Demethylating therapy increases cytotoxicity of CD44v6 CAR-T cells against acute myeloid leukemia

BackgroundCD44v6 chimeric antigen receptor T (CD44v6 CAR-T) cells demonstrate strong anti-tumor ability and safety in acute myeloid leukemia (AML). However, the expression of CD44v6 on T cells leads to transient fratricide and exhaustion of CD44v6 CAR-T cells, which affect the application of CD44v6 CAR-T. The exhaustion and function of T cells and CD44v6 expression of AML cells are associated with DNA methylation. Hypomethylating agents (HAMs) decitabine (Dec) and azacitidine (Aza) have been widely used to treat AML. Therefore, there may be synergy between CD44v6 CAR-T cells and HAMs in the treatment of AML.MethodsCD44v6 CAR-T cells pretreated with Dec or Aza were co-cultured with CD44v6+ AML cells. Dec or aza pretreated AML cells were co-cultured with CD44v6 CAR-T cells. The cytotoxicity, exhaustion, differentiation and transduction efficiency of CAR-T cells, and CD44v6 expression and apoptosis in AML cells were detected by flow cytometry. The subcutaneous tumor models were used to evaluate the anti-tumor effect of CD44v6 CAR-T cells combined with Dec in vivo. The effects of Dec or Aza on gene expression profile of CD44v6 CAR-T cells were analyzed by RNA-seq.ResultsOur results revealed that Dec and Aza improved the function of CD44v6 CAR-T cells through increasing the absolute output of CAR+ cells and persistence, promoting activation and memory phenotype of CD44v6 CAR-T cells, and Dec had a more pronounced effect. Dec and Aza promoted the apoptosis of AML cells, particularly with DNA methyltransferase 3A (DNMT3A) mutation. Dec and Aza also enhanced the CD44v6 CAR-T response to AML by upregulating CD44v6 expression of AML cells regardless of FMS-like tyrosine kinase 3 (FLT3) or DNMT3A mutations. The combination of Dec or Aza pretreated CD44v6 CAR-T with pretreated AML cells demonstrated the most potent anti-tumor ability against AML.ConclusionDec or Aza in combination with CD44v6 CAR-T cells is a promising combination therapy for AML patients

Optimization on the Law of Variable-Pitch Vertical-Axis Tidal Current Turbine

In order to improve the hydrodynamic performance of the vertical-axis variable-pitch current turbine, with analyzing on the existing design mentality of blade control mechanism, an optimized law of variable-pitch vertical-axis tidal current turbine was given in terms of the instantaneous moment coefficient of the blade. A method for solving the lift - drag coefficient of Blade by wind - hole test data is given. The optimized kinematic model has a significant reference value for the further development of vertical axis turbine model test

Optimization on the Law of Variable-Pitch Vertical-Axis Tidal Current Turbine

In order to improve the hydrodynamic performance of the vertical-axis variable-pitch current turbine, with analyzing on the existing design mentality of blade control mechanism, an optimized law of variable-pitch vertical-axis tidal current turbine was given in terms of the instantaneous moment coefficient of the blade. A method for solving the lift - drag coefficient of Blade by wind - hole test data is given. The optimized kinematic model has a significant reference value for the further development of vertical axis turbine model test

Analytical and Numerical Analysis of the Dynamics of a Moonpool Platform–Wave Energy Buoy (MP–WEB)

In this work the hydrodynamic performance of a novel wave energy converter configuration was analytically and numerically studied by combining a moonpool and a wave energy buoy, called the moonpool platform–wave energy buoy (MP–WEB). A potential flow, semi-analytical approach was adopted to assess the total (incident, diffraction, radiation) wave forces acting on the device, and the wave capture and energy efficiency performance of this configuration was assessed, both in the time and frequency domain. The performance of the two configurations, single float and double float, were analyzed and compared in terms of diffraction force, added mass radiation force, motion, and power in the frequency domain. Using an impulse response function-based (IRF) method, the frequency domain results were converted in the time domain. The same parameters in the time domain were derived and the main results were confirmed. Wave energy conversion efficiency was significantly increased due to the resonance phenomenon inside the moonpool

Effect of Dissipation on the Moonpool-Javelin Wave Energy Converter

In this work, the hydrodynamic performance of a novel wave energy converter (WEC) configuration which combines a moonpool platform and a javelin floating buoy, called the moonpool–javelin wave energy converter (MJWEC), was studied by semianalytical, computational fluid dynamics (CFD), and experimental methods. The viscous term is added to the potential flow solver to obtain the hydrodynamic coefficients. The wave force, the added mass, the radiation damping, the wave capture, and the energy efficiency of the configuration were assessed, in the frequency and time domains, by a semianalytical method. The CFD method results and the semianalytical results were compared for the time domain by introducing nonlinear power take-off (PTO) damping; additionally, the viscous dissipation coefficients under potential flow could be confirmed. Finally, a 1:10 scale model was physically tested to validate the numerical model and further prove the feasibility of the proposed system

Effect of Dissipation on the Moonpool-Javelin Wave Energy Converter

In this work, the hydrodynamic performance of a novel wave energy converter (WEC) configuration which combines a moonpool platform and a javelin floating buoy, called the moonpool–javelin wave energy converter (MJWEC), was studied by semianalytical, computational fluid dynamics (CFD), and experimental methods. The viscous term is added to the potential flow solver to obtain the hydrodynamic coefficients. The wave force, the added mass, the radiation damping, the wave capture, and the energy efficiency of the configuration were assessed, in the frequency and time domains, by a semianalytical method. The CFD method results and the semianalytical results were compared for the time domain by introducing nonlinear power take-off (PTO) damping; additionally, the viscous dissipation coefficients under potential flow could be confirmed. Finally, a 1:10 scale model was physically tested to validate the numerical model and further prove the feasibility of the proposed system

Investigation on PTO control of a combined axisymmetric buoy-WEC(CAB-WEC)

The Combined Axisymmetric Buoy (CAB), a vertical axisymmetric buoy, has the potential to deliver a high energy absorption power. Considering the CAB-Wave Energy Converters (WEC), in order to achieve higher efficiency, the Power Take Off (PTO) systems, which converts the float motion into energy output, needs to be properly controlled. In this paper, a PTO control method for a CAB-WEC under irregular wave conditions is proposed. Based on the semi-analytical solution obtained in the time domain, a numerical optimization is carried out. The optimal PTO damping coefficients under different wave conditions are obtained, by considering the parameter defined as “capture width ratio”. The expression of the optimal PTO damping coefficient in the frequency domain is derived by an analytical method. Based on the semi-analytical solution of time domain dynamic characteristics and analytical method, a comparison between frequency domain optimization and time domain optimization is presented. In general, the two approaches arrive to very similar conclusions, even if with the time domain methodology a slightly higher capture width ratio is achieved. The experimental results have been used to validate the time domain optimization method and the variation in optimal average capture width ratio results

Wind-Load Response and Evacuation Efficiency Analysis of Marine Evacuation Inflatable Slide

Flexible inflatable membrane structure has the characteristics of light weight, large span, and small stiffness, and it is very sensitive to wind load. Aiming at the dynamic response of marine evacuation inflatable slides under complex and changeable wind loads at sea, the response law of the inflatable slide under different wind directions, wind speeds, and internal pressure conditions is studied by using fluid–solid coupling theory. The most dangerous conditions of evacuation system installation and the ideal internal pressure of the inflatable slide meeting the stability requirements are deduced. The LS-DYNA module is used to simulate the inflation process of the slide. The evacuation sliding is rationally simplified. By changing the inflatable internal pressure of the slide, the variation law of displacement, deformation, and sliding speed of the slide is obtained, and the optimal inflation internal pressure satisfying the evacuation efficiency requirement is obtained. The results show that the inflow wind direction angle of 30° is the most dangerous condition for slideway installation, and the internal pressure of 4000 Pa is the ideal internal pressure to meet the double standards of stability and evacuation efficiency. The numerical results obtained are valuable for analyzing wind resistance of offshore inflatable membrane structures and their practical design and application in evacuation systems