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1
Hamed, G. R., and K. Umetsu. "Gum and Black-Filled Double Networks of cis-1,4-Polyisoprene Crosslinked with Sulfur Donors: Part I. Tensile Properties." Rubber Chemistry and Technology 78, no. 1 (March 1, 2005): 130–42. http://dx.doi.org/10.5254/1.3547866.
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Abstract Gum and black-filled double networks of cis-1,4 polyisoprene, crosslinked with sulfur donors, have been prepared by first partially curing sheets, then stretching them and completing cure. Double networks are anisotropic and exhibit a residual extension ratio λr, which is higher for filled compared to gum samples. Additionally, double networks of filled specimens have higher anisotropy than gum counterparts, presumably because carbon black promotes chain alignment and strain-crystallization. Tensile specimens cut parallel to the stretch direction are stiffer, less extensible, and sometimes stronger than simple isotropic networks, while perpendicular specimens have stress-strain responses much like that of the isotropic control.
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Takagaki, Kazunori, Shinsaku Hisada, Shu Minakuchi, and Nobuo Takeda. "Process improvement for out-of-autoclave prepreg curing supported by in-situ strain monitoring." Journal of Composite Materials 51, no. 9 (October 13, 2016): 1225–37. http://dx.doi.org/10.1177/0021998316672001.
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Vacuum-bag-only curing is an attractive out-of-autoclave method as an alternative to conventional autoclave curing. Previous extensive researches provided great insight into void formation during the vacuum-bag-only method and these findings are reflected in current vacuum-bag-only cure cycles to minimize void content. Cure process can be further improved by taking into consideration cure-induced residual stress/strain. The present paper proposed a residual stress/strain reduction method and evaluated its effectiveness using a commercially available vacuum-bag-only material by fiber-optic-based in-situ strain monitoring and tensile tests. First, cure process monitoring and tensile tests were conducted for the manufacturer’s recommended cure cycle. Cure process monitoring showed that the material vitrifies during post-cure temperature dwell. Furthermore, the tensile test revealed that the vacuum-bag-only material has lower strength than conventional autoclave materials, suggesting the importance of the effect of cure-induced residual stress/strain. Then, two cure cycles were proposed based on the findings from the manufacturer’s recommended cure cycle tests and a cure kinetics model. In the proposed cycles, resin vitrifies at a lower temperature than the manufacturer’s recommended cure cycle, leading to reduced residual stress/strain. Cure process monitoring and tensile test results for the new cycles showed that the residual strain was reduced by 12–18%, and the strength was increased by 26% in the best case. Moreover, void content was not significantly affected by changing the cure cycle. Although vacuum-bag-only material was used in this research, the proposed concept can be widely applied for autoclave cures and other types of vacuum-bag-only processes with slight modification.
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Jiang, Cheng Biao, Li Hua Zhan, Xiao Bo Yang, Xiao Ping Chen, Zi Jun Lin, and Cheng Long Guan. "Monitoring of Multidirectional and Cure-Induced Strain in CFRP Laminates Using FBG Sensors." Materials Science Forum 953 (May 2019): 72–79. http://dx.doi.org/10.4028/www.scientific.net/msf.953.72.
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During the curing cycle, the residual stress has influence on cure-induced deformation for carbon fiber reinforced plastics (CFRP) laminates, which is highly susceptible to the ply design. Therefore, the change laws of strain and the effect of residual stress in CFRP laminates after curing, which is of great significance to ply design, were cleared by using the combining pattern of thermocouple and fibre Bragg grating (FBG) sensors. For the FBG sensors embedded with different directions in lay-up CFRP laminates, the temperature and strain in different directions of composite laminates were obtained in real-time. Monitoring results show that compared with strain in 45° direction, the carbon fibers (CF) act stronger to inhibit strain in 0° direction and weaker to inhibit strain in 90° direction of resin. After curing, the residual strain in 0° direction is tensile strain, and the residual strain in 45° direction and 90° direction are compressive strain. Meanwhile the value of residual strain in 90° direction is greater than that in 45° direction.
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Drake, Daniel A., Rani W. Sullivan, Jonathan E. Spowart, and Katie Thorp. "Influence of cure parameters in polymer matrix composites using embedded optical fibers." Journal of Composite Materials 54, no. 19 (January 22, 2020): 2611–21. http://dx.doi.org/10.1177/0021998319899153.
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The influence of cure processing parameters was investigated using strain distributions from embedded optical fibers. The determination of optimized cure parameters is often needed to achieve material properties which meet aerospace industry design requirements. Optical fibers were embedded near the midplane of thin (5 mm; [0/90/90/0]3s) composite laminates to monitor the internal strain during cure for two different cure cycles (manufacturer-recommended and an alternative two-step cure). Each laminate was fabricated using a vacuum-assisted resin transfer molding process. The internal strain with respect to the spatial position and time were monitored. During cure, greater variations in the strain near the vicinity of the laminate edges were observed. However, a two-step cure cycle revealed that the variation of strain near the laminate edges is reduced. The results demonstrate the capability of high-spatial resolution optical fibers to measure the in-situ cure and residual strain during the processing of composite structures.
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Lee, Soo Yong, and Jung Sun Park. "Chemical Shrinkage and Residual Stresses in Laminated Composites during Cure." Key Engineering Materials 297-300 (November 2005): 2870–75. http://dx.doi.org/10.4028/www.scientific.net/kem.297-300.2870.
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The residual stress that occurs in fiber-reinforced thermosetting composite materials during cure is one of the severe factors that can deteriorate the performance of composite structures. To investigate residual stresses occurring in laminated composites during cure, an incremental viscoelastic constitutive equation is derived as a function of temperature, degree of cure and chemical shrinkage. A finite element program is developed on the basis of a 3-D degenerated shell element and the first order shear deformation theory. Experiments were performed to measure the coefficients of chemical shrinkage of the Hercules AS4/3501-6 composite during cure. Residual strains were measured using strain gages during cure and compared with the results of finite element analysis. Good agreement is found between numerical and experimental results. It is found that the chemical shrinkage seriously affects the residual strains of the composite during cure.
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Gasser, Elisabeth, Pamela Kogler, Andreas Lorenz, Reinhold Kafka-Ritsch, Dietmar Öfner, and Alexander Perathoner. "Do we still need CRS and HIPEC in colorectal cancer in times of modern chemotherapy and immunotherapy?" memo - Magazine of European Medical Oncology 13, no. 4 (September 18, 2020): 430–33. http://dx.doi.org/10.1007/s12254-020-00647-4.
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SummaryPeritoneal carcinomatosis from colorectal cancer is associated with a poor prognosis and is usually treated with systemic chemotherapy and immunotherapy alone. In patients with isolated peritoneal carcinomatosis (PC) without nonperitoneal metastases, however, cytoreductive surgery (CRS) has been shown to significantly improve outcome and to achieve even cure in selected patients in combination with systemic therapy. The additional use of a hyperthermic intraperitoneal chemotherapy (HIPEC) is primarily indicated to control microscopical residual tumor tissue in the peritoneal cavity after successful CRS. Another more recent option is the application of an adjuvant HIPEC to prevent peritoneal carcinomatosis in high risk patients with pT4 cancer or perforated cancer at the time of or after primary surgery. The aim of this short review is to highlight the corresponding available literature and assess the role of CRS and HIPEC in the context of modern chemotherapy and immunotherapy.
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Antonucci, V., A. Cusano, M. Giordano, J. Nasser, and L. Nicolais. "Cure-induced residual strain build-up in a thermoset resin." Composites Part A: Applied Science and Manufacturing 37, no. 4 (April 2006): 592–601. http://dx.doi.org/10.1016/j.compositesa.2005.05.016.
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Ifju, P. G., X. Niu, B. C. Kilday, S. C. Liu, and S. M. Ettinger. "Residual strain measurement in composites using the cure-referencing method." Experimental Mechanics 40, no. 1 (March 2000): 22–30. http://dx.doi.org/10.1007/bf02327544.
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Crasto, Allan S., Ran Y. Kim, and John D. Russell. "In situ monitoring of residual strain development during composite cure." Polymer Composites 23, no. 3 (June 2002): 454–63. http://dx.doi.org/10.1002/pc.10447.
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Edward, Aghogho Bright, P. Stephan Heyns, and Schalk Kok. "A Numerical Investigation of a Single-Shot in a DEM-FEM Approach to Shot Peening Simulation." Metals 9, no. 11 (November 2, 2019): 1183. http://dx.doi.org/10.3390/met9111183.
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Shot peening (SP) is a controlled and systematic process of surface treatment that has a large number of controllable process parameters that make its application highly challenging. It involves the shooting of small and hard metallic balls at a targeted surface, with the aim of enhancing the fatigue strength of the workpiece under unfavorable service conditions. The compressive residual stress (CRS) induced by this application is expensive to evaluate experimentally. This paper presents a numerical model of the impact of a single-shot on a metallic surface, with the aim to set the stage for a realistic multiple shots peening simulation. The approach proposed herein is a sequential Discrete Element-Finite Element (DE-FE) coupled simulation, based on the use of different types of coefficients of restitution (CoRs) with emphasis on the energetic CoR. The energetic CoR relates the shot/target contact forces to the fractional strain energy needed for localized plastic deformation of the near-surface layer in the workpiece. The generated results of the induced compressive residual stresses (CRS) and equivalent plastic strain (PEEQ) from single-shot simulations are validated with similar results from the literature. Our study clarifies the strain energy aspects of a single-shot impact responsible for the desired effects of CRS and PEEQ, thereby laying the groundwork for accurate and realistic modeling of the SP process via the DEM-FEM approach.
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Zou, Ai Hua, Xian Liang Zhou, Duo Sheng Li, and Xiao Zhen Hua. "Effects of Mg and Si in Al Matrix on Dimensional Stability of SiCp/Al Composites during Temperature Change." Advanced Materials Research 631-632 (January 2013): 335–40. http://dx.doi.org/10.4028/www.scientific.net/amr.631-632.335.
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In this paper, based on the parameters of cumulative residual strain(CRS), the effects of different contents of Mg and Si elements in Al matrix on the dimensional stability of SiCp/Al composites was investigated and analyzed in the temperature interval of 25～400°C. Results show that，with the increasing of Si content in Al matrix, the CRS fluctuates only in a small range of strain, adding Si in Al matrix is beneficial to the dimensional stability of the composites, which can be improved through pre-thermal cycling; with the increasing of Mg content in Al matrix, the absolute value of negative CRS of the composites becomes smaller at the beginning and then turns positive, adding Mg in Al matrix causes the composites expand after several thermal cycling, it is not good to the dimensional stability of the composites and is quite impossible to be improved by pre-thermal cycling. Besides, the CRS in thermal cycling is mainly caused by the plastic relaxation, which results in the irreversible dimensional variation of about 10-5~10-4.
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Lee, Sang Il, Dong Jin Yoon, Seung Seok Lee, and Joung Man Park. "Cure Monitoring and Stress-Strain Sensing of Single-Carbon Fiber Composites by the Measurement of Electrical Resistance." Key Engineering Materials 297-300 (November 2005): 676–84. http://dx.doi.org/10.4028/www.scientific.net/kem.297-300.676.
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Cure monitoring and stress-strain sensing of single-carbon fiber composites were nondestructively evaluated by the measurement of electrical resistance. The difference of electrical resistance before and after curing increased highest when gauge length of the specimen was the smallest. As curing temperature increased, the electrical behavior of steel fiber was different from that of semi-conductive carbon and SiC fibers. Residual stress built in the fiber was the highest at the fiber axis direction. Whereas residual stress built in the matrix was relatively high at the fiber circumference and radius directions. Residual stress calculated from the experiment was consistent with the results from the finite element analysis (FEA). The strain at low curing temperature was larger than that of higher temperature until the load reached maximum value. The apparent modulus of the electrodeposited composites was higher than that of the untreated composites due to the improved interfacial shear strength (IFSS). The electrical resistance was responded quantitatively with stress-strain behavior during the test. Electrical resistance measurement can be feasible nondestructive techniques to evaluate cure monitoring and stress-strain sensing in the conductive fiber composites.
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Li, Xue Qin, Zi Long Zhang, and Xiao Su Yi. "Monitoring and Characterization of Chemical Shrinkage during Curing in a RTM Resin." Advanced Materials Research 476-478 (February 2012): 2594–98. http://dx.doi.org/10.4028/www.scientific.net/amr.476-478.2594.
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Chemical cure shrinkage of polymer matrix is a significant source of residual strain formation in composite products during curing. In this paper, fiber Bragg grating (FBG) sensors were used to monitor the free strain development caused by chemical shrinkage and compared with results of differential scanning calorimetry and rheological analysis. The results showed that the gel point could be clearly identified by FBG sensors and compressive residual strain of around 800με was caused by isothermal curing reaction after gelation. The relationship between the chemical shrinkage ratio and conversion degree was found to be nonlinear.
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Namsone, Endija. "INVESTIGATION OF RESIDUAL STRESSES AND DEFORMATIONS OF A PULTRUDED THIN BEAM PROFILE." ENVIRONMENT. TECHNOLOGIES. RESOURCES. Proceedings of the International Scientific and Practical Conference 3 (June 16, 2021): 232–35. http://dx.doi.org/10.17770/etr2021vol3.6635.
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In the present study, a coupled 3D transient thermo-chemical analysis together with 2D plane strain mechanical analysis is carried out for the pultrusion process. For the mechanical analysis, a cure hardening instantaneous linear elastic (CHILE) approach is used of a thin beam profile made of glass fibre and epoxy resin. The applied approach is efficient and fast to investigate the residual stresses and deformations together with the distributions of temperature and degree of cure obtained from the thermo-chemical analysis.
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Pupure, Liva, Sibin Saseendran, Janis Varna, and Margherita Basso. "Effect of degree of cure on viscoplastic shear strain development in layers of [45/−45]s glass fibre/ epoxy resin composites." Journal of Composite Materials 52, no. 24 (March 12, 2018): 3277–88. http://dx.doi.org/10.1177/0021998318764275.
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Effect of degree of cure on irreversible (viscoplastic) shear strain development in layers of glass fibre/ epoxy resin (LY5052 epoxy resin) [+45 °/−45 °]s laminate is studied performing a sequence of constant stress creep and viscoelastic strain recovery tests. For fixed values of degree of cure in range from 79.7% to 100%, the viscoplastic strains were measured as dependent on time and stress and Zapa's integral representation was used to characterize the observed behaviour. It is shown that at all degrees of cure the viscoplastic behaviour can be described by Zapa's model with parameters dependent on degree of cure. It is shown that for degree of cure lower than 80% the viscoplastic strains grow much faster and are much more sensitive to the increase of the applied shear stress. These irreversible strains developing in the final phase of the curing can significantly alter the residual stress state in the composite structure.
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Yang, Miao, Liyun Xing, Xiaobo Liu, Yuqi Dong, and Jiliang Jin. "Dynamic corrosion mechanical properties of magnesium alloys with Erbium in the chloride ions environment." MATEC Web of Conferences 355 (2022): 01006. http://dx.doi.org/10.1051/matecconf/202235501006.
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The X-ray diffraction (XRD), scanning electron microscope (SEM), weight loss corrosion rate, corrosion residual strength (CRS), and slow strain rate tensile (SSRT) methods were used to study the effects of the addition of rare earth Erbium (Er) on the dynamic corrosion mechanical properties of the AM50 magnesium alloy. The results show that after Er was added, a new phase of Al3Er appeared and the microstructure was refined. The corrosion resistance of rare earth Er addition to the alloy was 0.5% > 1.5% > 1.0% > 0. Furthermore, the corrosion rates decreased in 432 h. The CRS results within 168 h show that the strength after an addition of 0.5% Er was the highest and the decline rate was the smallest. According to the shape of the tensile curve of CRS and the morphology of the tensile fracture, the addition of rare earth Er did not change the fracture form of the alloy, which remained as quasi-cleavage.
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Patham, Bhaskar, and Xiaosong Huang. "Multiscale Modeling of Residual Stress Development in Continuous Fiber-Reinforced Unidirectional Thick Thermoset Composites." Journal of Composites 2014 (March 24, 2014): 1–17. http://dx.doi.org/10.1155/2014/172560.
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The primary objective of this research is to develop a multiscale simulation framework to arrive at more realistic estimates of cure-induced residual stresses in the vicinity of the fiber-matrix interface in thick thermoset composites. The methodology involves simulations at the part level—employing homogenized rendering of the composite using micromechanics approach—within a finite element framework to obtain part-level temperature and degree-of-cure gradients and strains, and imposition of this information as boundary conditions at the mesoscale simulations, employing microstructural representative volume elements (RVE). A simple implementation of the multiscale framework, involving simulations at the part as well as the RVE levels, is demonstrated in the context of a thick, unidirectional continuous-glass-fiber-reinforced thermoset composite. The trends in the mesoscale residual stresses estimated by employing different RVE-level thermal and thermomechanical boundary conditions—displaying different degrees of coupling between the global and part-level simulations—are then examined. Significant differences are observed in the estimates of mesolevel cure-induced residual stress evolution obtained from simulations with a conventional symmetric RVE and those obtained by employing the multiscale approach involving detailed boundary conditions that realistically account for global thermal and mechanical strain histories.
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Li, Xue Qin, Zi Long Zhang, and Xiao Su Yi. "Cure-Induced Strain Development in an RTM Epoxy Resin as Monitored by Fiber Bragg Grating Sensors." Advanced Materials Research 694-697 (May 2013): 947–51. http://dx.doi.org/10.4028/www.scientific.net/amr.694-697.947.
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Optimizing the curing temperature to reducing the process costs may influence the properties of the material and bring quality assurance aspects. To solving the problem, real-time strain monitoring of the curing process has become more and more important and urgent. Fiber Bragg grating sensors were successfully used in this work to monitoring the residual strain building-up and the gelling phenomena of an RTM epoxy resin. The results shows chemical shrinkage strain during isothermal curing is bigger for higher curing temperature, but the average linear shrinkage ratio during cooling is smaller.
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Li, Zhao, Wei Ke, Mingyao Liu, and Yang Zhou. "Reduction of Thermal Residual Strain in a Metal-CFRP-Metal Hybrid Tube Using an Axial Preload Tool Monitored through Optical Fiber Sensors." Polymers 14, no. 20 (October 17, 2022): 4368. http://dx.doi.org/10.3390/polym14204368.
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Thermal residual strains/stresses cause several defects in hybrid structures and various studies have reported the reduction of residual strain. This paper describes a method for reducing thermal residual strains/stresses in metal-CFRP-metal hybrid tubes (MCMHT). The proposed axial preload tool provides two ways to reduce the thermal residual strains/stresses during the co-cure bonding process: pre-compressing of the metal layers and pre-stretching of the unidirectional carbon fiber reinforced polymer (CFRP) layers. An online measurement technique with embedded optical fiber Bragg grating (FBG) sensors is presented. Thermal residual strains are evaluated based on classical lamination theory with the assumption of plane stress. The theoretical calculations and measurement results agree well. Furthermore, the dynamic characteristics of the MCMHTs are tested. The results show that the reduction of residual strain increases the natural frequency of the MCMHT, but is detrimental to the damping capability of the MCMHT, which imply that the intrinsic properties of the metal-composite hybrid structure can be modified by the proposed axial preload tool.
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Bondarchuk, Darya, and Boris Fedulov. "PROCESS MODELING OF CARBON-EPOXY COMPOSITES: RESIDUAL STRESS DEVELOPMENT DURING CURE AND ANALYSIS OF FREE EDGE EFFECTS." Aviation 23, no. 1 (April 30, 2019): 15–22. http://dx.doi.org/10.3846/aviation.2019.9745.
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Last decades, increased attention is paid to the deep understanding of the process induced residual stresses (locked-in) and their effect on shape distortion and fracture. Residual stresses evaluation is particularly important in multilayered composites with anisotropic thermo-mechanical properties, where the ply orientations and stacking sequences highly influence the appearing of manufacturing stresses. In the present study, the effect of free edge on residual stresses inherited during manufacturing of thermoset multilayered composites was investigated. In order to understand the stress-strain state in samples after free edge cut a simplified 2D plane strain finite element analysis was performed. Many phenomena, such as sensitivity of the results to the size of the numerical grid, stress redistribution and size of the area affected by free edge was analyzed. In the current research, the behavior of AS4/8552-1 carbon-epoxy composite during manufacturing cycle was studied by means of finite element modeling in ABAQUS. To describe the behavior of the composite material during the manufacturing process − including processes of formation, polymerization, development of residual strains and stresses was done by developed user subroutine-UMAT, describing the visco-elastic material behavior of the material. The program was implemented in ABAQUS and validated on the basis of literature data. The results of the study can be applied for prediction of residual stresses in composite structure by means of virtual simulation and further understanding the nature of fracture of composites.
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Wiedemann, Johannes, Jan-Uwe R. Schmidt, and Christian Hühne. "Applicability of Asymmetric Specimens for Residual Stress Evaluation in Fiber Metal Laminates." Journal of Composites Science 6, no. 11 (November 2, 2022): 329. http://dx.doi.org/10.3390/jcs6110329.
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Residual stresses in fiber metal laminates (FML) inevitably develop during the manufacturing process. The main contributor to these stresses is the difference in the coefficients of thermal expansion (CTE) between fibers and metal in combination with high process temperatures. To quantify these stresses, the use of specimens with an asymmetric layup is an easily adaptable method. The curvature that develops after the manufacturing of flat laminates with an asymmetrical layer stack is a measure of the level of residual stresses evolving during cure. However, the accuracy of the curvature evaluation is highly dependent on specimen design and other influencing parameters. This leads to deviations when compared to other methods for residual stress quantification as can be seen from the literature. Therefore, in this work a large set of FML specimens is comprehensively investigated to identify relevant influencing parameters and derive conclusions about specimen design and evaluation techniques. For certain layups and process parameters, there is a good correlation between the curvature and the stress-free temperature, which is further covered by analytical solutions for bimetals. This correlation is the basis to transfer curvature into a stress-free temperature that can consequently be used for the quantification of residual stress levels in more complex FMLs. The transfer is validated by in situ strain measurements during cure using a strain gauge technique. Based on the results, the application of asymmetric specimens for residual stress characterization in more complex laminates is presented in the form of a workflow. The work shows the basic considerations and procedures necessary to use asymmetric specimens for residual stress quantification in FML. Furthermore, the results obtained can also be transferred to other composite materials.
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Sicot, Olivier, X. L. Gong, Xiao Jing Gong, Abel Cherouat, and Jian Lu. "Dependence Between Aging Treatments and Residual Stresses on Composite Laminate." Materials Science Forum 524-525 (September 2006): 813–17. http://dx.doi.org/10.4028/www.scientific.net/msf.524-525.813.
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The objective of this paper is to study the influence of residual stresses due to fabrication conditions on the thermomechanical behavior of carbon/epoxy laminate structures (cross ply). These studied laminates have undergone various cycles of thermal aging. The addition of a post-cure cycle after the end of the initial cycle makes it possible to reduce the residual stresses level. The incremental hole-drilling method is used to measure the residual strain in the laminates. These measured strains and the numerical calibration coefficients obtained by the finite element method allow to calculating the residual stress distribution in composite depth. The obtained results show that heat treatments of composite structures do not lead to an important reduction the initial residual stress due the fabrication conditions.
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Cui, Zhanxin, Haiyang Li, Zhibin Shen, and Huiru Cui. "Analysis of Load Optimization in Solid Rocket Motor Propellant Grain with Pressure Cure." International Journal of Aerospace Engineering 2021 (September 27, 2021): 1–11. http://dx.doi.org/10.1155/2021/5026878.
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At present, the casting of large-size motors often adopts pressure cure. This technology can effectively reduce the risk of damage to the structural integrity of the grain in the case-bonded casting solid rocket motor. In this paper, ABAQUS is used to establish a finite element model of star-shaped grains. The whole process of pressure cure was simulated and modeled, and the Python script was redeveloped. The Evol evolutionary algorithm was used in ISIGHT to optimize the load parameters such as pressure value, attenuation coefficient of the relief curve, and the attenuation coefficient of the cooling curve. The effects of different pressure values and different cooling and depressurizing rates on the residual stress and strain were analyzed. The optimization results show that the closer the pressure value is to the theoretical pressure, the more significant the effect of pressure cure. However, the effect of stress and strain reduction in different directions is slightly different. The different cooling and pressure relief rates have a great influence on the process quantity. Pressure cure works best when the pressure attenuation coefficient is equal to 6850, and the temperature attenuation coefficient is equal to 8650. The optimization analysis of pressure curing provides a reference for engineering practice.
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Baran, Ismet, Jesper Hattel, and Remko Akkerman. "The Effect of Mandrel Configuration on the Warpage in Pultrusion of Rectangular Hollow Profiles." Key Engineering Materials 611-612 (May 2014): 250–56. http://dx.doi.org/10.4028/www.scientific.net/kem.611-612.250.
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Thermo-mechanical process simulation of an industrially pultruded rectangular hollow profile is presented. Glass/polyester is used for the continuous filament mat (CFM) and the uni-directional (UD) layers. The process induced residual distortions together with the temperature and degree of cure are predicted using a three dimensional (3D) thermo-chemical model sequentially coupled with a 2D quasi-static generalized plane strain mechanical model. The predicted deformation pattern at the end of the process is found to agree quite well with the one observed for the real pultruded parts in a commercial pultrusion company. In addition, the predicted warpage behaviour is further analysed by adjusting the mandrel length as well as including the mandrel heating. Using the proposed process model, the effect of the mandrel configurations on the quality of the pultrusion is investigated in terms of temperature, degree of cure and distortions.These unwanted residual distortions may lead to not meeting the desired geometrical tolerances e.g. warpage of pultruded window frames and hollow profiles as well as spring-in of L-shaped profiles, etc.
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Bezerra, Fernando Schemelzer de Moraes, Paulo Marcos Zech Coelho, and Carlos Alberto Pereira Tavares. "Schistosoma mansoni: protective immunity in mice cured by chemotherapy at the chronic phase of the disease." Revista do Instituto de Medicina Tropical de São Paulo 35, no. 4 (August 1993): 337–44. http://dx.doi.org/10.1590/s0036-46651993000400006.
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Aiming at demonstrating a decrease of acquired immunity after chemotherapeutic cure, a group of mice was infected with 25 Schistosoma mansoni cercariae (LE strain). A part of these animals was treated with 400 mg/kg oxamniquine, at 120 days after infection. Challenge infections were carried out at 45, 90 and 170-day-intervals after treatment (185, 210 and 290 days after primoinfection, respectively). Recovery of worms at 20 days after reinfections showed that a residual immunity remains up to 90 days after treatment, and disappears at 170 days after cure. Using the ELISA method, it was possible to detect a decrease of antibody levels (total IgG) in the treated group, when antigens from different evolutive stages of S. mansoni were used. The epidemiological implications of the present results, and the possible mechanisms involved in the decrease of acquired immunity after treatment are discussed.
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Baran, Ismet, Cem C. Tutum, and Jesper Henri Hattel. "The Internal Stress Evaluation of Pultruded Blades for a Darrieus Wind Turbine." Key Engineering Materials 554-557 (June 2013): 2127–37. http://dx.doi.org/10.4028/www.scientific.net/kem.554-557.2127.
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This paper investigates the integrated modeling of a pultruded NACA0018 blade profile which is a part of the FP7 EU project DeepWind. The pultrusion process simulation is combined with the preliminary subsequent in-service load scenario. In particular, the process induced residual stresses and distortions are predicted by using a new approach combining a 3D Eulerian thermo-chemical analysis, in which the temperature and the cure degree distributions are obtained, and a 2D quasi-static plane strain mechanical analysis. The post-die region where convective cooling prevails is also included in the process model. The bending into shape of the pultruded blade profile is simulated with and without taking the residual stresses into account. The internal stress distribution in the profile is evaluated after the bending analysis and it is found that the process induced residual stresses have the potential to promote or to demote the internal stresses in the structural analysis.
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Li, Zhao, Mingyao Liu, Jintao Wang, and Wei Ke. "Residual Strain Monitoring and Dynamic Characteristics of Hybrid Hollow Square Tube with Metal–FRP–Metal Sandwich Walls." International Journal of Polymer Science 2022 (October 28, 2022): 1–12. http://dx.doi.org/10.1155/2022/9254833.
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In order to design and fabricate a novel hollow square tube (HST) for ram structure in machine tools, the hybrid HST with sandwich walls based on steel skins and unidirectional carbon fiber-reinforced polymer (CFRP) composite core is proposed. A detailed co-cured fabrication method with embedded fiber Bragg grating (FBG) sensors for residual strains/stresses determination in a hybrid metal–composite structure is presented. Results reveal that the hybrid HST has undergone complex residual strain history, and the strain rate is about 10 times the cooling rate. The tensile strains in the dwell stage transform into compressive strains in the cooling stage due to the mismatch of the coefficients of thermal expansion of the steel plates and the CFRP composite. A comparison of the residual strains in the cooling phase obtained by FBG sensors with those obtained by theoretical calculation is carried out. Furthermore, the dynamic characteristics of the hybrid HST and the steel HST are tested. The results showed that the damping of the hybrid HST is 586% higher than that of the steel HST, while the hybrid HST has a lower first natural frequency (4.6% reduction) and mass (15.9% weight reduction). The influence of co-cure temperature and cooling rate on the size and state of the residual strains is analyzed, which might be helpful to guide the manufacturing of sandwich structures in machine tools. This novel hybrid HST may be used for online health monitoring and safety evaluation to build intelligent machine tools structures.
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Wachtarczyk, Karol, Marcel Bender, Ewald Fauster, Ralf Schledjewski, Paweł Gąsior, and Jerzy Kaleta. "Gel Point Determination in Resin Transfer Molding Process with Fiber Bragg Grating Inscribed in Side-Hole Elliptical Core Optical Fiber." Materials 15, no. 18 (September 19, 2022): 6497. http://dx.doi.org/10.3390/ma15186497.
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Material as well as process variations in the composites industry are reasons to develop methods for in-line monitoring, which would increase reproducibility of the manufacturing process and the final composite products. Fiber Bragg Gratings (FBGs) have shown to be useful for monitoring liquid-composite molding processes, e.g., in terms of online gel point detection. Existing works however, focus on in-plane strain measurements while out-of-plane residual strain prevails. In order to measure out-of-plane strain, FBG inscribed in highly birefringent fiber (HB FBG) can be used. The purpose of this research is the cure stage detection with (a) FBG inscribed in single mode and (b) FBG inscribed in highly-birefringent side-hole fiber in comparison to the reference gel point detected with an in-mold DC sensor. Results reveal that the curing process is better traceable with HB FBG than with regular FBG. Thus, the use of HB FBG can be a good method for the gel point estimation in the RTM process.
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Ohlemacher, Crittenden J., and Gary R. Hamed. "Aging with Applied Strain of A Black-Filled Natural Rubber Vulcanizate. Part I: Network Changes." Rubber Chemistry and Technology 81, no. 4 (September 1, 2008): 650–70. http://dx.doi.org/10.5254/1.3548225.
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Abstract Black-filled natural rubber, with an inefficient sulfur cure, was aged at 90 °C and 110 °C under nitrogen, with and without applied strain. Samples aged under strain became “double networks” and retained a residual extension ratio. The crosslink density of samples passed through a maximum with increasing severity of aging. Presumably this arises because the thermally labile, polysulfidic crosslinks break, and new crosslinks of lower rank form, resulting in increased crosslink density; but, when aged at 110 °C, this is offset by chain scission and other main-chain modifications. For double networks, it is proposed that a second network, which tends to keep samples extended, is formed at the expense of crosslinks in the original, first network. Unaged and single network samples were isotropic in tensile behavior and only slightly anisotropic in swelling behavior. For double networks, swelling and tensile properties were anisotropic, and there was some evidence that parallel specimens have increased ability to strain-crystallize. The observed anisotropies in double networks are proposed to arise from the chain orientation that persisted after double network formation.
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Hamed, G. R., and M. Y. Huang. "Tensile and Tear Behavior of Anisotropic Double Networks of a Black-Filled Natural Rubber Vulcanizate." Rubber Chemistry and Technology 71, no. 5 (November 1, 1998): 846–60. http://dx.doi.org/10.5254/1.3538513.
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Abstract Double networks of a black-filled natural rubber composition have been prepared by partially curing a sheet, stretching it, and then completing cure. Upon release, a double network retracts to a residual extension ratio, αr. Samples cut perpendicular to the stretch direction have stress—strain responses like the isotropic single network, while parallel samples have enhanced stiffness and tensile strength, and reduced extensibility. Tensile strength is rather weakly dependent on αr. Tear strengths of the double networks, determined using edge-cut strip specimens, exceed that of the single network for low αr. However, when αr is high, double networks have very low tear strengths. Consistent with previous studies, high tear strengths are associated with extensive longitudinal cracking.
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Wündisch, Thomas, Christian Thiede, Andrea Morgner, Astrid Dempfle, Annette Günther, Hongxiang Liu, Hongtao Ye, et al. "Long-Term Follow-Up of Gastric MALT Lymphoma After Helicobacter Pylori Eradication." Journal of Clinical Oncology 23, no. 31 (November 1, 2005): 8018–24. http://dx.doi.org/10.1200/jco.2005.02.3903.
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Purpose Cure of infection induces remissions in most patients with early stage Helicobacter pylori- (Hp) positive gastric MALT (mucosa-associated lymphoid tissue) lymphoma (GML). We tracked the long-term stability of remissions in this prospective, multicenter trial. Patients and Methods In 120 patients with stage I1E disease, we performed sequential endoscopic-bioptic follow-up after Hp eradication and polymerase chain reaction of the rearranged immunoglobulin heavy chain gene. The status of t(11;18) was assessed in 65 patients. Results Median follow-up was 75 months (range, one to 116). Five-year survival was 90%. Eighty percent of patients (96 of 120) achieved complete histologic remission (CR). Eighty percent of CRs are in continuous complete histologic remission (CCR). Three percent of CR patients (three of 96) relapsed and were referred for alternative treatment. Seventeen percent of CR patients (16 of 96) showed histologic residual disease (RD) during follow-up; a watch-and-wait strategy was applied, and all entered into a second CR. After a median follow-up of 63 months, 14 of 52 analyzed patients reaching CR showed ongoing B-cell monoclonality. Fifteen percent of GMLs were t(11;18) positive. Both t(11;18) and ongoing monoclonality were associated with a significantly higher risk for no response or relapse (P =.004, P =.007), but also present in patients in CCR. Early gastric cancer was diagnosed in three cases during follow-up. Conclusion Cure of Hp infection results in CCR in most patients. Histologic RD, B-cell monoclonality, and t(11;18) were present in a considerable number of CR patients. A watch-and-wait strategy is justified when close follow-up is guaranteed.
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Montillo, Marco, Alessandra Tedeschi, Valentina Rossi, Anna Maria Cafro, Roberto Cairoli, Silvio Veronese, Barbara Scarpati, et al. "Alemtuzumab as Consolidation after a Response to Fludarabine Is Effective To Purge Residual Disease in Patients with Chronic Lymphocytic Leukemia." Blood 104, no. 11 (November 16, 2004): 479. http://dx.doi.org/10.1182/blood.v104.11.479.479.
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Abstract Although an increasing number of patients with chronic lymphocytic leukemia (CLL) may achieve complete remission (CR) relapse is almost inevitable, due to re-emergence of the malignant clone. The eradication of minimal residual disease (MRD) is associated with improved remission durability and has great potential in offering the possibility of cure in many lymphoid malignancies. The monoclonal antibody alemtuzumab is the foundation of many eradication-based treatment approaches because of its ability to achieve clinical remissions and to successfully purge MRD. We investigate the use of subcutaneous (sc) alemtuzumab for the eradication of residual disease in the bone marrow of patients in clinical response after fludarabine treatment, as determined by NCI criteria. At least 8 weeks after fludarabine treatment, 35 B-CLL patients (13 female, 22 male; median age 55 [range 39–64] years) received sc alemtuzumab, three times weekly for 6 weeks, at escalating doses up to 10 mg. Residual disease was assessed using a consensus polymerase chain reaction methodology to detect the clonality of IgH sequences. Patients obtaining a successfull peripheral blood stem cell (PBSC) harvest (CD34+ 2.5 x 109/l) after either granulocyte colony-stimulating factor (G-CSF) or intermediate-dose Ara-C (800 mg/m2, every 12 h, for six doses) plus (G-CSF) were considered eligible for autologous PBSC transplant. Pharmacokinetic parameters were estimated in seven patients. Serum samples of alemtuzumab were assayed by indirect immunofluorescence with target cells (HUT-78, a human T cells line) and antibody concentration was calculated by comparison with a standard curve. Post fludarabine responses were: 10 CRs, 11 nodular partial responses (PRn) and 14 partial responses (PR). Post alemtuzumab responses were: 29 CRs, 4 PRn, 2 PR. Overall, 51% of patients converted to polyclonal IgH pattern (MR). Of the patients in CR before alemtuzumab, 7 achieved MR; nine of the patients in PRn before immunotherapy, improved to CR, five achieving MR. Of the fourteen patients in PR before alemtuzumab, twelve improved (two PRn, ten CR) and six achieved MR. Twenty-three out of 25 patients successfully mobilized PBSC. Fourteen patients have been transplanted so far. Subcutaneous alemtuzumab was generally well tolerated; fifteen patients (57%) developed cytomegalovirus (CMV) reactivation, but CMV disease was prevented by prompt treatment with oral ganciclovir. Alemtuzumab serum concentrations measured at second week after the start of therapy, just before the next dose (Ctrough), were relatively stable: Ctrough = 0.79±0.6 mg/ml. Sequential treatment with fludarabine and alemtuzumab is feasible, effective and safe. Overall 83% of patients reached CR according to NCI criteria. Eighty-four percent of patients improved to CR or PRn after alemtuzumab. Residual disease was not detected in 51% of patients. Sequential treatment did not compromise PBSC mobilization, allowing patients to proceed to autologous transplantation.
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Deng, Biping, Alex Hongsheng Chang, Junfang Yang, Jing Pan, Xian Zhang, Yuehui Lin, Yanan Wu, et al. "Safety and Efficacy of Low Dose CD19 Targeted Chimeric Antigen Receptor T (CAR-T) Cell Immunotherapy in 47 Cases with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia (B-ALL)." Blood 128, no. 22 (December 2, 2016): 649. http://dx.doi.org/10.1182/blood.v128.22.649.649.
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Abstract Abstract Introduction: Patients (pts) with relapsed refractory B-ALL are mostly incurable by chemotherapy. The disease free survival (DFS) is low even treatment with allogeneic hematopoietic stem cell transplantation (allo-HSCT). We explored treatment of 47 cases of relapsed refractory B-ALL with low dose CD19 CAR-T cells and assessed the clinical safety and efficacy. Patients and Methods: (6-8)X107 pts' peripheral blood mononuclear cells(PBMCs) were activated with CD3 and CD28 antibodies for 24h, then transduced with the lentivirus encoding anti-CD19-CD3zeta-4-1BB CAR (Image1/Picture1) and cultured for 5-6 days in serum-free media containing IL2,IL7,IL15,IL21. All pts except one who had persistent cytopenia received cyclophosphamide 250 mg/m2/d X 3d, and fludarabine 30 mg/m2/d X 3d, then CAR-T cell infusion. Between Jul.31 2015 and Jul. 15 2016, a total of 47 cases were treated with CAR-T cells (Chart1). 37/47 cases had frank hematologically relapsed refractory B-ALL, who could not achieve complete remission (CR) after more than 1 cycles of chemotherapy. The median prior chemotherapy duration was 18 months. The median pre-treatment bone marrow blast percentage was 67% (6.5-98.5%). The most recently treated 15 cases had their PB blasts <30% and had no brain mass. 10/47 cases had persistent positive minimal residual disease (MRD) per flow cytometry (FCM) after more than 3 cycle of chemotherapy, except one who had severe pneumonia after 1 cycle of chemotherapy. The MRD pre-treatment were ranging from 0.01%-1.53%. Chart 1: Characteristics of Patients Pre-CAR-T Image 1/Picture 1: Results: The pts received a median of 10 (0.5-140) X104cells/kg CAR-T cells, and the most recently treated 15 cases all received 10 X 104cells/kg. The median observation period was 201 days (20-368 days). On day 16-20 after CAR-T infusion, 31/35 (88.6%) relapsed hematological refractory cases achieved CR or incomplete CR(Cri), and 29/35 cases (82.9%) achieved negative MRD by FCM(CMR: complete molecular remission). No extramedullary leukemia was detected in any cases with residual disease. The most recently treated 15 consecutive cases all achieved CR with only mild (<grade 2) cytokine release syndrome (CRS). 2 cases could not be evaluated for efficacy because 1 died from severe pancytopenia and 1 died from intracranial hemorrhage during the first month of the study. 4 cases did not achieve CR but all those pts only received less than 5x104/kg CAR-T cells. 15/17 CR cases were bridged into allo-HSCT and have remained in CMR with a median follow-up of 197 days (100-303 days). 25 CR cases have been followed up for more than 60 days, 5/25 pts had hematological relapse and 4/25 pts became MRD+ again. The median time to relapse was 64 days (52-193 days), with 5 pts CD19-, 2 CD19 dim and 2 CD19+ by FCM. The major side effect was CRS. The median time to development of CRS was 7 days (1-12) with median CRS grade 2 (1-5). 9/10 (90%) refractory MRD+ cases became MRD- after CAR-T treatment. The median time to development of CRS of this group of patients was at day 6 (day 6-7) with median CRS grade 1 (0-1). Conclusion: Our anti-CD19 CAR-T cell therapy can result in a high CR/CRi /CMR rate in pts with refractory B-ALL and could overcome pre-existing risk factors for poor outcomes, including complex chromosome abnormalities, poor gene mutations, inherited predisposing gene mutation, extramedullary leukemia etc. Pts could be safely bridged into allo-HSCT for potential cure. The dose of infused CAR-T cells in our patients was far lower than previously reported in the literature and the culture period was only 6-7 days, which could dramatically reduce the cost of the CAR-T therapy. 10X104cells/kg of CAR-T cells was a safe and effective number for treating B-ALL. The major complication was CRS and the severity of CRS was directly correlated with the number of malignant B cells in the PB. The efficacy of CAR-T therapy was correlated to the infused number of CAR-T cells. The most recently treated 15 consecutive cases all achieved CR without severe CRS suggesting that the optimal number of CAR-T cells and patient selection are important for the efficacy and safety. Table. Table. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Ernst, L. J., C. van ’t Hof, D. G. Yang, M. S. Kiasat, G. Q. Zhang, H. J. L. Bressers, J. F. J. Caers, A. W. J. den Boer, and J. Janssen. "Mechanical Modeling and Characterization of the Curing Process of Underfill Materials." Journal of Electronic Packaging 124, no. 2 (May 2, 2002): 97–105. http://dx.doi.org/10.1115/1.1459471.
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Thermo-setting polymers are widely used as underfill materials to improve the reliability of electronic packages. In the design phase, the influence of underfill applications on reliability is often judged through thermal and mechanical simulations, under assumed operating conditions. Because of lacking insight into the mechanical processes due to polymer curing, the impact of processing induced residual stress fields is often neglected. To investigate the evolution of stress and strain fields during the curing process it is important to assume a more appropriate starting point for subsequent process modeling. Furthermore, study of possible damage originating from the fabrication process then comes within reach. To facilitate future analysis of stress and strain fields during the curing process a cure dependent constitutive relation is assumed. An approximate investigation method for the process-dependent mechanical properties, based on Dynamic Mechanic Analysis (DMA), is developed. As an illustration the parameter identification is performed for a selected epoxy resin.
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Baran, Ismet, Johnny Jakobsen, Jens H. Andreasen, and Remko Akkerman. "Investigation of the Residual Stress State in an Epoxy Based Specimen." Key Engineering Materials 651-653 (July 2015): 375–80. http://dx.doi.org/10.4028/www.scientific.net/kem.651-653.375.
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Process induced residual stresses may play an important role under service loading conditions for fiber reinforced composite. They may initiate premature cracks and alter the internal stress level. Therefore, the developed numerical models have to be validated with the experimental observations. In the present work, the formation of the residual stresses/strains are captured from experimental measurements and numerical models. An epoxy/steel based sample configuration is considered which creates an in-plane biaxial stress state during curing of the resin. A hole drilling process with a diameter of 5 mm is subsequently applied to the specimen and the released strains after drilling are measured using the Digital Image Correlation (DIC) technique. The material characterization of the utilized epoxy material is obtained from the experimental tests such as differential scanning calorimetry (DSC) for the curing behavior, dynamic mechanical analysis (DMA) for the elastic modulus evolution during the process and a thermo-mechanical analysis (TMA) for the coefficient of thermal expansion (CTE) and curing shrinkage. A numerical process model is also developed by taking the constitutive material models, i.e. cure kinetics, elastic modulus, CTE, chemical shrinkage, etc. together with the drilling process using the finite element method. The measured and predicted in-plane residual strain states are compared for the epoxy/metal biaxial stress specimen.
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Soares, CJ, AA Bicalho, C. Verissimo, PBF Soares, D. Tantbirojn, and A. Versluis. "Delayed Photo-activation Effects on Mechanical Properties of Dual Cured Resin Cements and Finite Element Analysis of Shrinkage Stresses in Teeth Restored With Ceramic Inlays." Operative Dentistry 41, no. 5 (September 1, 2016): 491–500. http://dx.doi.org/10.2341/15-090-l.
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SUMMARY Objective: The aim of this study was to investigate the effect of delayed photo-activation on elastic modulus, Knoop hardness, and post-gel shrinkage of dual cure resin cements and how this affects residual shrinkage stresses in posterior teeth restored with ceramic inlays. Methods and Materials: Four self-adhesive (RelyX Unicem, 3M ESPE; GCem, GC; MonoCem, Shofu; and seT, SDI) and two conventional (RelyX ARC, 3M ESPE; and AllCem, FGM) dual cure resin cements for cementing posterior ceramic inlays were tested. Strain gauge and indentation tests were used to measure the post-gel shrinkage (Shr), elastic modulus (E), and Knoop hardness (KHN) when photo-activated immediately and 3 and 5 minutes after placement (n=10). Shr, E, and KHN results were analyzed using two-way analysis of variance followed by Tukey honestly significant difference post hoc tests (α=0.05). The experimentally determined properties were applied in a finite element analysis of a leucite ceramic inlay (Empress CAD, Ivoclar Vivadent) cemented in a premolar. Modified von Mises stresses were evaluated at the occlusal margins and cavity floor. Results: Shr, E, and KHN varied significantly among the resin cements (p<0.001). Highest overall Shr values were found for RelyX Unicem; GCem had the lowest. Increasing the photo-activation delay decreased Shr significantly. Delayed photo-activation had no effect on E (p=0.556) or KHN (p=0.927). RelyX Unicem had the highest E values; seT and MonoCem had the lowest E values. AllCem and RelyX Unicem had the highest KHN and MonoCem had the lowest KHN. Cements with high Shr and E values caused higher shrinkage stresses. Stresses decreased with delayed photo-activation for all cements. Conclusions: KHN and E values varied among the different resin cements. Residual shrinkage stress levels decreased with increasing photo-activation delay with all resin cements.
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Rocha, Helena, Christopher Semprimoschnig, and João P. Nunes. "Small-diameter optical fibre sensor embedment for ambient temperature cure monitoring and residual strain evaluation of CFRP composite laminates produced by vacuum-assisted resin infusion." CEAS Space Journal 13, no. 3 (March 10, 2021): 353–67. http://dx.doi.org/10.1007/s12567-021-00357-5.
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Tinkloh, Steffen, Tao Wu, Thomas Tröster, and Thomas Niendorf. "The Effect of Fiber Waviness on the Residual Stress State and Its Prediction by the Hole Drilling Method in Fiber Metal Laminates: A Global-Local Finite Element Analysis." Metals 11, no. 1 (January 15, 2021): 156. http://dx.doi.org/10.3390/met11010156.
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In this paper, fiber waviness, as one of the most frequently occurring defects in fiber reinforced composites, is numerically investigated with regard to the formation of residual stresses in fiber metal laminates. Furthermore, the prediction of the residual stress state in the thickness direction by means of the simulated hole drilling method is studied. To this regard, a global-local finite element analysis based on the submodel technique is presented. The submodel technique essentially consists of two governing steps: In the first step, a global model is first utilized to calculate and analyze the residual stress distribution and deformation in the intrinsically joined hybrid structure. Effective cure-dependent thermo–elastic properties predicted by a numerical homogenization procedure were used to simulate the curing-process and analyze the residual stresses state. However, the dimension of the intrinsically manufactured hybrid plate is large compared to the diameter of the drilled hole (2 mm), so that a local model is necessary, which provides only a geometric partial portion of the global model. The local model takes the global stress state into account and is subsequently used to simulate the incremental hole drilling method with a refined mesh discretization. The production-related fiber waviness is modeled by an element-wise orientation approximating a sinus function. In order to validate the global-local modeling approach, a comparison between numerical results and experimental data from literature is presented. The comparison between global residual stress state (global model) and the simulated hole drilling method (local model) is used to assess the applicability and reliability of the hole drilling method in case of fiber waviness. It is found that an in-plane fiber waviness leads to a rather low variance of residual stresses over thickness. In case of an out-of-plane fiber waviness, oscillating residual stress fields occur over the entire thickness along the fiber direction. Moreover, the current limits of the incremental hole drilling method could be pointed out by the presented investigations. It is seen that the simulated results of the incremental hole drilling method are sensitive to waviness, even if the amplitude-wavelength-ratio is small. Without further adjustment of the calibration coefficients the oscillating stress and strain fields lead, in particular fiber waviness in thickness direction, to unreliable predictions. For the experimental application it can be concluded that the specimens have to be carefully examined with regard to fiber waviness.
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Бондарчук, Дарья Александровна, Борис Никитович Федулов, and Евгений Викторович Ломакин. "Analysis of the influence of residual stresses on possible defects formed during production of carbon-epoxy composites." Вестник Чувашского государственного педагогического университета им. И.Я. Яковлева. Серия: Механика предельного состояния, no. 2(44) (December 14, 2020): 59–68. http://dx.doi.org/10.37972/chgpu.2020.44.2.006.
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В настоящей работе изучено влияние наличия остаточных напряжений в образце углерод-эпоксидного композита, сформировавшихся в процессе его производства, на такие возможные дефекты как межслоевое расслоение. Исследование посвящено анализу НДС в регулярных образцах вблизи зоны дефекта в течение цикла отверждения, а также при образовании свободного края в материале после разреза в зависимости от длины трещины. Для моделирования процесса отверждения решалась связанная тепловая и прочностная задача в условиях плоской деформации. Для описания поведения композитного материала в процессе производства, включая процессы формования, полимеризации, развития остаточных напряжений и деформаций, была разработана и реализована специальная пользовательская подпрограмма для ПО ABAQUS. В частности, в данной работе была проанализирована история величин скоростей энерговыделения в режимах раскрытия трещины по механизму нормального отрыва и поперечного сдвига в процессе полимеризации и последующего разрезания с образованием свободного края. Обнаружен незначительный рост значений GI , GII в вершине трещины в процессе полимеризации и многократное превышение этих значений после механического среза. В результате численного моделирования выявлено, что остаточные напряжения не оказывают существенного влияния на рост дефекта в композите на этапе его изготовления, но при приложении дальнейшей нагрузки на образец могут способствовать интенсивному росту расслоения. In the present study, the effect of presence of residual stresses inherited during manufacturing on delamination defect in carbon-epoxy composite specimen is investigated. The research is devoted to understanding of strain-stress state in regular specimens near defect zone during cure cycle and after free edge cut depending on crack length. To describe the behavior of the composite material during manufacturing process- including processes of formation, polymerization, development of residual stresses and strains, the special user subroutine was developed and implemented in ABAQUS FEM software. The history of energy release rates under mode I, II ( GIc , GIIc) where analyzed over time during process of polymerization and free edge cut. A slight increase in the GI and GII values at the crack tip during polymerization and a multiple excess of these values after a mechanical cut is shown. Obtained by modelling values for stress components are essential and cannot be ignored in consequent structural analysis. The results of the study can be applied for prediction of residual stresses in composite structure by means of simulation and further understanding the nature of fracture of composites.
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Grupp, Stephan, Zhen-Huan Hu, Yiyun Zhang, Amy Keating, Michael A. Pulsipher, Christine Philips, Steven P. Margossian, et al. "Tisagenlecleucel Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Children and Young Adults with Acute Lymphoblastic Leukemia (ALL): Real World Experience from the Center for International Blood and Marrow Transplant Research (CIBMTR) and Cellular Therapy (CT) Registry." Blood 134, Supplement_1 (November 13, 2019): 2619. http://dx.doi.org/10.1182/blood-2019-129279.
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Background Tisagenlecleucel is a CD19-directed genetically modified autologous T-cell immunotherapy approved for the treatment of patients up to 25 years of age with B-cell ALL that is refractory or in second or later relapse. In the pivotal ELIANA trial, 79 patients were treated with tisagenlecleucel. The best overall response rate (CR/CRi) was 82%; 98% of patients who achieved CR/CRi were also negative for minimal residual disease (MRD). With a median follow-up of 24 months, the median duration of remission was not reached. Grade 3 or higher cytokine release syndrome (CRS) by UPenn criteria and neurotoxicity within the first 8 weeks after infusion occurred in 49% and 13%, respectively (Grupp, et al. Blood 2018, Abstr 895). The CIBMTR CT Registry was developed to collect long-term safety and efficacy information on recipients of cellular immunotherapies and it is utilized for a post marketing study of tisagenlecleucel in the real world setting. Methods Clinical data from the CT registry were analyzed for baseline information. Efficacy and safety data were presented among patients with a minimum of 3 months follow-up. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported as per the ASTCT consensus criteria. Additionally, manufacturing product characteristics of tisagenlecleucel were compared to clinical outcomes. The association of number of cells administered, cell viability, potency, and transduction efficiency of tisagenlecleucel to overall response, CRS and ICANS grades was performed using descriptive summaries and univariate logistic regression analyses. Results Forty centers in the U.S. contributed data for refractory or relapsed pediatric or young adult patients with B-cell ALL through the CIBMTR CT registry as of May 31, 2019. Baseline information was available for 159 patients; 105 patients had at least the first follow up assessment reported at 3 months (Table 1). The median follow-up of survivors was 5.8 months (2.6-16.9 months). All patients received cells in the approved range for their weight with a median of 1.9 x 106/kg (range 0.2-4.6 x 106/kg) for children ≤ 50 kg and 0.9 x 108 (range 0.1-2.3 x 108) for children and young adults > 50 kg. The best overall response rate (CR) was 88% (95% CI 80%-94%). MRD was collected in 52 patients after tisagenlecleucel; all were negative. Importantly, among the 4 patients age < 3 years of age with more than 3 months of follow-up, all attained a CR. The 6-month duration of response, event-free survival and overall survival (OS) was 77%, 68% and 94%, respectively. After bridging therapy, there were 35 patients who attained CR and 63 patients who did not attain CR at the time of tisagenlecleucel infusion. The 6-month OS rate was 100% and 90.2% for patients attaining CR and not attaining CR, respectively. The rate of grade 3 or higher CRS and ICANS was 13.3% and 8.6%, respectively and was similar for patients age < 3 years. Clinically significant infections within the first 3 months occurred in 35.2% of patients; bacterial infections were most common. Deaths within 30 days following infusion occurred in 2 patients (due to disease progression and cerebral hemorrhage) and no deaths were attributed directly to tisagenlecleucel. Secondary malignancy was reported in 1 patient (myeloproliferative neoplasm). None of the manufacturing characteristics (cell viability, potency, nor transduction efficiency) or cell dose were associated with efficacy or safety. Importantly, analysis of cell viability showed no association with best overall response (Table 2). Conclusions The CIBMTR CT registry represents real world data for the treatment of pediatric patients with relapsed/refractory ALL and will allow follow up of these patients for 15 years. Tisagenlecleucel therapy in the real world setting demonstrated similar efficacy and safety compared to the pivotal ELIANA trial. None of the manufacturing characteristics analyzed (including % cell viability) correlated with response rates, CRS or ICANS. Updated results will be presented at the meeting. Disclosures Grupp: CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Pulsipher:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Lecture; Bellicum: Consultancy; Miltenyi: Research Funding; Medac: Honoraria. Margossian:Novartis: Membership on an entity's Board of Directors or advisory committees. Curran:Novartis: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Chawla:Novartis Pharma AG: Employment. Horowitz:Actinium: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant. Bleickardt:Novartis: Employment. Pasquini:Novartis: Research Funding; Kit Pharma: Research Funding; BMS: Research Funding; Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy.
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Chong, Elise A., James N. Gerson, Daniel J. Landsburg, Sunita Dwivedy Nasta, Jakub Svoboda, David L. Porter, Karen Dengel, et al. "Outcomes in Aggressive B-Cell Non-Hodgkin Lymphomas with Anti-CD19 CAR T-Cell (CTL019) Products Not Meeting Commercial Release Specifications." Blood 134, Supplement_1 (November 13, 2019): 594. http://dx.doi.org/10.1182/blood-2019-131078.
Full textAbstract:
Introduction: Tisagenlecleucel (CTL019, tisa-cel) was recently approved for treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), high grade B cell lymphoma (r/r HGBCL), and transformed follicular lymphoma (r/r tFL) after second line therapy. Prior to tisa-cel release for commercial use in the United States (US), the final manufactured, patient-specific product must meet specific Lot Release Specifications including requirements that the product's dose contains 0.6 to 6.0 x 108 CAR-positive viable T cells and total cell viability is at least 80%. CAR T cell products that do not meet predetermined release specifications are considered "out of specification" (OOS) and may only be administered via an expanded access protocol or a single patient IND. To date, there are no prospectively reported data with regard to the reasons that commercially manufactured CTL019 products are OOS or clinical outcomes after infusion of OOS CTL019 products. Methods: We are participating in a prospective, managed access protocol to allow administration of CTL019 to patients (pts) with r/r aggressive B-cell lymphomas meeting the approved prescribing information who are intended for treatment with US commercial tisa-cel but have OOS products. Pts were provided product via this managed access program and consent was obtained from all pts enrolled. Pts were unable to receive commercially manufactured product due to failure of apheresis material to meet acceptance specifications, failure of final manufactured product to meet the commercial release specifications, or failure to meet other product specifications within the prescribing information (e.g., interferon gamma release testing). Response was assessed at 3 months post CTL019 infusion by 2014 Lugano Classification criteria applied to FDG-PET/CT imaging. Adverse events were defined by CTCAE and ASTCT criteria. Results: From 9/2018 to 7/2019, 16 pts were enrolled at our institution. Nine pts were diagnosed with r/r DLBCL, 5 pts had r/r HGBCL, and 2 pts had r/r tFL; 44% of all pts had "double-hit" lymphoma. Median age at CTL019 infusion was 68 years (range: 42-75 years); 7 pts (44%) were female. Twelve pts (75%) had advanced stage lymphoma at leukapheresis. Median prior therapies before leukapheresis was 3 (range: 2-5). Median ECOG performance status was 0 (range: 0-2). Median absolute lymphocyte count and CD3 count were 900/uL (range: 200-1300/uL) and 614/uL (range: 228-1343/uL), respectively. Median CTL019 dose was 1.3 x 108 CAR-positive viable T cells (range: 0.5 x 108 to 2.1 x 108). Median product viability was 78.4% (range: 70.8-87.4%). Thirteen of 16 pts (81%) were enrolled due to low viability products (viability < 80%). The median viability for pts enrolled due to low product viability was 78.0% (range: 70.8-79.8%). The remaining 3 pts' products did not meet release specifications due to T cell dose below 0.6 x 108 CAR-positive T cells (dose administered, 0.5 x 108; n=1), residual beads by microscopy (n=1), or IFN gamma release level above the upper range (>1000 fg/transduced cell; n=1). All pts with low viability products had CAR-positive T cell doses that were within the product dose specifications for tisa-cel (13 of 13 pts). Of 16 pts enrolled, 11 pts have at least 3 months follow-up; 3 pts were never treated due to progressive lymphoma and 2 pts have not had 3 month response assessments. Median follow-up is 3.4 months. There were 3 pts with CRS grades 1 or 2 by ASTCT criteria and no pts had neurotoxicity. Of 3 pts with CRS, one received a low dose of CTL019 (grade 2 CRS), one had higher levels of IFN gamma (grade 1 CRS), and one had low viability (grade 1 CRS). For all pts infused with OOS products, the 3-month overall response rate (ORR) was 64% including 6/11 (55%) CR and 1/11 (9%) PR. Progression-free survival (PFS) is 64% at 3 months (median not reached, 95%CI: 30-85%). For OOS products due to low viability, ORR was 4/8 (50%) CR and 4/8 (50%) PD; 3-month PFS was 50% (95%CI: 15-77%). Conclusions: We report the first experience with commercially produced CTL019 products that do not meet product release specifications, primarily due to low viability. Three-month ORRs appear similar to published tisa-cel outcomes for aggressive B-cell non-Hodgkin lymphomas. Our results suggest that other product release characteristics such as potency and replicative capacity should also be more carefully evaluated prior to establishing criteria for release. Disclosures Chong: Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dwivedy Nasta:Debiopharm: Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Porter:Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Barta:Merck: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Celgene: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Mundipharma: Honoraria. Levine:Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Patents & Royalties, Research Funding; Novartis: Consultancy; CRC Oncology: Consultancy; Cure Genetics: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Avectas: Membership on an entity's Board of Directors or advisory committees. June:Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties; Novartis: Research Funding. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. OffLabel Disclosure: Out of specificity product release of tisagenlecleucel
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Garfall, Alfred L., Adam D. Cohen, Simon F. Lacey, Lifeng Tian, Wei-Ting Hwang, Dan T. Vogl, Adam Waxman, et al. "Combination Anti-Bcma and Anti-CD19 CAR T Cells As Consolidation of Response to Prior Therapy in Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 1863. http://dx.doi.org/10.1182/blood-2019-131515.
Full textAbstract:
BACKGROUND: Anti-BCMA CAR T cells are effective in relapsed/refractory multiple myeloma (RRMM), but most patients eventually progress. Extensive prior therapy and high disease burden in RRMM pts may compromise CAR T cell safety, feasibility, and efficacy, and rare BCMA-neg/CD19+ MM cells with enhanced clonogenic potential may mediate relapse after anti-BCMA CARs. We therefore initiated a trial of anti-BCMA CAR T cells (CART-BCMA) as consolidation of response to prior MM therapy, including high-risk (HR) pts responding to first-line therapy, and combined CART-BCMA with anti-CD19 CAR T cells (CTL119). Both CART-BCMA and CTL119 are 4-1BB/CD3z-based CARs transduced via lentiviral vector. CART-BCMA was previously reported (Cohen et al JCI 2019) and exhibited 64% response rate at 5x108 cell dose following cyclophosphamide (cy) alone as lymphodepleting chemo in RRMM. CTL119 is a humanized version of tisagenlecleucel. METHODS: To assess safety/feasibility of CART-BCMA + CTL119, Phase A (PhA) is evaluating the combination in pts responding (≥MR) to ≥3rd line therapy (or ≥2nd line if exposed to all major agents). After early PhA results showed no excessive toxicity, Phase B (PhB) began enrolling HR pts (R-ISS 3, complex karyotype, PC leukemia, or <PR or early progression on imid/PI induction) responding to first- or second-line therapy, <1y from diagnosis, and unexposed to cytotoxic chemo (except low-dose cy). PhB patients are randomized to receive CART-BCMA +/- CTL119. Both products are dosed at 5x108 CAR+ cells in 3 divided doses (10%, 30%, 60%) after cy 300 mg/m2 + fludarabine 30 mg/m2 daily x 3d (cy/flu). Pts receive maintenance (maint) lenalidomide or pomalidomide beginning d30 or upon recovery from toxicity. Here we report initial results of 6 PhA and 4 PhB pts. RESULTS: 6/7 enrolled PhA pts were infused; 1 pt died due to CNS progression before infusion. 4/4 enrolled PhB pts were infused (2 CART-BCMA alone, 2 CART-BCMA + CTL119). See table for age & prior # therapies; 9/10 had HR cytogenetics or were R-ISS 3. Regarding mfg feasibility, 2 PhA pts (05, 07) failed to meet full target doses; all 4 PhB pts achieved full dose. Two subjects (01, 03) had the 3rd (60%) dose held due to early fevers. CRS was gr 0-2 by ASTCT criteria and was observed in pts with both high and low disease burden (table). No neurologic toxicity was observed. Gr 3-4 toxicities were mainly hematologic; 3/6 PhA pts had either ANC <1000 and plt <50K at day 30, whereas 4/4 PhB pts recovered ANC & plts by day 30. Aside from CRS, serious AEs ≥possibly related to CAR T cells included pneumonia, sepsis-associated AKI, CMV, pancreatitis, and bone pain, all occurring in PhA pts. Among patients with IMWG-measurable disease, ≥PR was observed in 5/5 PhA pts, including 1 pt with VGPR despite only 10% CART-BCMA dose (pt 05), and 3/3 PhB pts. Responses are ongoing in 2/6 PhA and 3/4 PhB patients (table). Initiation of maint was feasible in 4/6 PhA (median start d67) and 4/4 PhB (median start d48) pts; no recurrence of CRS was observed with maint initiation. All pts exhibited in vivo expansion of both CART19 and CART-BCMA, including those with low disease burden; no re-expansion was observed with maint initiation. Among 5 patients with ongoing responses at day 90 who were evaluable for MRD by flow cytometry, 4 had MRD with detectable BCMA expression (dim in 2 pts, bright in 1 pt, variable in 1 pt), and 1 was MRD-negative (sensitivity ~10-5); 4/5 exhibited absence of normal plasma cells, suggesting possible ongoing anti-BCMA immune surveillance but resistance of residual MM PCs. Among 8 patients who received both CART-BCMA and CTL119 in either PhA or PhB, 5 had ongoing absence of circulating B cells at last follow-up, including two pts with ongoing responses at 1y and 4m, providing evidence for long-term CAR T cell activity in MM patients. CONCLUSIONS: Preliminary results support safety and high initial response-rate of CART-BCMA + CTL119 after cy/flu in MM. In pts with low disease burden responding to prior therapy, including first-line therapy, CAR T cells expanded in vivo and generated clinical responses with low-grade CRS and no neurotoxicity. Preliminarily, hematologic toxicity and feasibility of maint seem more favorable in first-line setting. Addition of CTL119 did not clearly prevent progression after CART-BCMA in the PhA population (3-9 prior lines); data from PhB with randomization +/- CTL119 are immature. Accrual is ongoing, and updated results will be presented at the meeting. Table. Disclosures Garfall: Surface Oncology: Consultancy; Novartis: Patents & Royalties: inventor on patents related to tisagenlecleucel (CTL019) and CART-BCMA, Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Honoraria, Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding. Lacey:Novartis: Research Funding; Tmunity: Research Funding; Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers. Tian:Novartis: Research Funding. Hwang:Novartis: Research Funding; Tmunity: Research Funding. Vogl:Active Biotech: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Lancaster:novartis: Research Funding. Nelson:Novartis: Research Funding. Ferthio:Novartis: Research Funding. Fesnak:Novartis: Research Funding. Melenhorst:National Institutes of Health: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Incyte: Research Funding; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding, Speakers Bureau; Stand Up to Cancer: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Genentech: Speakers Bureau. Young:novartis: Research Funding. Levine:Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Cure Genetics: Consultancy; Novartis: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership; CRC Oncology: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees. Brogdon:Novartis: Employment. Isaacs:Novartis: Employment. June:Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties; Novartis: Research Funding. Milone:Novartis: Patents & Royalties, Research Funding. Stadtmauer:Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy.
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Minson, Adrian, Nada Hamad, Jason P. Butler, David Alan Westerman, David Ritchie, Piers Blombery, John F. Seymour, Constantine S. Tam, and Michael Dickinson. "A Phase II, Open-Label, Single Arm Trial to Assess the Efficacy and Safety of the Combination of Tisagenlecleucel and Ibrutinib in Mantle Cell Lymphoma (TARMAC)." Blood 136, Supplement 1 (November 5, 2020): 34–35. http://dx.doi.org/10.1182/blood-2020-138946.
Full textAbstract:
Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.
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Hummel, Horst D., Gaby Kuntz, Takafumi Nakamura, Axel Greiner, Stephen J. Russell, Hermann Einsele, and Max S. Topp. "Fully Retargeted Oncolytic Measles Virus for Multiple Myeloma Therapy." Blood 108, no. 11 (November 16, 2006): 5474. http://dx.doi.org/10.1182/blood.v108.11.5474.5474.
Full textAbstract:
Abstract Multiple Myeloma (MM) is a disseminated plasma cell malignancy with approximately 14,600 new cases diagnosed in the USA annually. Despite recent progress in current therapeutical options the median survival is 3 to 5 years and cure is extremely rare. Therefore the evaluation of new treatment modalities for MM is highly warranted. An attractive approach to treat Myeloma with a minimum of undesired side effects is the use of a tumour antigen specific for MM cells. Wue-1, a monoclonal antibody binds very selectively normal and malignant plasma cells (50 of 51 MM samples, 14 of 15 immunocytoma and 13 of 13 MALT type lymphomas with plasma cell differentiation were Wue-1 positive, normal tissue including hematopoietic cells were negative) and offers the possibility to define MM cells as targets. The tool for selective killing of MM cells recognized by Wue-1 monoclonal antibody is in this study the measles virus vaccine strain Edmonston B in an ablated variant (MV-Wue) which no longer binds the usual measles receptors CD46 and CD150 (SLAM) expressed on almost every human cell type displaying a single-chain antibody (scFv) derived from the monoclonal Wue-1-antibody which has been tethered to the C-terminus of the H protein to restrict and retarget its interaction to malignant plasma cells especially MM cells. In addition, MV-Wue encodes EGFP facilitating the read out of infected cells. To determine if the fully retargeted MV-Wue would be able to infect MM cell lines and primary MM cells selectively an array of infection assays were performed using the MM cell lines U266 as well as primary CD138 positive MM cells expressing the Wue-1 antigen as expected targets and CD138 negative cells and normal B cells as controls negative for Wue-1. In these experiments selective infections of the MM cell line and primary MM cells were observed whereas the control cells were not infected with MV-Wue. In all cell types GFP expression indicating replicative infection correlated with the expression of the Wue-1 antigen determined by FACS. Infection experiments performed in the presence of monoclonal Wue-1 antibody showed a decreased GFP expression of about 78% in CD138 positive MM cells demonstrating specificity of the infection by MV-Wue. These results indicate that the engineered virus can be a safe and potential curative oncolytic agent to face the main problem in Multiple Myeloma which is responsible for frequent relapses, the minimal residual disease (MRD).
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Mahto, Brindaban, Sagar Kubher, and Suhasini Gururaja. "Characterization of cure residual strain development and associated structural distortion in carbon fiber polymer matrix composites." Journal of Composite Materials, June 28, 2022, 002199832211098. http://dx.doi.org/10.1177/00219983221109865.
Full textAbstract:
A comprehensive experimental methodology has been developed to measure the in situ cure residual strain (CRS) generation in carbon fiber reinforced polymer (CFRP) laminates using embedded fiber Bragg grating (FBG) sensors. In order to delineate the effect of anisotropy, heterogeneity, laminate thickness and geometry, in situ CRS is measured in pristine epoxy, uni-directional (UD)-CFRPs, multi-directional (MD)-CFRPs and L-shaped MD-CFRP laminates. In this study, emphasis is laid on quantifying the variation in CRS magnitudes as a function of laminates lay-up sequence and thickness. Calibration of FBG sensors are carried out by following well established procedures. Structural distortion due to CRS is correlated using embedded FBG sensor and measured using the coordinate measurement machine (CMM). The presented results show a uniform CRS development across the thickness in MD-CFRP laminates as compared to L-shaped MD-CFRP laminates.
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Wang, Wei, Huaiju Liu, Caichao Zhu, Philippe Bocher, Heli Liu, and Zhangdong Sun. "Evaluation of Rolling Contact Fatigue of a Carburized Wind Turbine Gear Considering the Residual Stress and Hardness Gradient." Journal of Tribology 140, no. 6 (May 14, 2018). http://dx.doi.org/10.1115/1.4040052.
Full textAbstract:
Carburized gears are applied extensively in large-scale heavy duty machines such as wind turbines. The carburizing and quenching processes not only introduce variations of hardness from the case to the core but also generate a residual stress distribution, both of which affect the rolling contact fatigue (RCF) during repeated gear meshing. The influence of residual stress distribution on the RCF risk of a carburized wind turbine gear is investigated in the present work. The concept of RCF failure risk is defined by combining the local material strength and the multi-axial stress condition resulting from the contact. The Dang Van multi-axial fatigue criterion is applied. The applied stress field is calculated through an elastic-plastic contact finite element model. Residual stress distribution and the hardness profile are measured and compared with existed empirical formula. Based upon the Pavlina–Tyne relationship between the hardness and the yield strength, the gradient of the local material strength is considered in the calculation of the RCF failure risk. Effects of the initial residual stress peak value and its corresponding depth position are studied. Numerical results reveal that compressive residual stress (CRS) is beneficial to RCF fatigue life while tensile residual stress (TRS) increases the RCF failure risk. Under heavy load conditions where plasticity occurs, the accumulation of the plastic strain within the substrate is significantly affected by the initial residual stress distribution.
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Sghaier, Rabiaa M., Fouad Benhnini, Fatma Z. Guerfali, Hanène Attia, Aymen Bali, Amor Zaatour, Ghada Mkannez, et al. "Healed Lesions of Human Cutaneous Leishmaniasis Caused By Leishmania major Do Not Shelter Persistent Residual Parasites." Frontiers in Cellular and Infection Microbiology 12 (July 27, 2022). http://dx.doi.org/10.3389/fcimb.2022.839216.
Full textAbstract:
In human cutaneous leishmaniasis (HCL) caused by Leishmania (L.) major, the cutaneous lesions heal spontaneously and induce a Th1-type immunity that confers solid protection against reinfection. The same holds true for the experimental leishmaniasis induced by L. major in C57BL/6 mice where residual parasites persist after spontaneous clinical cure and induce sustainable memory immune responses and resistance to reinfection. Whether residual parasites also persist in scars of cured HCL caused by L. major is still unknown. Cutaneous scars from 53 volunteers with healed HCL caused by L. major were biopsied and the tissue sample homogenates were analyzed for residual parasites by four methods: i) microscope detection of amastigotes, ii) parasite culture by inoculation on biphasic medium, iii) inoculation of tissue exctracts to the footpad of BALB/c mice, an inbred strain highly susceptible to L. major, and iv) amplification of parasite kDNA by a highly sensitive real-time PCR (RT-PCR). Our results show that the scars of healed lesions of HCL caused by L. major do not contain detectable residual parasites, suggesting that this form likely induces a sterile cure at least within the scars. This feature contrasts with other Leishmania species causing chronic, diffuse, or recidivating forms of leishmaniasis where parasites do persist in healed lesions. The possibility that alternative mechanisms to parasite persistence are needed to boost and maintain long-term immunity to L. major, should be taken into consideration in vaccine development against L. major infection.
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Cameron, Christopher, Dženan Hozić, Fredrik Stig, and Sjoerd van der Veen. "A method for optimization against cure-induced distortion in composite parts." Structural and Multidisciplinary Optimization 66, no. 3 (February 21, 2023). http://dx.doi.org/10.1007/s00158-023-03504-0.
Full textAbstract:
AbstractThis paper describes a novel method developed for the optimization of composite components against distortion caused by cure-induced residual stresses. A novel ply stack alteration algorithm is described, which is coupled to a parametrized CAD/FE model used for optimization. Elastic strain energy in 1D spring elements, used to constrain the structure during analysis, serves as an objective function incorporating aspects of global/local part stiffness in predicted distortion. Design variables such as the number and stacking sequence of plies, and geometric parameters of the part are used. The optimization problem is solved using commercial software combined with Python scripts. The method is exemplified with a case study of a stiffened panel subjected to buckling loads. Results are presented, and the effectiveness of the method to reduce the effects of cure-induced distortion is discussed.
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Greksák, R. "Characteristics and Treatment of Hairy Cell Leukaemia." Acta Facultatis Pharmaceuticae Universitatis Comenianae 61, no. 1 (August 30, 2014). http://dx.doi.org/10.2478/afpuc-2014-0002.
Full textAbstract:
AbstractHairy cell leukaemia (HCL) is a rare chronic indolent lymphoproliferative disease of B-lymphocytes. It always infiltrates the spleen, bone marrow or other organs and is also present in the peripheral blood in more than 95% of cases. The disease takes its name from its characteristic wrinkled surface with hair-like projections. The prognosis of this infaust diagnosis has dramatically changed since the 1980s through more precise diagnosis and efective treatment with purine analogues (1984, 2-deoxycoformy-cine (2-dCF); 1990, 2-chlorodeoxyadenosine (2-CdA)). In our group of 38 patients, we confrmed the diagnostic possibilities and their accuracy; in addition to morphological examination, these include fow cytometric detection of typical surface CD antigens and immunohistochemical recognition of hairy cells in the trephine biopsy. The treatment percentage in the number of response rates (RRs) (100%), complete remissions (CRs) (79%) and overall survival of patients is comparable with previously known data. Overall survival rate without symptoms of disease for more than 10 years after treatment is 87% (33/38). The presence and quantity of minimal residual disease (MRD) after frst-line treatment in bone marrow determine subsequent progression or relapse of the disease, sometimes even occurring many years after the treatment. Probably some new pharmacotherapeutical possibilities (monoclonal antibodies, immunotoxins, tyrosine kinase inhibitors or inhibitors of B-Raf enzyme) could demonstrate the ability to eliminate MRD and cure it in relapsed patients or patients refractory to purine analogues. HCL has become an oncological disease with a relatively good prognosis and long-term survival after standard treatment with purine analogues despite the persistence of indolent MRD in the bone marrow at varying degree of residual infiltration intensity.