hardening filling mixtures transportation through the pipeline over considerable distances vertically and horizontally to the point of placement, increased material and labor costs, and a shortage of material for preparing mixtures. Research aim is to improve the efficiency and safety of hardening backfill mixtures pipeline transportation into deep mines by determining the main parameters of hardening backfill mixture pipeline transportation installations (PTI), based on the conditions of its reliable delivery to the point of placement at minimal costs. Research methodology included literature review, the methods of theoretical generalizations using mathematical statistics, physical and mathematical modeling, calculations and feasibility studies, laboratory and field experimental studies, and industrial tests in deep mines using standard and new methods. Results. New USD-1 equipment has been developed and put into production for hardening filling mixtures delivery to deep mines; the equipment ensures overpressure reduction in the pipeline installed in the rise heading of 895–825 m floor in the Novaya-Glubokaya mine, Zheltye Vody, Ukraine. Conclusions. The recommended value of the maximum length of the pipeline between the reloading nodes is within the range of 415–508 m, and the excess of the emergency unloading point above the horizon is 11 m. In the last section of the vertical pipeline (turning into horizontal), a length is selected that ensures normal transportation of the mixture. The efficiency of hardening backfill mixture transportation has been established, which increases due to the elimination of stratification in the horizontal section of the pipeline under the condition of vmin <v <vmax, where v, vmin, vmax are mixture velocities corresponding to the steady design mode of transportation, the presence of solid aggregate particles at the limit in the weighted condition and maximum filling level of the filling pipeline vertical column.
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Rehni, Ashish, Vibha Shukla, Hever Navarro-Quero, Carlos Bidot, Conner Haase, Anise Crane, Shivam Patel, et al. "Preclinical Evaluation of Safety and Biodistribution of Red Cell Microparticles (RMP): A Novel Hemostatic Agent." Blood 132, Supplement 1 (November 29, 2018): 1044. http://dx.doi.org/10.1182/blood-2018-99-116508.
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Abstract BACKGROUND: Uncontrollable bleeding is a major cause of mortality and morbidity worldwide. Effective hemostatic agents are urgently needed. Red cell microparticles (RMP) have been introduced as a promising new hemostatic agent [Thromb Haemost 2013, 110:751-60]. It acts to promote both primary (platelet function) and secondary (coagulation, thrombin generation) hemostasis, thus meeting the criteria for a universal hemostatic agent. However, although no overt adverse effects were observed in limited animal studies, more rigorous evaluation of safety as well as biodistribution of RMP were addressed in this report. METHODS: RMP were prepared from Type O+ human RBC by high-pressure extrusion. Male rats were treated with either a 1× dose (=6x1010 RMP/kg BW), or 4×, or 20× dose, then monitored for at least 60 min for physiological responses of blood pressure, body and head temperature, hematocrit, and blood gases. A group of RMP-treated rats (n =6) were perfused with saline followed by formaldehyde - acetic acid - methanol mixture (1:1:8) at 4 hr post-RMP. Heart, brain and lung were harvested, sectioned and evaluated in blinded fashion by independent animal pathologist for signs of thrombosis or other pathology. For biodistribution study, RMP were labeled with Alexa-488 and unbound dye was removed by dialysis. At 15 min and 24 hours after infusion of labeled RMP, animals were perfused with saline for 2 min to remove labeled RMP in blood vessels, then organs were harvested, homogenized and sonicated. Fluorescence of the homogenates was measured by a fluorescence plate reader. RESULTS: (i) Toxicity. No adverse effects of RMP were detected by monitoring the above physiological parameters at any of the 3 dose regimens. In addition, histological examination of brain, heart and lung sections by an animal pathologist revealed no microthrombi or other abnormality. (ii) Biodistribution. After injection of fluorescence-labeled RMP, levels of RMP in blood rose rapidly (1 min), then declined to baseline at 15 min, demonstrating rapid clearance. Fluorescence of tissue homogenates at 15 min revealed the highest fluorescence (FAU/g tissue) in liver, followed by spleen, lymph nodes, and lung. At 24 hr, fluorescence of the above-mentioned organs had decreased by 20 - 60%. Surprisingly, the organ of greatest fluorescent intensity at 24 hr had shifted to the kidneys, followed by liver, spleen, and lymph nodes. DISCUSSION. Results further support safety of RMP as hemostatic agent. This is unexpected in view of reports finding proinflammatory properties of RMP obtained from stored blood or by calcium ionophore. This apparent discrepancy may be explained by the high-pressure extrusion method of production, since preliminary experiments show absence of lipid rafts on these RMP compared to RMP prepared by other ways. Lipid rafts are implicated as inflammatory mediators. Our biodistribution data demonstrated that RMP were sequestered mainly by liver, spleen, lymph nodes, and lung at 15 min post-RMP infusion. Our results also suggest that at 24 hr post-RMP infusion, many sequestered RMP have been degraded, leading to redistribution of fluorescent label to the kidney. Disclosures Ahn: RxMP Therapeutics, Inc.: Consultancy, Equity Ownership, Patents & Royalties, Research Funding.
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Guo, X. Y., Guo Hua Qin, and Hai Chao Ye. "A Deterministic Method of Application Region of Clamping Forces for Fixture Design." Materials Science Forum 697-698 (September 2011): 345–48. http://dx.doi.org/10.4028/www.scientific.net/msf.697-698.345.
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After being located, cutting force and torques will exert on a workpiece during the machining operation. In order to guarantee the location accuracy and production safety, the feasible clamping forces must be planned to stabilize the workpiece in the entire processing. Therefore, the workpiece stability is taken as a core to create a deterministic algorithm to the application region of clamping forces for the complex workpiece. Firstly, on the basis of the combination of the screw theory with the linear programming technology, an analysis algorithm is subjected to judge the workpiece stability. Secondly, according to the surface discretization method, a deterministic algorithm is further established to plan the application region of clamping force by analyzing the workpiece stability at all nodes in sequence. The proposed method can be utilized for the determination of the application region of clamping forces as well as the verification of the feasibility of the magnitudes of clamping forces.
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Sônego, Fabiane, Gaelle Martin, Chloé Beuraud, Audrey Beringer, Yacine Cherifi, Alexandre Fraichard, Patricia Isnard-Petit, and Kader Thiam. "15 A novel CD28 humanized mouse model for efficacy assessment of CD28-targeting therapies." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A15. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0015.
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BackgroundImmuno-intervention through targeting of activating and inhibitory immune checkpoints (ICP), has shown promising results in the clinic over the last years. To facilitate these researches, mouse models expressing humanized ICP instead of their mouse counterparts were developed. Herein, we describe a novel CD28 humanized mouse model (hCD28 model), designed to test compounds targeting human CD28 (hCD28).MethodsHuman and mouse CD28 (mCD28) have different signalling responses, with hCD28 being known for inducing higher levels of pro-inflammatory cytokines upon stimulation with ligands/superagonists. This can be explained by the expression of CD28i, a hCD28 amplifier isoform which is not found in mouse. Additionally, evidences suggested that the different signalling between human and mCD28 relies on one amino acid change in the intracellular domain (ICD).1 Because the hCD28 model was developed to assess hCD28-targeting therapeutics, we decided to keep the expression of both canonical and CD28i isoforms to avoid undermining the biological effects of the testing antibodies. Although keeping the human ICD could favour the evaluation of cytokine production and therefore the safety of the test therapeutics, we decided to keep the mouse ICD to enable a proper interaction of CD28 with its signalling partners, allowing a physiological stimulation of CD28 in efficacy studies.Results hCD28 mice express hCD28 on T cells and the frequency of CD3 T cells is comparable in both WT and hCD28 mice. Stimulation of hCD28 mice-isolated T cells with hCD28 ligands and agonist antibodies resulted in T cell proliferation and cytokine production, suggesting that hCD28 is functional in mouse cells. MC38 uptake rate and kinetic of growth were comparable in WT and hCD28 mice, suggesting no major defect in the immune response in the hCD28 mice. Importantly, splenocytes and tumor draining lymph nodes cells isolated from tumor-bearing hCD28 mice showed higher production of IL-2 and IFN-gamma upon in vitro re-challenged with MC38 when compared to WT cells. Since the frequency of CD3 cells (Treg, CD4+ and CD8+) is comparable to WT mice, this could be explained by the expression of the amplifier CD28i isoform, which is absent in WT mice.ConclusionsThe hCD28 model described here supports the efficacy assessment of hCD28-targeting biologics, enabling PK/PD studies as hCD28 expression levels and pattern are physiological. However, after careful consideration of the CD28 biology, we decided to keep the mouse ICD, although it triggers lower pro-inflammatory cytokine production than CD28 human ICD. As such, this model is not suitable for toxicology/safety studies.ReferencePorciello N, Grazioli P, Campese AF, et al. A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nat Commun 2018; 9:1–16.
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Lu, Yunmeng, Tiantian Wang, and Tiezhong Liu. "Bayesian Network-Based Risk Analysis of Chemical Plant Explosion Accidents." International Journal of Environmental Research and Public Health 17, no. 15 (July 25, 2020): 5364. http://dx.doi.org/10.3390/ijerph17155364.
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The chemical industry has made great contributions to the national economy, but frequent chemical plant explosion accidents (CPEAs) have also caused heavy property losses and casualties, as the CPEA is the result of interaction of many related risk factors, leading to uncertainty in the evolution of the accident. To systematically excavate and analyze the underlying causes of accidents, this paper first integrates emergency elements in the frame of orbit intersection theory and proposes 14 nodes to represent the evolution path of the accident. Then, combined with historical data and expert experience, a Bayesian network (BN) model of CPEAs was established. Through scenario analysis and sensitivity analysis, the interaction between factors and the impact of the factors on accident consequences was evaluated. It is found that the direct factors have the most obvious influence on the accident consequences, and the unsafe conditions contribute more than the unsafe behaviors. Furthermore, considering the factor chain, the management factors, especially safety education and training, are the key link of the accident that affects unsafe behaviors and unsafe conditions. Moreover, effective government emergency response has played a more prominent role in controlling environmental pollution. In addition, the complex network relationship between elements is presented in a sensitivity index matrix, and we extracted three important risk transmission paths from it. The research provides support for enterprises to formulate comprehensive safety production management strategies and control key factors in the risk transmission path to reduce CPEA risks.
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Wang, Ning, Changlu Qiu, Minnan Chen, Ting Liu, and Ting Wang. "Covering Aluminum Oxide Nanoparticles with Biocompatible Materials to Efficiently Deliver Subunit Vaccines." Vaccines 7, no. 2 (June 17, 2019): 52. http://dx.doi.org/10.3390/vaccines7020052.
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Subunit vaccines have advantages of good safety, minimal reactogenicity, and high specificity. However, subunit vaccines also show a crucial disadvantage of poor immunogenicity and, therefore, are often formulated with an adjuvant carrier to form a vaccine adjuvant-delivery system (VADS) to enhance their efficacies. Alums, the coarse aggregates of the insoluble aluminum salts, are the conventional adjuvants and have been widely used in clinical vaccines for a long time. Unfortunately, alums also show two main drawbacks of low potency in eliciting cellular immunity, and high reactogenicity to cause unwanted inflammations. Therefore, herein the phospholipid bilayer-coated aluminum oxide nanoparticles (PLANs) and the PEGylated PLANs (PEG-PLANs) were engineered as a VADS to overcome the drawbacks of both subunit vaccines and coarse alums, while synergizing their functions. In vitro experiments demonstrated that, unlike the micron-sized alums, the nanosized PLANs and PEG-PLANs loaded with model antigen of ovalbumin (OVA) showed a high safety profile and were able to promote APC (antigen-presenting cell) uptake and engender lysosome escape for enhancing the MHC (major histocompatibility complex)-I-antigen display. Subcutaneously administered to mice, PLANs and, especially, PEG-PLANs smoothly trafficked into the draining lymph nodes, wherein the densely clustered immune cells were activated in substantial numbers, leading to robust immunoresponses and efficient production of the anti-antigen antibodies and CD8+ T cells. Thus, the aluminum-based nanocarriers, especially the PEG-PLANs, are a promising VADS possessing the potential of eliciting strong and comprehensive immunity against pathogens.
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Tan, Thong Teck, Ruenn Chai Lai, Jayanthi Padmanabhan, Wei Kian Sim, Andre Boon Hwa Choo, and Sai Kiang Lim. "Assessment of Tumorigenic Potential in Mesenchymal-Stem/Stromal-Cell-Derived Small Extracellular Vesicles (MSC-sEV)." Pharmaceuticals 14, no. 4 (April 9, 2021): 345. http://dx.doi.org/10.3390/ph14040345.
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Mesenchymal-stem/stromal-cell-derived small extracellular vesicles (MSC-sEV) have been shown to ameliorate many diseases in preclinical studies. However, translating MSC-sEV into clinical use requires the development of scalable manufacturing processes for highly reproducible preparations of safe and potent MSC-sEVs. A major source of variability in MSC-sEV preparations is EV producer cells. To circumvent variability in producer cells, clonal immortalized MSC lines as EV producer lines are increasingly being used for sEV production. The use of sEVs from immortalized producer cells inevitably raises safety concerns regarding the tumorigenicity or tumor promoting potential of the EV products. In this study, cells from E1-MYC line, a MSC cell line immortalized with the MYC gene, were injected subcutaneously into athymic nude mice. At 84 days post-injection, no tumor formation was observed at the injection site, lungs, or lymph nodes. E1-MYC cells pre-and post-sEV production did not exhibit anchorage-independent growth in soft agar. Daily intraperitoneal injections of 1 or 5 μg sEVs from E1-MYC into athymic nude mice with FaDu human head and neck cancer xenografts for 28 days did not promote or inhibit tumor growth relative to the xenograft treated with vehicle control. Therefore, MYC-immortalized MSCs are not tumorigenic and sEVs from these MSCs do not promote tumor growth.
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Casucci, Monica, Benedetta Nicolis di Robilant, Laura Falcone, Barbara Camisa, Margherita Norelli, Bernhard Gentner, Pietro Genovese, et al. "Off-Tumor Target Expression Levels Do Not Predict CAR-T Cell Killing: A Foundation For The Safety Of CD44v6-Targeted T Cells." Blood 122, no. 21 (November 15, 2013): 142. http://dx.doi.org/10.1182/blood.v122.21.142.142.
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Abstract Introduction Off-tumor expression of the target antigen raises justified safety concerns about newly designed chimeric antigen receptors (CARs). We have recently developed a CAR targeting the tumor-promoting antigen CD44v6 and demonstrated potent antitumor effects against acute myeloid leukemia (AML) and multiple myeloma (MM) both in vitro and in vivo. Despite promising activity against epithelial tumors, the administration of the CD44v6-specific mAb used for deriving our CAR (bivatuzumab) showed reversible myelosuppression and mucositis when conjugated with radioisotopes, and severe skin toxicity when conjugated with the potent cytotoxic drug mertansine. Preclinically evaluating the potential off-tumor toxicities of CD44v6-targeted T cells is therefore crucial before they can be safely translated to the clinic. Aim To profile the off-tumor expression of CD44v6 and to verify the susceptibility of expressing cells to CAR-T cell killing. Results Quantitative RT-PCR analysis on a wide panel of cDNA from normal tissues revealed restricted CD44v6 expression on flat stratified epithelia, like the skin, albeit at considerably lower levels compared with primary leukemic blasts. We therefore addressed the issue of keratinocyte recognition in co-culture experiments. Strikingly, at the E:T ratios allowing the potent antitumor effects of CD44v6-targeted T cells, keratinocytes were not killed and there was no cytokine production. Interestingly, comparative analysis of accessory molecules showed that, differently from leukemic blasts, keratinocytes expressed significant lower levels of adhesion/costimulatory molecules, including (ICAM-1, LFA-3 and B7.2), but higher levels of the critical checkpoint molecule PD-L1. Of the different cells of the hematopoietic system analyzed, only circulating CD14+ monocytes expressed CD44v6 and were killed by CD44v6-targeted T cells. Interestingly, by immunohistochemistry, we found no CD44v6 expression on bone-marrow monocytes, lymph-node macrophages, brain microglia, liver Kuppfer cells and dermal macrophages, suggesting a low risk for by-stander toxicity against these tissues. Moreover, CD44v6-targeted T cells did not interfere with the generation of virus-specific CTLs by antigen-specific stimulation in vitro. Importantly, both RT-qPCR and FACS demonstrated lack of CD44v6 expression on hematopoietic stem cells (HSCs) and progenitors. Accordingly, CD44v6-targeted T cells did not interfere with their clonogenic potential in vitro and, in co-culture experiments with whole bone marrow from MM patients, were able to selectively eliminate tumor cells, while sparing HSCs and progenitors. Finally, we tested the potential hematological toxicities of CD44v6-targeted T cells in NSG mice transgenic for human IL-3, SCF and GM-CSF (NSG-3GS). NSG-3GS mice transplanted with human CD34-selected cord blood cells showed enhanced myeloid reconstitution compared to NSG mice, including CD44v6+ monocytes. The infusion of CD44v6-targeted T cells in reconstituted NSG-3G mice resulted in the selective elimination of monocytes, but in the preservation of other cell subsets. Importantly, after in vivo exhaustion of CD44v6-targeted T cells, NSG-3G mice reconstituted monocytes de novo, indicating preservation of the HSC pool. For enabling rapid and conditional ablation of CD44v6-targeted T cells, we have finally co-expressed the CD44v6-CAR with TK or the inducible caspase-9 and validated the suicide gene approach in hyperacute xenogeneic GVHD surrogating maximal toxicity. Conclusions Our results indicate that off-tumor target expression levels do not automatically predict the susceptibility to CAR T-cell killing. Moreover they suggest that, differently from mAb-derived pharmaceuticals, therapeutic doses of suicidal CD44v6-targeted T cells might associate with acceptable and/or reversible toxicities. Disclosures: Bordignon: MolMed SpA: Employment.
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Holmes, Emma, Keith Kerr, Cihan Kadipasaoglu, and Nitin Tandon. "SURG-19. REORGANIZATION OF LANGUAGE ENABLES SAFE RESECTION OF TUMORS IN AND AROUND BROCA’S AREA." Neuro-Oncology 21, Supplement_6 (November 2019): vi243. http://dx.doi.org/10.1093/neuonc/noz175.1019.
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Abstract INTRODUCTION Since its discovery in the 1800s, Broca’s area has been viewed as a critical node for language production. Previously, pathologies in this area have been considered unresectable due to concern for producing iatrogenic language production deficits. Emerging literature suggests that although acute lesions in this area can cause widespread deficits, slow growing lesions are less correlated with these deficits due to cortical language reorganization. Based on this data, we managed a cohort with Broca’s area lesions with surgical resection using awake intra-operative language mapping. METHODS All 150 awake craniotomies performed by the senior author over a twelve-year period (2006–2017) at a single institution were reviewed. For each patient the imaging was carefully evaluated to localize the neoplasm relative to pars triangularis or pars opercularis in the language dominant hemisphere. Language dominance was confirmed using WADA testing or fMRI. All patients underwent cortical language mapping using a battery of tasks coupled with cortical stimulation. RESULTS A total of 31 surgeries in 29 patients (65.5% male, 86.2% righthanded) were identified. The average age was 41. Patients presented with seizures (64.5%), speech difficulties (35.5%) or headaches (19.4%). A gross or near total resection was achieved in 26/29 (89.7%) of patients. Pathological evaluation revealed grade 2 gliomas (8), grade 3 gliomas (13) and glioblastoma (9). Post-operatively, 8 (25.8%) patients had new or worsening speech deficits, all of which resolved to baseline at follow-up. CONCLUSION Broca’s area lesions can be safely resected in patients using an awake craniotomy technique with language mapping. In our series, the majority of patients had gross or near total resections, few patients had new deficits, and none had permanent new deficits. Considering the increasing evidence in favor of cytoreduction to manage glial neoplasms, this technique should be employed routinely for pathologies in this area to optimize patient outcomes.
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Mocchi, Michela, Stefano Grolli, Silvia Dotti, Dario Di Silvestre, Riccardo Villa, Priscilla Berni, Virna Conti, et al. "Equine Mesenchymal Stem/Stromal Cells Freeze-Dried Secretome (Lyosecretome) for the Treatment of Musculoskeletal Diseases: Production Process Validation and Batch Release Test for Clinical Use." Pharmaceuticals 14, no. 6 (June 10, 2021): 553. http://dx.doi.org/10.3390/ph14060553.
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In the last decades, it has been demonstrated that the regenerative therapeutic efficacy of mesenchymal stromal cells is primarily due to the secretion of soluble factors and extracellular vesicles, collectively known as secretome. In this context, our work described the preparation and characterization of a freeze-dried secretome (Lyosecretome) from adipose tissue-derived mesenchymal stromal cells for the therapy of equine musculoskeletal disorder. An intraarticular injectable pharmaceutical powder has been formulated, and the technological process has been validated in an authorized facility for veterinary clinical-use medicinal production. Critical parameters for quality control and batch release have been identified regarding (i) physicochemical properties; (ii) extracellular vesicle morphology, size distribution, and surface biomarker; (iii) protein and lipid content; (iv) requirements for injectable pharmaceutical dosage forms such as sterility, bacterial endotoxin, and Mycoplasma; and (v) in vitro potency tests, as anti-elastase activity and proliferative activity on musculoskeletal cell lines (tenocytes and chondrocytes) and mesenchymal stromal cells. Finally, proteins putatively responsible for the biological effects have been identified by Lyosecretome proteomic investigation: IL10RA, MXRA5, RARRES2, and ANXA1 modulate the inflammatory process RARRES2, NOD1, SERPINE1, and SERPINB9 with antibacterial activity. The work provides a proof-of-concept for the manufacturing of clinical-grade equine freeze-dried secretome, and prototypes are now available for safety and efficacy clinical trials in the treatment of equine musculoskeletal diseases