H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2(+) patients with diffuse midline glioma

Diffuse midline glioma is the leading cause of solid cancer-related deaths in children with very limited treatment options. A majority of the tumors carry a point mutation in the histone 3 variant (H3.3) creating a potential HLA-A*02:01 binding epitope (H3.3K27M(26-35)). Here, we isolated an H3.3K27M-specific T cell receptor (TCR) from transgenic mice expressing a diverse human TCR repertoire. Despite a high functional avidity of H3.3K27M-specific T cells, we were not able to achieve recognition of cells naturally expressing the H3.3K27M mutation, even when overexpressed as a transgene. Similar results were obtained with T cells expressing the published TCR 1H5 against the same epitope. CRISPR/Cas9 editing was used to exclude interference by endogenous TCRs in donor T cells. Overall, our data provide strong evidence that the H3.3K27M mutation is not a suitable target for cancer immunotherapy, most likely due to insufficient epitope processing and/or amount to be recognized by HLA-A*02:01 restricted CD8(+) T cells

In vitro proteasome processing of neo-splicetopes does not predict their presentation in vivo

Proteasome catalyzed peptide splicing (PCPS) of cancer-driving antigens could generate attractive neoepitopes to be targeted by TCR-based adoptive T cell therapy. Based on a spliced peptide prediction algorithm TCRs were generated against putative KRAS(G12V) and RAC2(P29L) derived neo-splicetopes with high HLA-A*02:01 binding affinity. TCRs generated in mice with a diverse human TCR repertoire specifically recognized the respective target peptides with high efficacy. However, we failed to detect any neo-splicetope specific T cell response when testing the in vivo neo-splicetope generation and obtained no experimental evidence that the putative KRAS(G12V)- and RAC2(P29L)-derived neo-splicetopes were naturally processed and presented. Furthermore, only the putative RAC2(P29L)-derived neo-splicetopes was generated by in vitro PCPS. The experiments pose severe questions on the notion that available algorithms or the in vitro PCPS reaction reliably simulate in vivo splicing and argue against the general applicability of an algorithm-driven 'reverse immunology' pipeline for the identification of cancer-specific neo-splicetopes

A Cell-Centred CVD-MPFA Finite Volume Method for Two-Phase Fluid Flow Problems with Capillary Heterogeneity and Discontinuity

A novel finite-volume method is presented for porous media flow simulation that is applicable to discontinuous capillary pressure fields. The method crucially retains the optimal single of freedom per control-volume being developed within the flux-continuous control-volume distributed multi-point flux approximation (CVD-MPFA) framework (Edwards and Rogers in Comput Geosci 02(04):259–290, 1998; Friis et al. in SIAM J Sci Comput 31(02):1192–1220, 2008) . The new methods enable critical subsurface flow processes involving oil and gas trapping to be correctly resolved on structured and unstructured grids. The results demonstrate the ability of the method to resolve flow with oil/gas trapping in the presence of a discontinuous capillary pressure field for diagonal and full-tensor permeability fields. In addition to an upwind approximation for the saturation equation flux, the importance of upwinding on capillary pressure flux via a novel hybrid formulation is demonstrated

Online adaptive space vector modulation

In this paper, we present a new modulation method for multilevel three-phase inverters, called online adaptive space vector modulation (oaSVM). The task of a modulator is to reconstruct the desired voltage υ* from the available discrete voltage vectors that correspond to the inverter switch positions. State-of-the-art SVM chooses three voltage vectors that form the closest triangle containing υ*. On the other hand, oaSVM explores every possible triangle that contains υ* and selects the three voltage vectors such that the trade-off between inverter switching losses and load current total harmonic distortion (THD) is improved. Inverter switching constraints and neutral-point voltage balancing are also included. The resulting mixed-integer optimization problem is solved using a branch and bound method. Through MATLAB-simulations, the loss-THD trade-off between SVM and oaSVM will be compared and we show that oaSVM can improve the inverter's efficiency

Online adaptive space vector modulation

In this paper, we present a new modulation method for multilevel three-phase inverters, called online adaptive space vector modulation (oaSVM). The task of a modulator is to reconstruct the desired voltage υ* from the available discrete voltage vectors that correspond to the inverter switch positions. State-of-the-art SVM chooses three voltage vectors that form the closest triangle containing υ*. On the other hand, oaSVM explores every possible triangle that contains υ* and selects the three voltage vectors such that the trade-off between inverter switching losses and load current total harmonic distortion (THD) is improved. Inverter switching constraints and neutral-point voltage balancing are also included. The resulting mixed-integer optimization problem is solved using a branch and bound method. Through MATLAB-simulations, the loss-THD trade-off between SVM and oaSVM will be compared and we show that oaSVM can improve the inverter's efficiency

Model predictive control strategies for DC-DC boost voltage conversion

This paper proposes a Model Predictive Control (MPC) for the boost dc-dc converter. Based on the state space description of the converter, a constrained optimal problem is formulated and solved. By regulating the current of the power circuit's inductor to a proper reference, set by an outer loop based on an observer, the main control objective, which is the regulation of the output voltage at a reference value, is achieved despite changes in the input voltage and the load. Experimental results are presented to verify the controller's feasibility and performance.acceptedVersionPeer reviewe