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1
Romanov, Vladimir S., and Valery G. Goldshtein. "To the question of damage, maintenance and repairs of submersible electric equipment for oil production." Vestnik of Samara State Technical University. Technical Sciences Series 28, no. 2 (July 27, 2020): 111–23. http://dx.doi.org/10.14498/tech.2020.2.8.
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In optimizing and managing the life cycles of submersible electrical equipment (SEE) for oil production, an integrated approach to the organization of maintenance and repairs (MRO) is advisable based on the development of a more advanced strategy for carrying out repair cycles. It is stated that the maintenance and repair strategies adopted by the oil industry do not fully ensure operational efficiency, which leads to an increase in premature equipment failures, a reduction in turnaround times and, as a result, losses for oil companies. The advantages and disadvantages of approaches to organizing the operation of SEE on the operating time and the actual state in the planning, implementation of maintenance and repair, as well as the feasibility of their complex application are evaluated. It is proposed to use statistical models to make an informed decision on determining the composition and period of MRO, forecasting the boundary states of sets in general and specific SEE electrical installations. At a given operating time, it is possible to determine the basic laws of the appearance of defects and the mean time between failures (MTBF) of the elements, as well as the fleet of equipment of oil-producing enterprises as a whole. The results obtained are the rationale for a set of recommendations to improve operational efficiency and optimize life cycle management of submersible electrical equipment for oil production.
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Islam, Md Shafiqul, Shayla Sharmin, and Jebunnesa Islam. "Multiple repair scenario of life cycle cost of RCC girder bridge using Markov chain model." Challenge Journal of Concrete Research Letters 10, no. 4 (December 21, 2019): 75. http://dx.doi.org/10.20528/cjcrl.2019.04.001.
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At present, many road authorities in the world face challenges in condition monitoring diagnosis of distress and forecasting deterioration, strengthening and convalescence of aging bridge structures. The accurate prediction of the future condition is crucial for optimizing the maintenance activities. It is very tough to predict the actual performance scenario or actual in–situ structures without carrying out inspection. Limited availability of detailed inspection data is considered as one of the major drawbacks in developing deterioration models. In State Based Markov deterioration (SNMD) modelling, the main job is to estimate transition probability matrixes (TPMs). In this paper, Markov Chain Monte Carlo (MCMC) is used to estimate TPMs. In Markov Chain Model, future conditions depend on only present bridge inspection data. Multiple repair options are adopted in order to optimize life cycle cost. Repairs are needed when the critical chloride concentration exceeds 0.2. Three distinct types of cost corresponding to each repair option is considered. The objective of this paper is to minimize the life cycle cost considering appropriate repair timings of mixed repair methods. Variation of life cycle cost of five different concretes (stronger to weaker) using three different repair option is shown in this paper. For specific normalized condition of concrete’s failure probability (0.3) and specific type of concrete, variation of life cycle cost using multiple repair options is also shown in this paper.
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Cardeal, Gonçalo, Kristina Höse, Inês Ribeiro, and Uwe Götze. "Sustainable Business Models–Canvas for Sustainability, Evaluation Method, and Their Application to Additive Manufacturing in Aircraft Maintenance." Sustainability 12, no. 21 (November 3, 2020): 9130. http://dx.doi.org/10.3390/su12219130.
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The topic of sustainable business models is growing in literature and in the industry, driving companies to search for opportunities to improve their impact on the three pillars of sustainability—profit, people, and planet (economic, social, and environmental). However, the process of developing sustainable business models is often complex, due to conflicting objectives from the three dimensions of sustainability. This paper presents a procedure model that supports the design and assessment of business models with a sustainable perspective, by integrating a new business model canvas for sustainability (BMCS) and an evaluation method to assess it. A comprehensive assessment is proposed, performed in a life cycle perspective. The proposed model is applied and validated with a real case study, based on a new business model for an aircraft maintenance, repair, and overhaul company. The case is based on shifting from traditional maintenance, repair, and overhaul activities to adopting additive manufacturing as an activity that allows manufacturing optimized spare parts with benefits for the costumer. The results show the application of the procedure model on a specific case study, as well as the potential of additive manufacturing as a driver for more sustainable business models in the aircraft maintenance sector.
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Tomasova, Kristyna, Michal Kroupa, Asta Forsti, Pavel Vodicka, and Ludmila Vodickova. "Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer." Mutagenesis 35, no. 3 (February 21, 2020): 261–71. http://dx.doi.org/10.1093/mutage/geaa005.
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Abstract Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.
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Apryshkin, A. S., and G. S. Khazanovich. "Determination of capacity and comfort indicators of a passenger elevator." SAFETY OF TECHNOGENIC AND NATURAL SYSTEMS, no. 1 (2021): 38–50. http://dx.doi.org/10.23947/2541-9129-2021-1-38-50.
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Introduction. Elevators are mass weight-handling units used by millions of residents of multi-storey buildings. Safety of elevator units and comfort of their use are determined not only by the correct choice of their design and parameters, but first of all, by the organization of the maintenance system. Each elevator is an individual unit that serves a residential building with a specific number of passengers, number of floors and other features. However, regulatory documents recommend standard maintenance plans. There is the need to establish the relationship between the loading modes of the main components and the optimal scheme of technical and repair works. The present work is devoted to the solution of this problem, along with the study of transport comfort. Problem Statement. The operation of the elevator in a residential building with a number of floors N occurs in separate cycles. Standing, lift call, and destination floors are random variables for which probabilistic characteristics must be reliably established. In general, the elevator operation mode includes three stages: calling to the passenger boarding level, moving with passengers to the destination level, and waiting for the next cycle. There are stops inside the movement stages. The specific problem of mathematical description of the random process of implementing the operating characteristics of the main drive of the elevator is reduced to two directions: 1) the development of mathematical models for the formation of the main indicators of the main elevator drive load during the cycle (net machine time τmi and the number of switches n)i; 2) the study of the relationship between passenger traffic, building residential density and cycle duration. Theoretical Part. To meet these objectives the authors have performed the studies of the following main processes characterizing the functioning of the lift, the level of capacity of the transport drive and comfort: the development of mathematical models of formation of indicators of the elevator drive load; the establishment of the relationship of traffic flow, residential density and the duration of the cycle; development of methodology for calculation of the number of flights went by the elevator in different modes; development of methods of calculating the transport comfort indicator; justification of the structure of the algorithm for modeling the operating modes of the elevator. Conclusion. The paper provides the results, which complement the theoretical provisions for determining the capacity and transport comfort of elevators.
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Strømland, Øyvind, Marc Niere, Andrey A. Nikiforov, Magali R. VanLinden, Ines Heiland, and Mathias Ziegler. "Keeping the balance in NAD metabolism." Biochemical Society Transactions 47, no. 1 (January 9, 2019): 119–30. http://dx.doi.org/10.1042/bst20180417.
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Abstract Research over the last few decades has extended our understanding of nicotinamide adenine dinucleotide (NAD) from a vital redox carrier to an important signalling molecule that is involved in the regulation of a multitude of fundamental cellular processes. This includes DNA repair, cell cycle regulation, gene expression and calcium signalling, in which NAD is a substrate for several families of regulatory proteins, such as sirtuins and ADP-ribosyltransferases. At the molecular level, NAD-dependent signalling events differ from hydride transfer by cleavage of the dinucleotide into an ADP-ribosyl moiety and nicotinamide. Therefore, non-redox functions of NAD require continuous biosynthesis of the dinucleotide. Maintenance of cellular NAD levels is mainly achieved by nicotinamide salvage, yet a variety of other precursors can be used to sustain cellular NAD levels via different biosynthetic routes. Biosynthesis and consumption of NAD are compartmentalised at the subcellular level, and currently little is known about the generation and role of some of these subcellular NAD pools. Impaired biosynthesis or increased NAD consumption is deleterious and associated with ageing and several pathologies. Insults to neurons lead to depletion of axonal NAD and rapid degeneration, partial rescue can be achieved pharmacologically by administration of specific NAD precursors. Restoring NAD levels by stimulating biosynthesis or through supplementation with precursors also produces beneficial therapeutic effects in several disease models. In this review, we will briefly discuss the most recent achievements and the challenges ahead in this diverse research field.
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Chlon, Timothy M., Elizabeth E. Hoskins, Sonya Ruiz-Torres, Christopher N. Mayhew, Kathryn A. Wikenheiser-Brokamp, Stella M. Davies, Parinda A. Mehta, Kasiani C. Myers, James M. Wells, and Susanne I. Wells. "Inducible Loss of the Fanconi Anemia Pathway in iPSC Causes Rapid Cell Cycle Arrest and Apoptosis through ATM/ATR and p53 Signaling." Blood 124, no. 21 (December 6, 2014): 3528. http://dx.doi.org/10.1182/blood.v124.21.3528.3528.
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Abstract As the source of all cells in the developing embryo proper, embryonic stem cells (ESC) bear the unique responsibility to prevent mutations from being propagated throughout the entire organism and the germ line. It is likely for this reason that ESC and induced pluripotent stem cells (iPSC) maintain a dramatically lower mutation frequency than cultured somatic cells. Multiple mechanisms for this enhanced genomic surveillance have been proposed, including hypersensitivity of DNA damage response signaling pathways and increased activity of error-free DNA repair pathways, such as homologous recombination. However, the effect of loss of function of DNA repair pathways in these cells remains poorly understood. The Fanconi Anemia (FA) pathway is a DNA repair pathway that is required for the repair of DNA interstrand crosslink damage and also promotes repair of DNA double-strand breaks by homologous recombination . Genetic defects in this pathway cause a disease characterized by bone marrow failure and extreme cancer incidence. Several recent studies have revealed that the FA pathway is required for efficient somatic cell reprogramming to iPSC and suggest that FA cells undergo cell death during this process. Another recent study found that the growth of FA patient-specific iPSC was attenuated with a G2/M arrest when compared to control iPSC, suggesting that these cells arrest upon failed DNA repair. In this study, we sought to determine the effects of acute loss of function of the FA pathway in iPSC through the generation of FA patient-derived iPSC with inducible complementation of the defective FA gene. Fibroblasts were cultured from skin biopsies of multiple FA patients and transduced with a lentiviral vector expressing the complementing FA gene product under DOX-inducible control. Cells were then reprogrammed to iPSC using episomal transfection. These cells formed iPSC colonies only when reprogramming was carried out in the presence of DOX, confirming that the FA pathway is required for efficient reprogramming. Once cell lines were obtained, DOX-dependent FA functionality was verified based on FANCD2 monoubiquitination and nuclear focus formation after treatment with DNA damaging agents. We then cultured the iPSC for extended periods of time in the presence and absence of DOX. Interestingly, the cultures underwent profound cell death and cell cycle arrest within 7 days of DOX-withdrawal and completely failed to expand after one passage. EdU cell cycle analysis confirmed cell cycle arrest in the G2/M phase. Furthermore, cleaved caspase 3 staining confirmed that the number of apoptotic cells increased by 3-fold in the -DOX culture. Despite these effects, cells cultured in both the presence and absence of DOX formed teratomas in nude mice, thus indicating the maintenance of full differentiation capacity in the absence of the FA pathway. In order to determine the mechanisms underlying G2/M arrest and cell death, expression of p53 and its target genes was detected by both western blot analysis and qRT-PCR. Only a slight increase in p53 activation was observed by 7 days post DOX-withdrawal. Furthermore, knockdown of p53 resulted in rescue from apoptosis to normal levels but not rescue from cell cycle arrest. Increased ATM and ATR DNA damage sensor kinase activities were also detected in –DOX cells, concominant with increased phosphorylation of the ATM-target Chk2 and reduced abundance of the G2/M checkpoint protein CDC25A. These results reveal hyperactive DNA damage responses upon FA loss which may underlie the attenuated cell cycle progression of FA-iPSC independent of p53. Remarkably, effects in this FA model system appear equivalent to those responsible for the depletion of HSC in the bone marrow of FA patients. Thus, iPSC models may be useful for future studies of the mechanisms underlying FA stem cell arrest and for the development of therapeutics that alleviate these phenotypes. Disclosures No relevant conflicts of interest to declare.
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Shi, Wei, Therese Vu, Glen Boyle, Fares Al-Ejeh, Tej Pandita, Krzysztof Ginalski, Maga Rowicka, Steven W. Lane, and Kum Kum Khanna. "SSB1/NABP2 and SSB2/NABP1 Have Essential and Overlapping Roles in Maintaining Hematopoietic Stem and Progenitor Cells." Blood 126, no. 23 (December 3, 2015): 2405. http://dx.doi.org/10.1182/blood.v126.23.2405.2405.
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Abstract Single-stranded DNA binding (SSB) proteins are essential for a variety of DNA metabolic processes and the maintenance of genomic stability. SSB1 and its homolog SSB2, share greater sequence and domain homology to the archaeal and bacterial SSBs than eukaryotic RPA. They form complexes with two other proteins, C9Orf80 and INTS3, and play roles in mediating transcription and DNA repair. SSB1 (also known as OBFC2B or NABP2) is recurrently mutated in various cancers, however the precise function in normal development is incompletely understood. We have previously shown that Ssb1 is required for skeletogenesis, telomeric homeostasis and genomic stability in vivo while Ssb2 knockout mice are viable and grow normally without any detectable phenotype. Interestingly, we observed pronounced upregulation of Ssb2 in response to Ssb1 deletion and modest up-regulation of Ssb1 in response to Ssb2 deletion, suggesting that Ssb1 and Ssb2 may have some overlapping functions. To investigate the specific roles of both Ssb1 and Ssb2 in adult tissue homeostasis, we generated conditional double-knockout (DKO) mouse models of both genes. DKO in adult mice was achieved by using a tamoxifen-inducible Cre (Ssb1fl/fl Ssb2fl/fl R26-CreERT2), in which Ssb1 and Ssb2 are conditionally deleted by the administration of tamoxifen. Induced DKO mice become moribund within seven days featured with pancytopenia and dramatic loss of hematopoietic stem and progenitor cells (HSPCs), suggesting that Ssb1 and Ssb2 are required for the maintenance of haematopoietic stem and progenitors cells (HSPCs). DKO bone marrow was markedly hypocellular with reduction in all lineages of haematopoietic development. Functionally, HSPCs in DKO mice show decreased quiescence at the early stage followed by decreased proliferation and increased cell loss due to apoptotic cell death at the later stage, suggesting the imbalanced bone marrow homeostasis upon DKO may eventually result in exhaustion of the stem cell pool in DKO mice. Furthermore, bona fide HSPC intrinsic functional deficiency caused by DKO was confirmed by competitive bone marrow transplant, where DKO bone marrows showed abolished differentiation capacity and failed to repopulate the bone marrows of recipient mice after induction of DKO in the established engraftments from the Ssb1fl/fl Ssb2fl/fl R26-CreERT2 donors. Gene expression of DKO HSPCs demonstrated an exacerbated p53/p21 DNA damage response and pronounced interferon response. Validating these findings, stabilization of p53 and increased apoptotic cell death were observed in DKO bone marrows and HSPCs and induction of cell cycle and expression of interferon target genes was confirmed by QPCR. DKO HSPCs have increased expression of IFN induced surface markers such as Sca1. The IFN response was intrinsic to HSPCs. Mechanistically, DKO HSPCs manifest a profile of stalled replication forks on DNA combing analysis, unrepaired double strand breaks (increased gammaH2Ax foci and alkaline comet tail moment) and telomeric loss resulting in widespread chromosomal instability. DKO HSPC showed aberrant cytoplasmic accumulation of single stranded DNAs, with R-loop formation (DNA:RNA hybrid), driving this genetic instability and cell-intrinsic interferon response. Altogether, these data provide strong evidence that Ssb1 and Ssb2 have essential functions in regulating haematopoiesis through repairing replication associated DNA damage as well as resolution of R-loop generated during transcription, to maintain genomic stability during normal HSPC homeostasis. Disclosures No relevant conflicts of interest to declare.
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Dash, Sanjit Kumar, Satyam Raj, Rahul Agarwal, and Jibitesh Mishra. "Automobile Predictive Maintenance Using Deep Learning." International Journal of Artificial Intelligence and Machine Learning 11, no. 2 (July 2021): 1–12. http://dx.doi.org/10.4018/ijaiml.20210701.oa7.
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There are three types of maintenance management policy Run-tofailure (R2F), Preventive Maintenance (PvM) and Predictive Maintenance (PdM). In both R2F and PdM we have the data related to the maintenance cycle. In case of Preventive Maintenance (PvM) complete information about maintenance cycle is not available. Among these three maintenance policies, predictive Maintenance (PdM) is becoming a very important strategy as it can help us to minimize the repair time and the associated cost with it. In this paper we have proposed PdM, which allows the dynamic decision rules for the maintenance management. PdM is achieved by training the machine learning model with the datasets. It also helps in planning of maintenance schedules. We specially focused on two models that are Binary Classification and Recurrent Neural Network. In Binary Classification we classify whether our data belongs to the failure class or the non failure class. In Binary Classification the number of cycles is entered and classification model predicts whether it belongs to the failure/non failure class.
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Sime, Muluneh, Gary Bailey, Elie Y. Hajj, and Rami Chkaiban. "Road Load Based Model for Vehicle Repair and Maintenance Cost Estimation." Transportation Research Record: Journal of the Transportation Research Board 2674, no. 11 (September 10, 2020): 490–97. http://dx.doi.org/10.1177/0361198120945977.
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A techno-economic model is developed based on road-load simulation results expressed in relation to slip energy (SE) at the tire–pavement interface and the repair and maintenance (R&M) cost obtained from published sources and data from state agencies. Tire SE allows for the consideration of aggressive acceleration and deceleration, high torque conditions (for instance, driving an upslope grade), and roadway curvature. Tire SE data used in this effort were generated using physics-based simulation models of different vehicle types for arrays of road conditions (e.g., grades, curvatures) and driving cycles (i.e., vehicle speed profiles). R&M costs were estimated for various vehicle categories and accumulated vehicle mileage. The approach is based on relating the probability density functions (PDFs) of SE and R&M costs. Asymptotic series expansion for an incomplete gamma function was used to approximate the gamma functions and to determine the gamma ratio function that is used as the coefficient to SE to estimate R&M costs. The average R&M cost per mile results from the model compared with the arithmetic mean R&M cost data from fleet operators and published data. The model can serve as a method for predicting R&M cost as a function of road load to vehicle fleet.
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Belyaev, Sergey V., Aleksey V. Malafeev, and Evgeniy Ya Omelchenko. "Development of Optimum Repair Schedule of Electrical Network Equipment to Improve the Reliability of its Functioning." Electrotechnical Systems and Complexes, no. 2(43) (June 28, 2019): 4–11. http://dx.doi.org/10.18503/2311-8318-2019-2(43)-4-11.
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To ensure uninterrupted power supply to consumers, maintenance of the electrical networks in a working condition is today carried out through the use of a system of preventive maintenance. In the general case such a system allows building equipment repair schedules based on repair cycles for a long time predetermining the list of necessary material and labor resources in advance. However, in practice, the use of this system is rather difficult and not always effective. This is due to the need to change the repair schedule for emergency or urgent repairs taking into account the seasonality of work performed and the organizational structure of the production department of electrical networks and related departments as well as taking into account the specific features of the operation of specific equipment. Taking into account the current pace of development of electrical networks with a steady increase in the number of consumers (which also leads to a complication of the configuration of electrical networks) this is impossible without the use of appropriate mathematics and software that automates the planning processes for the maintenance and repair of electrical networks with a large number of factors. The minimum equipment downtime was taken as the main criterion for optimality, as a factor that largely determines the reliability of power supply. A planning algorithm has been developed that takes into account the ranking of works in order of importance, the possibility of their shift in time and the likely adjustment of the schedule based on the results of assessing the technical condition of the equipment. A method for minimizing the downtime of repair crews by using them in adjacent areas as well as a technique for identifying a set of equipment that may be under repair in the same period of time are proposed.
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Prizeman, Oriel. "Maintenance of shared spaces: courtyards of Tbilisi." Journal of Cultural Heritage Management and Sustainable Development 6, no. 3 (November 21, 2016): 316–29. http://dx.doi.org/10.1108/jchmsd-11-2015-0043.
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Purpose The courtyard dwellings of Tbilisi form a critical part of the city’s architectural identity. However, the multiple occupation of these buildings is blamed for confounding their prospects for repair and consequent valorisation as a World Heritage Site. Models for the shared ownership of residential blocks have been adapted globally. Some have established communal sources for rehabilitation and maintenance applicable to historic buildings. The purpose of this paper is to assess the relevance of such precedents to the complex and urgent context of Tbilisi’s threatened architectural heritage. Design/methodology/approach The paper uses existing literature and data to establish a hypothesis in support of adopting a collaborative approach for the maintenance and rehabilitation of shared buildings in a challenging and specific context. Using socio-economic data to characterise the occupants of such buildings and current critical sources, the paper investigates how existing collective communities can be empowered to capitalise from their unique social frameworks. Findings It finds evidence to support theoretical claims that there is scope for co-operative networks to flourish there. Research limitations/implications The paper is limited to a desktop analysis and relies upon available data and literature to draw its conclusions. Originality/value This paper addresses a critical problem in the formulation of conservation plans for Old Tbilisi, it tests the relevance of global exemplars for community repair programmes by reference to existing data for the care of the predominantly domestic architecture of Old Tbilisi at a time of rapid change.
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Capodieci, Antonio, Antonio Caricato, Antonio Paolo Carlucci, Antonio Ficarella, Luca Mainetti, and Cristian Vergallo. "Using different machine learning approaches to evaluate performance on spare parts request for aircraft engines." E3S Web of Conferences 197 (2020): 11014. http://dx.doi.org/10.1051/e3sconf/202019711014.
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The Aircraft uptime is getting increasingly important as the transport solutions become more complex and the transport industry seeks new ways of being competitive. To reach this objective, traditional Fleet Management systems are gradually extended with new features to improve reliability and then provide better maintenance planning. Main goal of this work is the development of iterative algorithms based on Artificial Intelligence to define the engine removal plan and its maintenance work, optimizing engine availability at the customer and maintenance costs, as well as obtaining a procurement plan of integrated parts with planning of interventions and implementation of a maintenance strategy. In order to reach this goal, Machine Learning has been applied on a workshop dataset with the aim to optimize warehouse spare parts number, costs and lead-time. This dataset consists of the repair history of a specific engine type, from several years and several fleets, and contains information like repair claim, engine working time, forensic evidences and general information about processed spare parts. Using these data as input, several Machine Learning models have been built in order to predict the repair state of each spare part for a better warehouse handling. A multi-label classification approach has been used in order to build and train, for each spare part, a Machine Learning model that predicts the part repair state as a multiclass classifier does. Mainly, each classifier is requested to predict the repair state (classified as “Efficient”, “Repaired” or “Replaced”) of the corresponding part, starting from two variables: the repairing claim and the engine working time. Then, global results have been evaluated using the Confusion Matrix, from which Accuracy, Precision, Recall and F1-Score metrics are retrieved, in order to analyse the cost of incorrect prediction. These metrics are calculated for each spare part related model on test sets and, then, a final single performance value is obtained by averaging results. In this way, three Machine Learning models (Naïve Bayes, Logistic Regression and Random Forest classifiers) are applied and results are compared. Naïve Bayes and Logistic Regression, that are fully probabilistic methods, have best global performances with an accuracy value of almost 80%, making the models being correct most of the times.
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Asghar, Iqra, and Jong Soo Kim. "An Automated Smart EPQ-Based Inventory Model for Technology-Dependent Products under Stochastic Failure and Repair Rate." Symmetry 12, no. 3 (March 3, 2020): 388. http://dx.doi.org/10.3390/sym12030388.
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With the ever-growing technology development, high-tech products such as mobile phones, computers, electromagnetic devices and smart devices are facing high design and production modification requirements with relatively shorter life cycles. For instance, every forthcoming smart phone goes out of production in a shorter period after its launch, followed by its next generation. The design of high-tech products requires high investments in smart and automated manufacturing technology to ensure higher production efficiency. For high-tech products with short life spans, the manufacturing performance-quality variable is an important design parameter that affects system reliability, production efficiency and manufacturing costs. Major performance-quality factors of a manufacturing system which affect productivity and reliability of the manufacturing process are discussed in this research. The study investigates an integrated smart production maintenance model under stochastic manufacturing reliability for technology dependent demand and variable production rate. The smart unit production cost is a function of manufacturing reliability and controllable production rate, as a manufacturing system can be operated at different production rates within designed limits μ ϵ [ μ m i n , μ m a x ] . Manufacturing reliability is increased through investment in smart manufacturing technology and resources. The integrated smart production maintenance model is formulated under general failure and repair time distributions and the optimal production maintenance policy is investigated under specific failure and repair time distributions. A mathematical model is developed to optimize the manufacturing quality-performance parameter, variable production rate, per unit technology investment and production lot size. The total cost function is optimized through the Khun–Tucker method. The mathematical model is also validated with numerical analysis, comparative study, and sensitivity analysis for model key parameters.
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Ovchar, R. F. "Analysis of effectiveness of process operational and technological reliability of agricultural mashines." Naukovij žurnal «Tehnìka ta energetika» 11, no. 4 (September 10, 2020): 143–52. http://dx.doi.org/10.31548/machenergy2020.04.143.
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The analysis suggests that to solve the contradiction between the need of ensuring the required level of serviceability of combine harvesters and capabilities of existing system and repair management of the technical state of combine harvesters at the present stage, there is a need to improve the subsystem recovery combine harvesters subject to the requirements of readiness to perform tasks on purpose and financial capacity for its maintenance. Analysis of scientific literature showed that today the unsolved problem of search and introduction of effective methods and repair combine harvesters are: development of mathematical models of the process and repair, which would allow comparative assessment of technical and economic efficiency of different modes, and repair objects combine harvesters, alternative strategies for their repair, with the aim of improving the quality of control of technical condition of the vessel in conditions of limited funding. Consideration of the process of technical maintenance of combine harvesters as a set of stages and repair objects combine harvesters allows to identify possible directions of improving the system restore. The analysis allowed to determine four basic options for its organization and to make a qualitative assessment of the benefits and disadvantages of each of these options. Reduced operating costs in the operation of combine harvesters, along with other measures of organizational and technical nature require greater automation of control of technical condition. Automation of technical state control of combine harvesters developed in the following areas: embedded systems control, on-board automated control systems, specialized control systems and universal control systems dismantled equipment. A large share of false failures in equipment, violation of industrial relations in the repair network on-board equipment, the shortage of maintenance fund requires implementation and operation. Most fully able to examine the efficiency of the process of operation of complex technical systems using analytical models. Existing approaches to the assessment of the recovery system can be classified also according to the used indicators of effectiveness: the number of constructive variables of units that are replaced (restored) for a predetermined period of operation of the control object, repair cost of the constituent elements of the functional system for a specific period at different depths of the control and completeness of the recovery, the downtime of the test object within a certain period, for comprehensive reliability, such as coefficient of readiness, coefficient of technical use.
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Tewari, Krishnansu S., Robert A. Burger, Danielle Enserro, Barbara M. Norquist, Elizabeth M. Swisher, Mark F. Brady, Michael A. Bookman, et al. "Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer." Journal of Clinical Oncology 37, no. 26 (September 10, 2019): 2317–28. http://dx.doi.org/10.1200/jco.19.01009.
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PURPOSE We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.
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Ninou, Anna Huguet, Jemina Lehto, Dimitrios Chioureas, Hannah Stigsdotter, Korbinian Schelzig, Emma Åkerlund, Greta Gudoityte, et al. "PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair." Cancers 13, no. 14 (July 18, 2021): 3604. http://dx.doi.org/10.3390/cancers13143604.
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Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments.
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Dickson, Kristie-Ann, Tao Xie, Christian Evenhuis, Yue Ma, and Deborah J. Marsh. "PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer." International Journal of Molecular Sciences 22, no. 16 (August 7, 2021): 8506. http://dx.doi.org/10.3390/ijms22168506.
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Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.
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Joly, Florence, Pierre Emmanuel Brachet, Sophie Abadie Lacourtoisie, Bernard Asselain, Anne Floquet, Olivier Collard, Manuel Rodrigues, et al. "Multicentre randomized phase II trial of olaparib as maintenance therapy in platinum-sensitive advanced endometrial carcinoma: The GINECO-UTOLA study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS6109. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps6109.
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TPS6109 Background: Advanced endometrial cancer (EC) patients relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Data from the TGCA suggest opportunities to targeting DNA repair in women with EC. Particularly type 4 (High copy number or serous like, with frequent TP53 mutations) and type 2 (microsatellite instability hypermutated) EC can be associated with defects in double strand break DNA repair by homologous recombination (HR) and could potentially be targeted by olaparib. We propose a placebo-controlled, multicenter, two-arm, phase II trial comparing olaparib versus placebo in maintenance therapy after chemotherapy in patients with advanced/metastatic EC. Methods: The primary objective of this trial is to evaluate the efficacy of maintenance olaparib in comparison to placebo after platinum based chemotherapy, defined by PFS according to Recist. Key eligibility criteria include: advanced/metastatic histologically confirmed EC (excepted carcino-sarcoma, small cells& neuroendocrine); prior surgery, adjuvant chemotherapy, radiation and hormonal therapy are permitted; objective or stable response after first-line chemotherapy is mandatory. 147 patients are randomized (2:1) after chemotherapy to receive Olaparib 300mg twice daily or placebo in maintenance after at least 4 cycles of platinum based chemotherapy. Olaparib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Stratification is on IHC P53 and MMR status. Primary hypothesis is a 66.7% relative increase in the median PFS rate in the olaparib arm (from 4.5 to 7.5 months), corresponding to a 0.60 Hazard Ratio. Secondary endpoints include PFS according to P53, MMR and NGS HRD status, PFS2, disease specific survival, time to subsequent therapy, overall survival, objective response, disease control rate, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24, EORTC-FA, EQ5D) and safety. Trial is recruiting in France (in February n= 40 randomization). Conclusion: this will be the first study that evaluate the efficacy of olaparib in maintenace after chemotherapy in advanced/metastastic EC, stratified on molecular profil. Clinical trial information: NCT03745950.
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Amadei, Bernard. "Agent-Based and System Dynamics Modeling of Water Field Services." Challenges 11, no. 2 (July 20, 2020): 13. http://dx.doi.org/10.3390/challe11020013.
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This paper explores the applicability of the agent-based (AB) and system dynamics (SD) methods to model a case study of the management of water field services. Water borehole sites are distributed over an area and serve the water needs of a population. The equipment at all borehole sites is managed by a single water utility that has adopted specific repair, replacement, and maintenance rules and policies. The water utility employs several service crews initially stationed at a single central location. The crews respond to specific operation and maintenance requests. Two software modeling tools (AnyLogic and STELLA) are used to explore the benefits and limitations of the AB and SD methods to simulate the dynamic being considered. The strength of the AB method resides in its ability to capture in a disaggregated way the mobility of the individual service crews and the performance of the equipment (working, repaired, replaced, or maintained) at each borehole site. The SD method cannot capture the service crew dynamics explicitly and can only model the average state of the equipment at the borehole sites. Their differences aside, both methods offer policymakers the opportunity to make strategic, tactical, and logistical decisions supported by integrated computational models.
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dos Santos, Luís Gustavo. "EMBRAER Perspective on the Challenges for the Introduction of Scheduled SHM (S-SHM) Applications into Commercial Aviation Maintenance Programs." Key Engineering Materials 558 (June 2013): 323–30. http://dx.doi.org/10.4028/www.scientific.net/kem.558.323.
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This paper presents an overview of the challenges an original equipment manufacturer (OEM) such EMBRAER may face to introduce scheduled structural health monitoring (S-SHM) applications in the maintenance programs of its commercial aviation aircraft models. S-SHM solutions have the potential to reduce aircraft operators direct maintenance costs and fleet downtime while keeping aircraft airworthiness at a minimum maintenance downtime and costs. As part of new approach in terms of scheduled maintenance practices, the replacement or complementation of traditional structural inspections tasks by new maintenance procedures taking credit of SHM technologies must be done in ways that meet the expectations and requirements of Regulatory Authorities, OEMs and airlines maintenance and engineering departments related to topics such as: safety, continued airworthiness, cost/benefits ratio, S-SHM systems built-in redundancies and reliability to support higher fleet availability, as well as necessary mechanics qualification. Besides the efforts for validation, verification, qualification and certification of such systems to deliver the expected effectiveness levels to verify structural integrity and withstanding the operational conditions to which it will be exposed, an OEM intended to offer their customers with the benefits of S-SHM solutions will be required initially to revise its policy and procedures handbooks (PPH) to adopt the new S-SHM Air Transport Associations Maintenance Steering Group 3 (MSG-3) Methodology guidelines. This will alter in different ways the current Maintenance Review Board processes conducted by each OEM to develop and revise the minimum scheduled maintenance program for a given commercial aircraft type certificate. The contents of the Maintenance Review Board Reports (MRB) will need to be revised in order to clearly indicate the scope and frequencies of each approved S-SHM task, and how they will replace, complement and/or be an alternative means of compliance of the more traditional maintenance tasks types such as general and detailed visual inspections (GVI and DET, respectively). Additionally, the Airplane Maintenance Manuals (AMM) will need to be revised to include specific S-SHM procedures on how to perform the intended inspection, how to proceed when degradation is detected in the monitored structures and how to repair such systems in case of failures.
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Xavier-Elsas, Pedro, Bruno M. Vieira, Daniela Masid-de-Brito, Monica G. Barradas, and Maria I. C. Gaspar-Elsas. "The Need to Consider Context in the Evaluation of Anti-infectious and Immunomodulatory Effects of Vitamin A and its Derivatives." Current Drug Targets 20, no. 8 (May 10, 2019): 871–78. http://dx.doi.org/10.2174/1389450120666181217095323.
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Vitamin A and its derivatives (retinoids) act as potent regulators in many aspects of mammalian reproduction, development, repair, and maintenance of differentiated tissue functioning. Unlike other vitamins, Vitamin A and retinoids, which have hormonal actions, present significant toxicity, which plays roles in clinically relevant situations, such as hypervitaminosis A and retinoic acid ("differentiation") syndrome. Although clinical presentation is conspicuous in states of insufficient or excessive Vitamin A and retinoid concentration, equally relevant effects on host resistance to specific infectious agents, and in the general maintenance of immune homeostasis, may go unnoticed, because their expression requires either pathogen exposure or the presence of inflammatory co-morbidities. There is a vast literature on the roles played by retinoids in the maintenance of a tolerogenic, noninflammatory environment in the gut mucosa, which is considered by many investigators representative of a general role played by retinoids as anti-inflammatory hormones elsewhere. However, in the gut mucosa itself, as well as in the bone marrow and inflammatory sites, context determines whether one observes an anti-inflammatory or proinflammatory action of retinoids. Both interactions between specialized cell populations, and interactions between retinoids and other classes of mediators/regulators, such as cytokines and glucocorticoid hormones, must be considered as important factors contributing to this overall context. We review evidence from recent studies on mucosal immunity, granulocyte biology and respiratory allergy models, highlighting the relevance of these variables as well as their possible contributions to the observed outcomes.
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Saygin, Caner, Andrew Wiechert, Vinay S. Rao, Ravi Alluri, Elizabeth Connor, Praveena S. Thiagarajan, James S. Hale, et al. "CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors." Journal of Experimental Medicine 214, no. 9 (August 24, 2017): 2715–32. http://dx.doi.org/10.1084/jem.20170438.
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Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors.
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Bassan, Renato, Orietta Spinelli, Elena Oldani, Tamara Intermesoli, Manuela Tosi, Giuseppe Rossi, Enrico M. Pogliani, et al. "Minimal Residual Disease (MRD) and Risk-Oriented Therapy in Adult Acute Lymphoblastic Leukemia (ALL)." Blood 106, no. 11 (November 16, 2005): 1836. http://dx.doi.org/10.1182/blood.v106.11.1836.1836.
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Abstract In adult ALL standard prognostic models do not predict relapse with great accuracy, which implies under-/over-exposure to a given therapy, especially transplants. A study is exploiting MRD as “best” predictive factor and decisional aid for therapy in unselected patients. Adults with ALL underwent induction-consolidation with IDR/V/ASP/P/CY (cycles 1–3,5,6,8), HD-MTX/Ara-C (cycles 4,7), and CNS prophylaxis. Imatinib was added in Ph+ ALL. For MRD, 3 marrow samples were taken before cycles 4, 6, 8, to be analyzed by PCR/RQ-PCR with case-specific probe(s) targeting fusion genes or Ig-H/TCR rearrangements. MRD negativity was defined as negative/low-positive (<10e-4) timepoint (TP) 2 and negative TP3. MRD- patients received standard maintenance (1st year 6MP/MTX and V/P or CY pulses; 2nd year 6MP/MTX); MRD+ ones were eligible to allogeneic SCT (related/unrelated donor) or alternatively, to autologous stem cell-supported “hypercycles” with MEL/VP/6MP (cycles 1,3) and HD-MTX/Ara-C (cycles 2,4) plus Rituximab if CD20+, and maintenance. Patients with Ph/t(4;11)+ ALL were eligible to early SCT regardless MRD study, and those with undefined MRD were treated by clinical risk class. MRD monitoring was planned at 6, 12 and 24 months since TP3. The trial was activated 05/’00, enrolling 215 ALLs and 15 lymphoblastic lymphomas. Diagnostic characteristics were: age 16–66 years (median 37), B-lin 182, T-lin 48, Ph+ 49, t(4;11)+ 11. CR rate was 84%. So far, 109 patients completed consolidation and were eligible to MRD-oriented therapy. The MRD study was informative in 80 (73%), 14 lacked a probe(s) and 15 were poorly sampled. Altogether, 36/80 were MRD− (45%), with few variations among subsets: B-lin low-risk 38%, high-risk 44%, Ph+ 25%, T-lin 54%. Only a WBC count >100 and adverse cytogenetics predicted to some extent an MRD+ result (P=0.05), while MRD negativity was always confirmed as early as TP1 (week 10). Only 6 MRD− cases relapsed (17%), 1 with a new clone and 4 with suboptimal MRD study, compared to 20/44 (45.5%) MRD+ (P=0.000). DFS at 4 years was 76% in MRD− vs. 24% in MRD+ vs. 54% in the unknown MRD group. In multivariate analysis MRD was stronly predictive for relapse (RR 5.51, P=0.000) followed by a WBC count >30 (RR 3.64, P=0.001), the latter effect being almost exclusively seen in MRD+ patients. As regards MRD monitoring, conversion rate from MRD+ to MRD− was similar after SCT and “hypercycles” in the few cases evaluable (4/6 in each group), with a strong correlation in every prognostic/treatment group between overt relapse and prior positive MRD test (2/35 MRD− vs. 9/20 MRD+; P=0.000). MRD is an invaluable prognostic tool for risk-oriented trials. Both an early analysis and monitoring support optimal therapeutic choices (with some reported exceptions), identify patients at greatest risk of relapse, and could allow comparative trials testing specific treatment elements in different ALL subsets.
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Magdalena, Juana, Thomas H. Millard, Sandrine Etienne-Manneville, Sophie Launay, Helen K. Warwick, and Laura M. Machesky. "Involvement of the Arp2/3 Complex and Scar2 in Golgi Polarity in Scratch Wound Models." Molecular Biology of the Cell 14, no. 2 (February 2003): 670–84. http://dx.doi.org/10.1091/mbc.e02-06-0345.
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Cell motility and cell polarity are essential for morphogenesis, immune system function, and tissue repair. Many animal cells move by crawling, and one main driving force for movement is derived from the coordinated assembly and disassembly of actin filaments. As tissue culture cells migrate to close a scratch wound, this directional extension is accompanied by Golgi apparatus reorientation, to face the leading wound edge, giving the motile cell inherent polarity aligned relative to the wound edge and to the direction of cell migration. Cellular proteins essential for actin polymerization downstream of Rho family GTPases include the Arp2/3 complex as an actin nucleator and members of the Wiskott–Aldrich Syndrome protein (WASP) family as activators of the Arp2/3 complex. We therefore analyzed the involvement of the Arp2/3 complex and WASP-family proteins in in vitro wound healing assays using NIH 3T3 fibroblasts and astrocytes. In NIH 3T3 cells, we found that actin and Arp2/3 complex contributed to cell polarity establishment. Moreover, overexpression of N-terminal fragments of Scar2 (but not N-WASP or Scar1 or Scar3) interfere with NIH 3T3 Golgi polarization but not with cell migration. In contrast, actin, Arp2/3, and WASP-family proteins did not appear to be involved in Golgi polarization in astrocytes. Our results thus indicate that the requirement for Golgi polarity establishment is cell-type specific. Furthermore, in NIH 3T3 cells, Scar2 and the Arp2/3 complex appear to be involved in the establishment and maintenance of Golgi polarity during directed migration.
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Henzi, Anna, Assunta Senatore, Asvin K. K. Lakkaraju, Claudia Scheckel, Jonas Mühle, Regina Reimann, Silvia Sorce, Gebhard Schertler, Klaus V. Toyka, and Adriano Aguzzi. "Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice." PLOS ONE 15, no. 11 (November 12, 2020): e0242137. http://dx.doi.org/10.1371/journal.pone.0242137.
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The adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the early molecular signs demyelination was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.
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Lee, Min Gin, and Yi Shuo Huang. "Fire-Damage or Freeze-Thaw of Strengthening Concrete Using Ultra High Performance Concrete." Advanced Materials Research 79-82 (August 2009): 2047–50. http://dx.doi.org/10.4028/www.scientific.net/amr.79-82.2047.
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There are some reinforced concrete structures exposed to severe environmental conditions might require maintenance or strengthening. Many of these severe circumstances are the result of extreme climate conditions such as low temperature, freeze–thaw action, fire attack, and exposure to deicing salts. Because of this, the environmental durability of both the repair materials and methods used in rehabilitation applications are of utmost importance. A small fire can reach 250°C, while a common blaze can easily produce temperatures of around 800°C. In major conflagrations the temperature can even reach 1100°C. At this level, the heat affects most materials, provoking the spontaneous combustion of some of them and affecting the resistance of others. However, very little research has been performed in evaluating the environmental durability of strengthening materials for concrete members. Very little work has been done on the effects of freeze–thaw cycling on bonding and repair materials. In this study, ultra high performance concrete (UHPC) was used to investigate the effect of strengthening concrete members by fire-damage test or freeze-thaw test. The results show that the mechanical properties of UHPC possess high strength, toughness, and freeze-thaw resistance. The CFRP (carbon fiber reinforced plates) wrapping specimens exposed at 300 °C showed totally failure with the deterioration of the adhesive. The UHPC with bonding 10 mm thickness specimens exposed at 400 °C and duration of 1 hour still in good shape. The UHPC with 1-cm or 2-cm thickness on strengthening concrete members could be obtained specific retrofit effects. The performance of UHPC specimens is better than those of CFRP wrapping specimens during high temperature exposure. The results of slant shear tests show that the bond strength of PC/PC, UHPC/PC and UHPC/UHPC decreased significantly after 600 freeze–thaw cycles or high temperature exposure.
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Burrow, Michael P. N., Jin Shi, Mohamed Wehbi, and Gurmel S. Ghataora. "Assessing the Damaging Effects of Railway Dynamic Wheel Loads on Railway Foundations." Transportation Research Record: Journal of the Transportation Research Board 2607, no. 1 (January 2017): 62–73. http://dx.doi.org/10.3141/2607-09.
Full textAbstract:
Dynamic train wheel loads, which can be significantly greater than static loads, occur because of a variety of factors and unless they are properly considered in track structural design, significant unplanned maintenance and premature track failure may result. This is particularly so for traditional ballasted railways built on soft foundations, because although ballast lends itself to maintenance, it is often problematic and costly to repair damaged foundations. A novel rigorous analytical–numerical approach is described to predict and characterize, for the first time, the damage to which railway foundations can be subjected as a result of dynamic loads. The approach marries a sophisticated three-dimensional dynamic model of the train–track system incorporating vertical track quality, foundation soil distress models, statistical analysis methods, and results of field investigation. The resulting analyses demonstrate that the magnitudes and distributions of dynamic loads are a function of train speed and track quality, and that specific locations experience significantly higher amounts of damage, which can lead to a variety of track faults. The approach is illustrated via a study of a heavy haul railway line in China where the wheel loads and tonnage carried are set to increase significantly. Findings from the study suggest that the thickness of the ballasted layer would need to increase by over 20% to prevent premature foundation failure provided that the track is maintained in good condition, and by significantly more should the track condition be allowed to deteriorate.
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Liu, Xiaosong, and Zelieann R. Craig. "Environmentally relevant exposure to dibutyl phthalate disrupts DNA damage repair gene expression in the mouse ovary†." Biology of Reproduction 101, no. 4 (July 18, 2019): 854–67. http://dx.doi.org/10.1093/biolre/ioz122.
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Abstract Phthalates have a history of reproductive toxicity in animal models and associations with adverse reproductive outcomes in women. Human exposure to dibutyl phthalate (DBP) occurs via consumer products (7–10 μg/kg/day) and medications (1–233 μg/kg/day). Most DBP toxicity studies have focused on high supraphysiological exposure levels; thus, very little is known about exposures occurring at environmentally relevant levels. CD-1 female mice (80 days old) were treated with tocopherol-stripped corn oil (vehicle control) or DBP dissolved in oil at environmentally relevant (10 and 100 μg/kg/day) or higher (1000 μg/kg/day) levels for 30 days to evaluate effects on DNA damage response (DDR) pathway genes and folliculogenesis. DBP exposure caused dose-dependent effects on folliculogenesis and gene expression. Specifically, animals exposed to the high dose of DBP had more atretic follicles in their ovaries, while in those treated with environmentally relevant doses, follicle numbers were no different from vehicle-treated controls. DBP exposure significantly reduced the expression of DDR genes including those involved in homologous recombination (Atm, Brca1, Mre11a, Rad50), mismatch repair (Msh3, Msh6), and nucleotide excision repair (Xpc, Pcna) in a dose-specific manner. Interestingly, staining for the DNA damage marker, γH2AX, was similar between treatments. DBP exposure did not result in differential DNA methylation in the Brca1 promoter but significantly reduced transcript levels for the maintenance DNA methyltransferase, Dnmt1, in the ovary. Collectively, these findings show that oral exposure to environmentally relevant levels of DBP for 30 days does not significantly impact folliculogenesis in adult mice but leads to aberrant ovarian expression of DDR genes.
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Holmberg, Ingrid Martins. "Urban Heritage as Ethos in Resource-Based Small-Scale Property Management." Sustainability 11, no. 19 (September 27, 2019): 5354. http://dx.doi.org/10.3390/su11195354.
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This study puts urban heritage in the setting of property owners’ small-scale and resource-based management of ordinary old buildings. This phenomenon indicates a need not only to reconceptualize urban heritage in its actual complex web of negotiations over constraints of the regulation (urban planning, including preservation) and economy (the real estate market) but also to pay attention to the emergence of a new ethos. The case concerns a Swedish second-city context and the specific moment in time: When the 1990s recession had disarmed the real estate market. Based upon ethnographic fieldwork, this study used an assemblage perspective to allow for a following of entanglements of material and matter. The study sheds light upon the emergence of a small-scale and resource-based management in the midst of managerially defined cycles of investment. Important for the output was 1) the set-up of a network of skilled craftsmen, antiquarians, and entrepreneurs ‘of the right mindset that enabled for the authentic material result but that also helped navigate regulation and financial parties, 2) the “alternative market for reverential maintenance and repair” that guaranteed the appropriate supply of materials, products, and skills that differed from the mainstream construction market. For the means of understanding the ethos involved, the study introduced the notion of “factual life-span of buildings”. The overall aim of this article was to contribute to research on heritage urbanism by adding a resource management perspective that focusses on the entanglements of material and matter.
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Vaquero-Melchor, Diego, Ana M. Bernardos, and Luca Bergesio. "SARA: A Microservice-Based Architecture for Cross-Platform Collaborative Augmented Reality." Applied Sciences 10, no. 6 (March 19, 2020): 2074. http://dx.doi.org/10.3390/app10062074.
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Augmented Reality (AR) functionalities may be effectively leveraged in collaborative service scenarios (e.g., remote maintenance, on-site building, street gaming, etc.). Standard development cycles for collaborative AR require to code for each specific visualization platform and implement the necessary control mechanisms over the shared assets. in order to face this challenge, this paper describes SARA, an architecture to support cross-platform collaborative Augmented Reality applications based on microservices. The architecture is designed to work over the concept of collaboration models which regulate the interaction and permissions of each user over the AR assets. Five of these collaboration models were initially integrated in SARA (turn, layer, ownership, hierarchy-based and unconstrained examples) and the platform enables the definition of new ones. Thanks to the reusability of its components, during the development of an application, SARA enables focusing on the application logic while avoiding the implementation of the communication protocol, data model handling and orchestration between the different, possibly heterogeneous, devices involved in the collaboration (i.e., mobile or wearable AR devices using different operating systems). to describe how to build an application based on SARA, a prototype for HoloLens and iOS devices has been implemented. the prototype is a collaborative voxel-based game in which several players work real time together on a piece of land, adding or eliminating cubes in a collaborative manner to create buildings and landscapes. Turn-based and unconstrained collaboration models are applied to regulate the interaction. the development workflow for this case study shows how the architecture serves as a framework to support the deployment of collaborative AR services, enabling the reuse of collaboration model components, agnostically handling client technologies.
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VAZHYNSKYI, A., and S. ZHUKOV. "Methods and tools of ensuring the operational reliability of complex industrial facilities." Journal of Electrical and power engineering 14, no. 1 (February 27, 2020): 34–42. http://dx.doi.org/10.31474/2074-2630-2020-1-34-42.
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Approaches and algorithms for processing experimental data and data obtained as a result of using modern means of measuring equipment, selecting diagnostic parameters, pattern recognition, which constitute the methodological basis for developing methods and designing tools for creating a service system for complex industrial facilities based on predicting their performance and residual life are described in submitted article. Along with classical methods, methods based on using the full potential of the modern elemental base of microprocessor technology and the use of artificial neural networks, machine learning, and "big data" are discovered. The given examples can serve as the basis for constructing a methodology for the application of the considered approaches for organizing predictive maintenance of complex industrial equipment. An analytical review of a number of scientific publications showed that the creation of new automated diagnostic systems that can increase fault tolerance and extend the life of sophisticated modern power equipment is extremely relevant. For this, various approaches are applied, based on mathematical models, expert systems, artificial neural networks and other algorithms. Summarizing the results of scientific publications, it can be argued that the implementation of a systematic approach to the organization of repair service at the enterprise requires a comprehensive solution to the following urgent problems: • monitoring is formulated as the task of interrogating sensors and collecting information necessary for further analysis; • diagnostics, it is solved as tasks of identifying informative signs with further detection and classification of failures and anomalies in data sets; • improving the accuracy of algorithms aimed at pattern recognition; • condition forecasting is the task of assessing the current and accumulated readings of monitoring systems for making decisions regarding either a specific element of the complex or the facilities. Thus, modern technology make it possible to arrange arbitrarily complex algorithms. However, to use the full potential that artificial neural networks, expert systems, and classical methods for identifying and diagnosing equipment it is necessary to have a conceptual development of the foundations of building systems for organizing maintenance and repair of complex energy equipment
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Yang, Xifeng, Shihao Chen, Jiaxin Chen, Yunqi Liu, Ying Bai, Shengli Yin, and Daping Quan. "The Different Effect of Decellularized Myocardial Matrix Hydrogel and Decellularized Small Intestinal Submucosa Matrix Hydrogel on Cardiomyocytes and Ischemic Heart." Applied Sciences 11, no. 17 (August 24, 2021): 7768. http://dx.doi.org/10.3390/app11177768.
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Injectable decellularized matrix hydrogels derived from either myocardium or small intestinal submucosa (pDMYO-gel, pDSIS-gel) have been successfully used for myocardial injury repair. However, the relationship between tissue-specific biological functions and protein composition in these two materials is not clear yet. In this study, the protein composition, mechanical properties, and morphology of these two hydrogels and their effects on the behavior of neonatal rat cardiomyocytes (NRCMs) and human umbilical vein endothelial cells (HUVECs), are investigated. The results show that pDMYO-gel is more conducive to growth, adhesion, spreading, and maintenance of normal NRCM beating, due to its higher proportion of extracellular matrix (ECM) glycoproteins (49.55%) and some unique functional proteins such as annexin-6 (ANXA6), agrin (AGRN), cathepsin D (CTSD) and galectin-1 (LGALS1), whereas pDSIS-gel is more conducive to the proliferation of HUVECs. Animal study shows that pDMYO-gel has a better effect on improving cardiac function, inhibiting myocardial fibrosis and maintaining ventricular wall thickness in acute myocardial infarction models in vivo. Therefore, it is proposed that injectable pDMYO-gel hydrogel may be more suitable for functional recovery of myocardial injuries.
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Moll, Solange, Andrea Angeletti, Leonardo Scapozza, Andrea Cavalli, Gian Marco Ghiggeri, and Marco Prunotto. "Glomerular Macrophages in Human Auto- and Allo-Immune Nephritis." Cells 10, no. 3 (March 9, 2021): 603. http://dx.doi.org/10.3390/cells10030603.
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Macrophages are involved in tissue homeostasis. They participate in inflammatory episodes and are involved in tissue repair. Macrophages are characterized by a phenotypic heterogeneity and a profound cell plasticity. In the kidney, and more particularly within glomeruli, macrophages are thought to play a maintenance role that is potentially critical for preserving a normal glomerular structure. Literature on the glomerular macrophage role in human crescentic glomerulonephritis and renal transplantation rejection with glomerulitis, is sparse. Evidence from preclinical models indicates that macrophages profoundly modulate disease progression, both in terms of number—where depletion has resulted in a reduced glomerular lesion—and sub-phenotype—M1 being more profoundly detrimental than M2. This evidence is corroborated by better outcomes in patients with a lower number of glomerular macrophages. However, due to the very limited biopsy sample size, the type and role of macrophage subpopulations involved in human proliferative lesions is more difficult to precisely define and synthesize. Therefore, specific biomarkers of macrophage activation may enhance our ability to assess their role, potentially enabling improved monitoring of drug activity and ultimately allowing the development of novel therapeutic strategies to target these elusive cellular players.
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Hameed, Abdul, Syed Asif Raza, Qadeer Ahmed, Faisal Khan, and Salim Ahmed. "A decision support tool for bi-objective risk-based maintenance scheduling of an LNG gas sweetening unit." Journal of Quality in Maintenance Engineering 25, no. 1 (March 11, 2019): 65–89. http://dx.doi.org/10.1108/jqme-04-2017-0027.
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Purpose The purpose of this paper is to develop a decision support tool for risk-based maintenance scheduling for a large heavily equipped gas sweetening unit in a Liquefied Natural Gas (LNG) plant. Two conflicting objectives, i.e., total maintenance cost and the reliability, are considered in the tool. The tool is tested with the real plant data and suggests several Pareto-optimal schedules for a decision maker to choose from. The financial impacts are assessed. Design/methodology/approach A bi-objective scheduling optimization model is developed for maintenance scheduling using a risk-based framework. The model is developed integrating genetic algorithm and simulation-based optimization to find Pareto-optimal schedules. The model delivered true Pareto front optimal solutions for given plant-specific data. The two conflicting objectives: the minimization of total expenditures incurred on maintenance-related activities and improving the total reliability are considered. Findings For large and complex processing facilities such as LNG plant, a shutdown of facility generates a significant financial impact, resulting in millions of dollars in production loss. The developed risk-based equipment selection strategy helps to minimize such an event of production loss by generating a thorough maintenance strategy for inspection, repair, overhaul or replacement schedule of the unit without initiating the shutdown. The proposed model has been successfully applied to obtain an optimize maintenance schedule for a gas sweetening unit. Research limitations/implications A future work may consider the state-dependent models for various failure modes that will result in obtaining a better representation of the model. The proposed scheduling can further be extended to multi-criteria scheduling including availability, resource limitation and inflationary condition. A comparative analysis with other meta-heuristic techniques such as harmony search algorithm, tabu search, and simulated annealing will further help in confirming the schedule obtained from this application. Practical implications Maintenance scheduling using a conventional approach for special equipment generally does not consider the conflicting objectives. This research addresses this aspect using a bi-objective model. The usefulness of risk-based method is to assist in minimizing the financial and safety risk exposure to the operating companies, but some variation in results is expected due to varying risk matrix for different organizations. Social implications Managing two objectives, i.e., minimizing the cost of maintenance-related activities, while at the same time maximizing the overall reliability dramatically, helps in mitigating adverse safety and financial risk due to fires, explosions, fatality and excessive maintenance cost. Originality/value Research develops a decision support tool for managing conflicting objectives for an LNG process. This research highlights the impact of utilizing the simulation-based approach coupled with risk-based equipment selection for complex processing unit or plant maintenance scheduling optimization.
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Sweiss, Karen, Benjamin G. Barwick, Gregory Sampang Calip, Damiano Rondelli, Craig C. Hofmeister, and Pritesh Patel. "Increased DNA Repair Gene Expression Correlates with MYC Expression and Inferior Progression-Free Survival in Multiple Myeloma Patients." Blood 136, Supplement 1 (November 5, 2020): 48–49. http://dx.doi.org/10.1182/blood-2020-143422.
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High dose melphalan and autologous stem cell transplantation is standard of care for the upfront treatment of multiple myeloma (MM). Several studies have shown upregulation of single DNA repair genes and whole DNA repair pathways as associated with melphalan resistance and poor outcomes after ASCT. Here we set out to identify the most important DNA repair enzymes and pathways to predict outcomes after ASCT using the MMRF CoMMpass dataset but instead found DNA repair gene expression to be a poor prognostic feature regardless of treatment. Of the 561 MM patients who received ASCT as part of frontline therapy, 378 (67%) patients had whole transcriptome sequencing data available for analysis in this study. The majority of patients in this cohort received a 3-drug novel agent-based regimen for first line treatment. We selected 81 genes of known function related to DNA damage repair across multiple pathways. Using the median mRNA expression as cutoff for each gene, we first compared PFS for high vs. low expressers and found 38 genes in non-homologous end joining (NHEJ), homologous recombination (HR), nucleotide excision repair (NER), base excision repair (BER) and Fanconi anemia (FA) pathway which predicted for inferior survival with higher expression (p≤0.05). We subsequently analyzed each gene individually in a multivariate Cox proportional hazards models adjusted for known prognostic and treatment-related factors (age, gender, race, ISS stage, LDH, normal/abnormal cytogenetics, high risk FISH/cytogenetics, cycles to first response, frontline treatment, and time to transplant) and found that 9 genes retained significance including 3 genes in NHEJ (POLL, PRKDC, NHEJ1), 3 in FA pathway (BRIP1, RMI1, FANCE) and 3 in MMR (MLH3, MSH2 and PMS1). In addition, increased pathway level gene overexpression for NHEJ (p=0.02) and MMR (0.009) pathways conferred worse PFS. Genes involved in NER did not retain significance despite this pathway being involved with repair of melphalan-induced bulky adducts formation. Additionally, high MMR pathway expression was significant despite this pathway not having a known role in repair of melphalan-induced DNA damage. To validate the specific importance of these genes in predicting response to ASCT, we tested whether high expression predicted outcomes in patients who did not undergo ASCT. In 387 non-ASCT patients with whole transcriptome sequencing available, NHEJ and MMR gene expression were significant predictors of PFS confirming that this finding was not specific to patients undergoing ASCT. We next correlated the expression of NHEJ and MMR genes and found significant co-expression of these genes (r=0.55-0.8), suggesting a common mediator leading to global upregulation of DNA repair. As increased MYC activity is a common finding in MM and is a master regulator of transcription, we hypothesized the DNA damage repair genes were upregulated by increased MYC activity. Gene Set Enrichment Analysis of hallmark gene sets confirmed that patients with increased DNA repair were also enriched for MYC targets (FDR=0.0063). Based on this, we hypothesized that oncogene-mediated constitutive DNA damage and replication stress (RS) are a hallmark of high risk and aggressive myeloma. Here we present novel findings to show that global DNA repair upregulation occurs in high risk disease as evidenced by the inferior PFS. We hypothesize that this could be attributed to MYC-related increased gene transcription resulting in DNA damage and RS which in turn recruits several DNA repair pathways. These specific DNA repair pathways and signal activation pathways involved with replication stress represent novel therapeutic targets in myeloma. Disclosures Calip: Flatiron Health: Current Employment. Hofmeister:Sanofi: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Nektar: Honoraria, Research Funding; Imbrium: Honoraria; Janssen: Honoraria, Research Funding; Oncopeptides: Honoraria; Karyopharm: Honoraria, Research Funding; Oncolytics Biotech: Research Funding. Patel:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy.
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Ciardiello, Fortunato, Yung-Jue Bang, Johanna C. Bendell, Andres Cervantes, Rainer Karl Brachmann, Yuting Zhang, Mitch Raponi, Heinrich Farin, and Shen Lin. "A phase III, double-blind, randomized study of pamiparib versus placebo as maintenance therapy in patients with inoperable, locally advanced, or metastatic gastric cancer (GC) that responded to platinum-based first-line chemotherapy." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): TPS173. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.tps173.
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TPS173 Background: Gastric cancer is the fifth most common cancer, and is the third leading cause of cancer deaths worldwide. In patients with locally advanced or metastatic GC, fluoropyrimidine- and platinum-based combination chemotherapy is first-line standard of care. Despite refinement in chemotherapy regimens, outcomes are poor and survival after first-line treatment remains low. A subset of GCs exhibit platinum sensitivity and genomic instability that is characteristic of homologous recombination deficiency (HRD). Poly (ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) are involved in DNA damage repair, and their inhibition is cytotoxic for cells with HRD. Pamiparib is a selective PARP1/2 inhibitor that crosses the blood-brain barrier, has shown potent DNA–PARP trapping, and has demonstrated antitumor activity in preclinical models. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg oral twice daily (BID) was established as the recommended dose. Methods: This ongoing, global, double-blind, placebo-controlled, randomized, multicenter phase III study (NCT03427814) is designed to compare the efficacy, safety, and tolerability of pamiparib vs placebo as maintenance therapy in ~540 patients with advanced GC who have responded to first-line, platinum-based chemotherapy. Patients who are ≤ 8 weeks after their last dose of first-line platinum based chemotherapy will be randomized 1:1 to receive either pamiparib 60 mg BID or placebo in 28-day cycles. Patient randomization will be stratified by genomic loss of heterozygosity status (ie, high vs low), region, and ECOG status. Radiologic assessments will be centrally evaluated per RECIST every 8 weeks after first dose. The primary endpoint is progression-free survival; key secondary endpoints include safety/tolerability, overall survival, objective response rates, time and duration of response, and time to second subsequent treatment. Correlative biomarker analyses in tumor tissues and blood will be performed. Clinical trial information: NCT03427814.
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Lund-Ricard, Yasmine, Patrick Cormier, Julia Morales, and Agnès Boutet. "mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases." International Journal of Molecular Sciences 21, no. 8 (April 14, 2020): 2718. http://dx.doi.org/10.3390/ijms21082718.
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A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.
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Lamb, Lawrence S., Shirley Gibbs, Thriumaine Pillay, Melissa Beelen, William Ho, and Louis B. Nabors. "Phase I trial of drug resistant immunotherapy: A first-in-class combination of MGMT-modified γδ t cells and temozolomide chemotherapy in newly diagnosed glioblastoma multiforme." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS3150. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3150.
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TPS3150 Background: Temozolomide (TMZ) transiently upregulates GBM-specific stress-induced NKG2D ligands that are targeted by innate immune effector cells. Leveraging this effect is problematic, however, due to the lymphodepleting effects of TMZ.Genetic modification of ex vivo expanded and activated with an MGMT-expressing lentivector allows simultaneous chemotherapy and γδ T cell therapy that targets the tumor when NKG2DL are maximally expressed. We have termed this Drug Resistant Immunotherapy (DRI). Patient-derived xenograft mouse models of both primary and recurrent GBM treated with DRI have shown a significant survival advantage that were otherwise impervious to either cell therapy or TMZ. These preclinical findings and associated safety data provide the rationale to initiate a Phase I trial of DRI in primary GBM. Methods: This first in human study will evaluate the safety and optimal dosing frequency of the DRI with TMZ (NCT04165941).Eligibility criteria include the following: GBM eligible for resection, ≥18y, adequate organ and marrow function, and KPS≥70. Six to 12patients with newly diagnosed GBM are being enrolled in a 3 + 3 design into 1 of 2 fixed dose levels (DL) of DRI. Following tumor resection and immediately prior to induction chemo/radiotherapy, an apheresis product is collected and γδ T cells expanded in Zoledronic Acid (Novartis) and rhIL-12 (Miltenyi) and transduced with a P140K-MGMT lentivector (Miltenyi Lentigen, Gaithersburg, MD), harvested, and cryopreserved. At initiation of maintenance phase TMZ therapy, patients receive 150mg/m2 intravenous TMZ concurrently with intracranial injection of 1 x 107 γδ T cells (DL1) delivered through a Rickham reservoir previously inserted into the tumor cavity at resection. The patient then receives 4 daily doses of oral TMZ followed by 24d rest. Treatment cycles escalate from 1 to 3 (DL2) DRI doses following a safety observation period and absence of dose limiting toxicity. Maintenance TMZ treatment will continue for 6 cycles. Safety evaluations consist of routine laboratory analyses, clinical measurements (physical exams, vital signs), neurological function and evidence DRI γδ T cell related toxicity. Peripheral blood will be obtained for comprehensive immuno-phenotyping and T cell function analysis. Clinical benefit of DRI will be characterized by evaluating responses (CR, PR, SD and PD) and determining progression-free, median, and overall survival. As of February 2020, enrollment into DL 1 is ongoing. Clinical trial information: NCT04165941 .
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Patnaik, Srinivas, Sudeep P. George, Eric Pham, Swati Roy, Kanchan Singh, John M. Mariadason, and Seema Khurana. "By moonlighting in the nucleus, villin regulates epithelial plasticity." Molecular Biology of the Cell 27, no. 3 (February 2016): 535–48. http://dx.doi.org/10.1091/mbc.e15-06-0453.
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Villin is a tissue-specific, actin-binding protein involved in the assembly and maintenance of microvilli in polarized epithelial cells. Conversely, villin is also linked with the loss of epithelial polarity and gain of the mesenchymal phenotype in migrating, invasive cells. In this study, we describe for the first time how villin can switch between these disparate functions to change tissue architecture by moonlighting in the nucleus. Our study reveals that the moonlighting function of villin in the nucleus may play an important role in tissue homeostasis and disease. Villin accumulates in the nucleus during wound repair, and altering the cellular microenvironment by inducing hypoxia increases the nuclear accumulation of villin. Nuclear villin is also associated with mouse models of tumorigenesis, and a systematic analysis of a large cohort of colorectal cancer specimens confirmed the nuclear distribution of villin in a subset of tumors. Our study demonstrates that nuclear villin regulates epithelial–mesenchymal transition (EMT). Altering the nuclear localization of villin affects the expression and activity of Slug, a key transcriptional regulator of EMT. In addition, we find that villin directly interacts with a transcriptional corepressor and ligand of the Slug promoter, ZBRK1. The outcome of this study underscores the role of nuclear villin and its binding partner ZBRK1 in the regulation of EMT and as potential new therapeutic targets to inhibit tumorigenesis.
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Przespolewski, Amanda, Elizabeth A. Griffiths, James E. Thompson, Amro Elshoury, Ashkan Emadi, Vu H. Duong, Sandrine Niyongere, et al. "Phase 1/1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-141736.
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Background: Poly (ADP-ribose) polymerase (PARP) enzymes are involved in repair of single-strand DNA breaks through base excision repair pathways. Inhibitors of PARP are approved for the treatment of BRCA1/2-mutant malignancies where they result in compromise of dual DNA damage repair pathways, leading to induction of double-strand DNA breaks during replication and ultimately cell death. We have previously demonstrated (Portwood et al, ASH 2019 abstract) that PARP inhibitors can reduce in vitro acute myeloid leukemia (AML) growth and can synergistically enhance the anti-leukemic activity of antibody-drug conjugates containing DNA-damaging cytotoxic agents in preclinical human AML models. Talazoparib (Tala) is a novel selective PARP inhibitor which has been shown to exert more potent growth inhibitory effects across a panel of human AML cell lines than four other PARP inhibitors (veliparib, olaparib, rucaparib, niraparib). Gemtuzumab ozogamicin (GO) is an approved drug consisting of an antibody against human CD33 (gemtuzumab) linked to a cytotoxic component (calicheamicin). Hypothesis: We hypothesize that the combination of Tala + GO will be well tolerated and will result in improved clinical efficacy as compared with historical outcomes of GO monotherapy in patients with relapsed or refractory (R/R) AML. Objectives: The primary objectives of this study are (a) to determine the safety and tolerability of Tala + GO therapy in R/R AML; (b) to determine the overall response rate (ORR = complete remission (CR) + complete remission with incomplete hematologic recovery (CRi)) of combination therapy in patients with R/R AML. Additional anti-leukemic effects will be reported including complete remission rate, best response rate, duration of remission, leukemia-free survival, transfusion independence, and overall survival. Exploratory aims include measurable residual disease, evidence of PARP inhibition and DNA damage, feasibility of subsequent allogeneic stem cell transplant, and quality of life. Study Design: This open-label multi-center, Phase 1/1b trial is designed to determine whether the combination of Tala and GO represents a safe and effective approach for R/R AML. Eligible patients are adults aged ≥18 years with CD33-positive AML whose disease has failed to respond to and/or has recurred following at least one prior line of chemotherapy. There are two parts of the study: dose escalation and dose expansion. The dose escalation portion will establish the recommended Phase 2 dose (RP2D) of Tala in combination with GO. Cohorts of 3 subjects will be treated at one of three dose levels of Tala (0.5 mg, 0.75 mg, and 1 mg orally daily) in combination with fixed doses of GO (3 mg/m2/day on days 1,4, and 7, capped to one 4.5 mg vial) using a standard 3+3 subject cohort dose evaluation. Treatment will be given in 28-day cycles. The dose limiting toxicity (DLT) window will be Cycle 1 Day 1 to 28. Therapy may be given in the outpatient setting. Following determination of the RP2D, an expansion cohort of patients will be treated with the combination of Tala + GO for preliminary assessment of toxicities and anti-leukemic efficacy. Bone marrow assessment will be performed on Day 28 of Cycles 1 and 2. Safety and activity will be assessed using descriptive statistical analysis. If a patient achieves CR/CRi after cycles 1-2, the GO dose will be reduced to a maintenance dose of 2 mg/m2 on day 1 only of every subsequent cycle until disease progression or for a maximum of 6 total cycles of therapy. Patients not achieving a clinical response after 2 cycles will stop treatment. Treatment duration will be up to six months. This trial was activated in July 2020 and is registered at ClinicalTrials.gov (NCT04207190). Accrual is ongoing. Disclosures Griffiths: Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Boston Biomedical: Honoraria; Persimmune: Research Funding; AbbVie Inc: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Emadi:Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Wang:Stemline: Speakers Bureau; Astellas: Consultancy; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau.
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Sharma, Ricky A., Tom Macgregor, Richard Gillies, Stephanie Hatch, Lonnie Swift, TIM Humphrey, Runjan Chetty, Peter J. McHugh, and Mark R. Middleton. "Use of DNA repair proteins translated from biomarker screening to predict overall survival in patients with esophageal cancer treated with oxaliplatin chemotherapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13587-e13587. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13587.
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e13587 Background: Oxaliplatin is first-line chemotherapy for colorectal, gastric, and esophageal cancers. Aim was to identify key determinants of oxaliplatin sensitivity and optimise these biomarkers to select patients for chemotherapy. Methods: High-throughput screening of oxaliplatin sensitivity was performed in a Schizosaccharomyces pombe deletion library of 229 DNA repair strains and Chinese Hamster Ovary (CHO) cell lines with mutations in specific proteins. Biopsies were taken from 50 patients with esophageal cancer, who then received two cycles of oxaliplatin and fluorouracil chemotherapy prior to surgery. Levels of DNA repair proteins were quantified by immunohistochemistry and by qRT-PCR. Results: Twelve lead biomarkers were identified from the preclinical models. In CHO cells, XPF and ERCC1 mutants were approximately 30 times more sensitive than the WT cells (p<0.01). In comparison to WT CHO cells, XPF-deficient cells had prolonged delay in mid-late S-phase after oxaliplatin treatment, and persistence of double strand breaks for at least 48 hours. Modified Comet assay confirmed persistence of inter-strand crosslinks created by oxaliplatin. Cells deficient in DNA polymerase eta (pol eta) also accumulated in S-phase and were 3-fold more sensitive (p<0.01) to oxaliplatin treatment than pol eta-complemented cells. Knockdown of XPF, ERCC1 or pol eta sensitised both oxaliplatin-resistant and oxaliplatin-sensitive HCT116 cells to oxaliplatin. In patients with esophageal cancer, low or absent XPF protein expression predicted complete pathological response to chemotherapy with a sensitivity of 58% and specificity of 72%. Cyclin A protein levels (univariate analysis, p<0.005) and pol eta mRNA levels (multivariate analysis, P<0.005) in pre-treatment esophageal biopsies correlated with overall survival. Conclusions: Results suggest that inter-strand DNA cross-links are the principal cytotoxic lesions created by oxaliplatin. Homologous recombination and damage checkpoint proteins are leading biomarkers for patient selection. In patients with esophageal cancer, XPF and pol eta predict response to oxaliplatin chemotherapy.
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Sadridinov, A. B. "Analysis of energy performance of heading sets of equipment at a coal mine." Gornye nauki i tekhnologii = Mining Science and Technology (Russia) 5, no. 4 (January 6, 2021): 367–75. http://dx.doi.org/10.17073/2500-0632-2020-4-367-375.
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The growth of volume of tunneling, power supplied per job, and consumption of fuel and energy resources makes it necessary to increase energy performance of production processes with reducing energy losses. Tunneling conditions are determined by a combination of mutually influencing factors (geological, technological and organizational), and assessing their impact on tunneling energy performance requires a deep detailed study. For criterion assessment of tunneling performance, indicators of energy consumption, performance, and quality of tunneling performed by shift crews, allowing to objectively assess their work, were proposed. Indicators of process and specific power consumption in the process of tunneling vary over a wide range, therefore, to ensure smooth equipment operation, shift crews must adhere to the recommended indicators that determine the optimum rates of tunneling and enables adherence to permissible operation modes. Statistical models of energy performance indicators of heading sets of equipment operation were investigated using the example of the Severnaya coal mine. Indicators of energy consumption, energy performance, and tunneling (on shift basis) were proposed. Distribution laws have been determined for the main indicators characterizing tunneling energy performance. Recommendations have been developed to ensure sustainable operation of heading sets of equipment throughout the entire period of tunneling. Tunneling requires permanent monitoring its parameters and rates of advance, the quality of face preparation, timely maintenance and repair of machinery and equipment, control of the process through ensuring optimal operating modes of the heading sets of equipment.
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Sadridinov, A. B. "Analysis of energy performance of heading sets of equipment at a coal mine." Gornye nauki i tekhnologii = Mining Science and Technology (Russia) 5, no. 4 (January 6, 2021): 367–75. http://dx.doi.org/10.17073/2500-0632-2020-4-367-375.
Full textAbstract:
The growth of volume of tunneling, power supplied per job, and consumption of fuel and energy resources makes it necessary to increase energy performance of production processes with reducing energy losses. Tunneling conditions are determined by a combination of mutually influencing factors (geological, technological and organizational), and assessing their impact on tunneling energy performance requires a deep detailed study. For criterion assessment of tunneling performance, indicators of energy consumption, performance, and quality of tunneling performed by shift crews, allowing to objectively assess their work, were proposed. Indicators of process and specific power consumption in the process of tunneling vary over a wide range, therefore, to ensure smooth equipment operation, shift crews must adhere to the recommended indicators that determine the optimum rates of tunneling and enables adherence to permissible operation modes. Statistical models of energy performance indicators of heading sets of equipment operation were investigated using the example of the Severnaya coal mine. Indicators of energy consumption, energy performance, and tunneling (on shift basis) were proposed. Distribution laws have been determined for the main indicators characterizing tunneling energy performance. Recommendations have been developed to ensure sustainable operation of heading sets of equipment throughout the entire period of tunneling. Tunneling requires permanent monitoring its parameters and rates of advance, the quality of face preparation, timely maintenance and repair of machinery and equipment, control of the process through ensuring optimal operating modes of the heading sets of equipment.
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Aulin, Viktor, Andrey Grinkiv, and Artem Holovatyi. "Cyberphysical Approach to the Creation, Operation and Improvement of Transport and Production Systems." Central Ukrainian Scientific Bulletin. Technical Sciences, no. 3(34) (October 2020): 331–43. http://dx.doi.org/10.32515/2664-262x.2020.3(34).331-343.
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The content of the cyberphysical approach to the creation, functioning and improvement of transport and production systems is analyzed. It was found out how, on the basis of the approach, cyberphysical transport and production systems are created as the integration of special technologies of the Internet of Things; embedded systems; ubiquitous and cloud computing. It was revealed that cyberphysical transport and production systems have a trinitarian concept and are defined by three entities: communication, computation and control, which unites information. It is determined that the main functions of cyberphysical transport and production systems are: information processing, intelligent communications, performance and process control. A component model of such a system has been built, which includes two groups of components - evolutionary and technological. The evolutionary group of components includes subsystems: digital; integrated; robotic, intelligent distributed. These components are a kind of basis for the presence of prerequisites for the creation of transport and production systems. It is noted that the technology group of components is the basis for concrete implementations of the Internet of Things, embedded systems and ubiquitous and cloud computing. A cyberphysical system of technical service is proposed as a specific implementation of cyberphysical transport and production systems. It was determined that the modes of the proposed functional cyber system are: high adaptability; an appropriate level of efficiency; intelligence of management; high level of reliability; the use of a new on-net online simulation type; using a new type of self-verifying models; internal online optimization, etc. It is shown that the presence of intelligent models in the cyberphysical model of technical service makes the system resistant to cyberattacks and increases the degree of safety when ensuring traffic in transport and the development of an occupational safety system during maintenance and repair operations.
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Young, In-Chi, Sung-Ting Chuang, Amit Gefen, Wei-Ting Kuo, Chun-Ting Yang, Chia-Hsien Hsu, and Feng-Huei Lin. "A novel compressive stress-based osteoarthritis-like chondrocyte system." Experimental Biology and Medicine 242, no. 10 (March 22, 2017): 1062–71. http://dx.doi.org/10.1177/1535370217699534.
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Mechanical stress damage and insufficient self-repair can contribute to osteoarthritis (OA) in the affected joint. As the effects of stress on chondrocyte metabolism can regulate cartilage homeostasis, the specific stress–response condition is therefore a key to the generation of an OA disease model. We aimed to produce a specific stress- and cell-based OA model after evaluating the metabolic responses of chondrocytes in response to a series of static and cyclic compression stressors. A static load exceeding 40 psi initiated extracellular matrix (ECM) degradation through a decrease in the sulphated-glycosaminoglycan (GAG) content, upregulation of catabolic matrix metalloproteinase (MMP)-13 encoding gene expression, and downregulation of the ECM-related aggrecan and type II collagen encoding genes within 24 h. Indicators of pro-inflammatory events and oxidative stress were found to correlate with increased IL-6 expression and reactive oxygen species (ROS) production, respectively. However, chondrocytes stimulated by moderate cyclic loading (30–40 psi) exhibited increased ECM-related gene expression without significant changes in catabolic and pro-inflammatory gene expression. BMP-7 expression increased at cyclic loading levels above 30–60 psi. These results demonstrated that static compression exceeding 60 psi is sufficient to produce OA-like chondrocytes that exhibit signs of ECM degradation and inflammation. These OA-like chondrocytes could therefore be used as a novel cell-based drug screening system. Impact statement The lack of an effective treatment for osteoarthritis (OA) reflects the great need for alternative therapies and drug discovery. Disease models can be used for early-stage compound screening and disease studies. Chondrocytes are solely responsible for the maintenance of the articular cartilage extracellular matrix. Our strategy involved the generation of a cell-based model of OA, a more readily studied disease. Instead of using animal cartilage explants, we incorporated isolated porcine chondrocytes with hydrogel to form three-dimensional assemblies. We could identify the specific magnitude-dependent metabolic responses of chondrocytes by applying a series of static and cyclic compression, and therefore successfully generated a novel OA-like cell-based model for drug screening.
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Gouda, K., P. Rycerz, A. Kadiric, and GE Morales-Espejel. "Assessing the effectiveness of data-driven time-domain condition indicators in predicting the progression of surface distress under rolling contact." Proceedings of the Institution of Mechanical Engineers, Part J: Journal of Engineering Tribology 233, no. 10 (March 27, 2019): 1523–40. http://dx.doi.org/10.1177/1350650119838896.
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Condition monitoring of machine health via analysis of vibration, acoustic and other signals offers an important tool for reducing the machine downtime and maintenance costs. The key aspect in this process is the ability to relate features derived from the recorded sensor signals to the physical condition of the monitored asset in real time. This paper uses simple machine learning techniques to examine the ability of specific time-domain features obtained from vibration signals to predict the progression of surface distress in lubricated, rolling-sliding contacts, such as those found in rolling bearings and gears. Controlled experiments were performed on a triple-disc rolling contact fatigue rig using seeded-fault roller specimens where micropitting damage was generated and its progression directly observed over millions of contact cycles. Vibration signals were recorded throughout the experiments. Features known as condition indicators were then extracted from the recorded time-domain signals and their evolution related to the observed physical state of the associated specimens using simple machine learning techniques. Five time-domain condition indicators were examined, peak-to-peak, root-mean-square, kurtosis, crest factor and skewness, three of which were found not to be redundant. First, a classification model using KNN nearest neighbor was built with the three informative condition indicators as training data. The cross-validation results indicated that this classifier was able to predict the presence of micropitting damage with a relatively high precision and a low rate of false positives. Secondly, a k-means clustering analysis was performed to measure the significance of each condition indicator by leveraging patterns. The peak-to-peak condition indicator was found to be a good predictor for progression of micropitting damage. In addition, this indicator was able to distinguish between micropitting and pitting failure modes with a high success rate. Finally, the condition indicator response was correlated with the predicted damage state of the test specimen obtained through an existing physics-based surface distress model in order to illustrate the potential of hybrid models for improved prognostics of damage progression in rolling-sliding tribological contacts.
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Stewart, Rainey A. "Endosymbiont bacteria Holospora undulata confers oxidative tolerance in host Paramecium caudatum." IU Journal of Undergraduate Research 2, no. 1 (May 31, 2016): 41. http://dx.doi.org/10.14434/iujur.v2i1.20912.
Full textAbstract:
Paramecium is a genus of ciliated protozoan that, while unicellular, has a complex intracellular structure, comparable to Metazoan cells, which has made them excellent models for the study of genetics and cellular functions. Holospora undulata is a bacterial endosymbiont specific to the species Paramecium caudatum; they are unable to grow outside of P. caudatum. The presence of this endosymbiont has proven to have an effect on the subsequent gene expression and cellular maintenance of its host cells. Recent studies have demonstrated that infection by H. obtusa increases the expression of host heat-shock genes and leads to both resistance at normally-lethal high temperatures and heat resistance in ciliary movement (Fujishima, Kawai, & Yamamoto, 2005; Hori & Fujishima, 2003). Heat-shock resistance occurs because bacterial DNA triggers the upregulation of its P. caudatum host’s heat-shock genes (i.e., hsp60 and hsp70), although the mechanisms are not known (Hori & Fujishima, 2003). These studies demonstrate that infection of P. caudatum by H. undulata (a closely-related species to H. obtusa) induces heat-shock resistance, but fail to address whether H. undulata protects against other common environmental stressors such as oxidative damage. To determine if infection by H. undulata has the ability to induce additional tolerances, we examined differences in oxidative tolerance, based on percent survival, between P. caudatum with and without H. undulata infection. Samples of both lines were treated with increasing concentrations of hydrogen peroxide, the number of surviving cells were counted, and the percent survivability of each sample was calculated. There was an approximate 20% increase in survival when P. caudautum was infected with H. undulata—thus H. undulata infections confer oxidative tolerance. Further studies will be conducted to determine if an increase in survivability occurs in response to other damaging mechanisms. Future work will also investigate if the genes responsible for oxidative damage repair are upregulated, in addition to the already characterized heat-shock genes.
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Ovsiannikov, V. E., and V. I. Vasiliev. "Development of model for human factor influence assessment on construction and road machines operation efficiency." Russian Automobile and Highway Industry Journal 17, no. 4 (August 28, 2020): 476–86. http://dx.doi.org/10.26518/2071-7296-2020-17-4-476-486.
Full textAbstract:
Introduction. The human factor and the characteristics of construction and road machine operators, such as experience, work experience, professional skills, skill, etc., have a significant impact on the efficiency of equipment operation. The human factor, on average, is the cause of about a third of the failures of construction and road machines. One of the most effective ways out of this situation is to improve the machines from the point of view of ensuring the compatibility of the elements of the human-machine system. The article considers the issues of the engineering and psychological component of compatibility.Materials and methods. The method of analysis of hierarchies is used, when solving the problem of identifying the causes of operators’ errors and fuzzy logic, to build a model for assessing the impact of the human factor on the efficiency of construction and road machines.Results. As a result of a comprehensive assessment of the causes of errors, it was found that the largest combination of criteria is a group of errors associated with the peculiarities of the task being performed, as well as the properties of the information processed by a person. The developed model for assessing the influence of the human factor on the efficiency of machine operation uses risk as an output variable, and input variables a generalized indicator of the complexity of the algorithm and the level of qualification of the machine operator.Discussion and conclusions. The resulting model allows you to make a primary assessment of the impact of the human factor and maintenance and repair planning, as well as be used in personnel management processes, for example, in terms of sending personnel for training. Further improvement is seen in the development of neurofuzzy anfys models which provide a knowledge base for more effective risk assessment by specific precedents. The structure of the model in terms of input variables for a more correct risk assessment is also possible to be changed.
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Teixeira, Luis, Jacques Medioni, Ludovic Doucet, Stephane Culine, Stephane Oudard, Olivier Adotevi, Marie-Agnès Dragon Durey, et al. "Results of a first-in-human phase I study of INVAC-1, an optimized plasmid DNA encoding an inactive form of human telomerase reverse transcriptase (hTERT), in patients with advanced solid tumors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 3087. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.3087.
Full textAbstract:
3087 Background: INVAC-1 is an optimized plasmid encoding an inactive form of human telomerase reverse transcriptase (hTERT). hTERT is a prototype of shared tumor antigen expressed in more than 85% of human tumors. Telomerase activation is associated with maintenance of telomere length and accounts for the unlimited proliferative capacity of cancer cells. In preclinical models, INVAC-1 triggered Th1-polarized hTERT-specific CD8+ and CD4+T-cell immune responses and anti-tumor effects. Here, we report clinical and pharmacodynamics results of the first clinical study with INVAC-1 as a single agent in solid tumors. Methods: A 3+3 design phase 1 First in Human study evaluating INVAC-1 given monthly for 3 cycles using electroporation-based intra-dermal (ID) injection was conducted. Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included immune response and anti-tumor activity. Results: 20 patients (pts) with refractory/progressive solid tumors were enrolled in two centers. 3 escalating doses were studied: 100 µg (3 pts), 400 µg (3 pts) and 800 µg (14 pts). At 3-month data cut-off, no dose limiting toxicities or treatment related SAEs have been reported; no MTD was defined. The most common treatment-related adverse events were grade 1 or 2: asthenia and local reaction at injection site. 12 pts experienced stable disease and clinical benefit. For 10 pts, the treatment was extended beyond the per-protocol 3-month duration, up to nine months for 2 pts. IFN-g polarized anti-hTERT immune responses were detected in 55% of pts, in response to INVAC-1 treatment. Conclusions: Results from this study indicate that INVAC-1 ID was safe, well tolerated and strongly immunogenic at the doses and schedule tested. Early anti-tumor activity has been observed. The RP2D of INVAC-1 is therefore a monthly ID injection of 800 µg. These results encourage a future evaluation of INVAC-1 is solid tumors, as well as in hematologic malignancies, either as monotherapy or in combination with various immunotherapeutic drugs. Clinical trial information: NCT02301754.