Ewsr1-wt1 target genes and therapeutic options identified in a novel dsrct in vitro model

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options

An overview of DLR compound rotorcraft aerodynamics and aeroacoustics activities within the CleanSky2 NACOR Project

The challenge of increasing range and speed of a rotorcraft is encountered in the scope of the European CleanSky2 “Fast Rotorcraft” project by Airbus Helicopters with the compound helicopter design RACER (RapidAndCostEfficientRotorcraft) for which the box wing and the tail parts designs are respectively protected by patent. This paper presents the DLR contributions to the RACER development. This includes the aerodynamic design of the wing and tail section as well as an overall assessment of performance and noise. In a first step the aerodynamic properties of the configuration are evaluated both isolated and with consideration of the main rotor and lateral rotor interferences by the use of actuator discs. In the second step, the investigated possibilities to improve the configurations performance are described. These include airfoil design for improved high lift performance of the wing and tail section, an optimization of the box wing circulation distribution on the upper and lower wing. Additionally, the intersection fairings were improved and the efficiency of the trim flaps was evaluated. In this regard, it could be determined for which cases an isolated approach is appropriate and when the rotor interference should be considered. At the end the evaluation of the aero acoustics of the configuration is conducted. The applied configuration shows good aerodynamic characteristics with some further cruise and off design optimization potential

Single-cell atlas of developing murine adrenal gland reveals relation of Schwann cell precursor signature to neuroblastoma phenotype

Neuroblastoma is the most common extracranial solid tumor and accounts for ∼10% of pediatric cancer-related deaths. The exact cell of origin has yet to be elucidated, but it is generally accepted that neuroblastoma derives from the neural crest and should thus be considered an embryonal malignancy. About 50% of primary neuroblastoma tumors arise in the adrenal gland. Here, we present an atlas of the developing mouse adrenal gland at a single-cell level. Five main cell cluster groups (medulla, cortex, endothelial, stroma, and immune) make up the mouse adrenal gland during fetal development. The medulla group, which is of neural crest origin, is further divided into seven clusters. Of interest is the Schwann cell precursor (“SCP”) and the “neuroblast” cluster, a highly cycling cluster that shares markers with sympathoblasts. The signature of the medullary SCP cluster differentiates neuroblastoma patients based on disease phenotype: The SCP signature score anticorrelates with ALK and MYCN expression, two indicators of poor prognosis. Furthermore, a high SCP signature score is associated with better overall survival rates. This study provides an insight into the developing adrenal gland and introduces the SCP gene signature as being of interest for further research in understanding neuroblastoma phenotype

Central venous catheter–associated complications in pediatric patients diagnosed with Hodgkin lymphoma: implications for catheter choice

Purpose: The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications. Methods: A retrospective study including patients diagnosed with HL from 2015 to 2021 at the Princess Máxima Center was performed. Patients were followed from CVC insertion until removal or 06–2021, whichever came first. The primary outcome was the CVC-related complication incidence rate (IR) per 1000 CVC-days. Furthermore, the incidence rate ratio (IRR) was calculated by comparing complication IRs between peripherally inserted central catheters (PICC) and totally implantable venous access ports (TIVAP). Additionally, risk factors for central venous thrombosis (CVT) were identified. Results: A total of 98 patients were included. The most frequently observed complications were local irritation/infections (18%; IR 0.93), malfunctions (15%; IR 0.88), and CVC-related CVTs (10%; IR 0.52). Single lumen PICCs were associated with a higher risk of complications (49% vs. 26%; IRR 5.12, CI95% 2.76–9.50), severe complications (19% vs. 7%; IRR 11.96, CI95% 2.68–53.42), and early removal (18% vs. 7%; IRR 9.96, CI95% 2.18–45.47). A single lumen PICC was identified as a risk factor for CVC-related CVT when compared to TIVAPs (12% vs. 7%, IRR 6.98, CI95% 1.45–33.57). Conclusion: The insertion of a TIVAP rather than a PICC should be recommended for pediatric patients with HL, especially in the presence of CVT-related risk factors. Future trials should evaluate the efficacy and safety of direct oral anticoagulants for the primary prevention of CVT in pediatric patients with a PICC and other CVT-related risk factors

Drag reduction of a transport helicopter by application of an adjoint-based fuselage optimization chain and modification of the rotor head

In this paper two approaches are investigated to reduce the parasite drag of a helicopter. The first approach is to optimize the surface of the fuselage back door. This is done by applying an automatic, adjoint-based optimization chain; developed by DLR for these purposes. This optimization chain combines the RANS-solver TAU with a solver for the discrete adjoint equation and a conjugate-gradient based optimization algorithm. The parameterization is done by Free Form Deformation. A description of the functionality of the chain is given, before the results of the optimization run are presented. The resulting surfaces were able to bring benefits, up to 3.75% drag reduction compared to the baseline geometry. The second approach is to reduce the main rotor head drag, by installing a hub fairing. During this investigation, two different hub geometries were tested. By using a fully closed fairing, a drag reduction of about 19% could be achieved

AN ADJOINT BASED OPTIMIZATION CHAIN FOR COMPLEX HELICOPTER FUSELAGE PARTS USING A FREE FORM DEFORMATION OR CAD BASED PARAMETERIZATION METHOD

In this paper a gradient based optimization chain for aerodynamic shape optimization is described. The chain includes the DLR TAU-code for flow evaluations, while a discrete adjoint approach is used to compute the gradient of a high count of design variables. For parameterization of complex helicopter fuselage parts, two different methods were implemented. The first method uses the Free Form Deformation technique to modify the shape by manipulating the control points of a NURBS-volume. The second approach is to use the CAD software CATIA V5 to build up a parametrical model for optimization. To investigate both methods with different settings, the ROBIN-mod7 fuselage was chosen to reduce drag by optimizing the relative simple back door geometry. After gaining experience with this example, the optimization chain is used to optimize the shape of the common helicopter platform sponsons in the scope of the European Clean Sky GRC2-project. It could be shown that for both examples a reduction of the drag force was achieved (drag reduction of 21.76% for the ROBIN-mod7 test case and 1.49% drag reduction for the sponsons optimization)

Investigation of the performance of the TAU-Code in combination with the grid generator Pointwise for a helicopter fuselage with different pitch angles using the GOAHEAD database

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Aerodynamic analysis and optimization of wings and tail surfaces of a compound helicopter with box wing

DLR was involved in the aerodynamic design and evaluation of the innovative high-speed compound helicopter demonstrator RACER, developed under the lead of Airbus Helicopters. This paper presents low-fidelity analyses and optimizations performed to supplement RANS simulations in the design and evaluation process of the RACER wings and tail. A toolchain based on the 3D panel method VSAERO was implemented to quickly perform such tasks. The presented applications include component interaction analyses, optimization of circulation distribution, evaluation of flap efficiency and evaluation of different tail designs. The results helped to gain better understanding of the complex RACER configuration aerodynamics including interaction effects of various components. Moreover, the computational effort could be considerably reduced by the proposed method compared to RANS simulations. Nevertheless, one must be aware of the method restrictions and carefully check whether their application is reasonable for each use case

The efficient use of CFD in Rotorcraft Optimization

Computational Fluid Dynamics enables the accurate prediction of the flow about complete rotorcraft configurations. However, depending on the complexity of test case under consideration the execution time of a single CFD computation may be prohibitive. Therefore, efficient optimization strategies are required. Two examples of recent optimizations by DLR are reported: A first example is given by the optimization of a helicopter fuselage to minimize drag. The adjoint equations are solved to efficiently compute the design sensitivities for up to 200 design variables and to find the optimum with a gradient based optimizer. A second example is given by the multi-objective optimization of a helicopter rotor blade using ten design variables. The Pareto-front for the goal functions hover and forward flight performance is predicted by surrogate based optimization. A variable-fidelity approach combining low- and high fidelity predictions is employed to reduce the number of required high-fidelity samples

DLR ANALYSIS ON THE NOISE EMISSION FROM THE RACER CONFIGURATION

To answer the challenge of increasing range and speed of a rotorcraft, RACER (Rapid And Cost-Effective Rotorcraft) is developed by Airbus Helicopters. The RACER configuration incorporates an innovative 'box-wing' design to provide lift and 'pusher' propellers at the wing tips to generate thrust in forward flight. The noise sources from RACER do not only include conventional helicopter main rotor noise, but also propeller noise which can be significantly affected by interferences with the main rotor, wings and other parts of the configuration. Having been widely applied to the simulations of rotor and propellers, the DLR free wake code UPM and the aeroacoustic analysis tool APSIM are used for a detailed analysis and an improved understanding of the complex aerodynamics and aeroacoustics of the RACER configuration. The noise generation mechanisms of the various interactions among the propeller, the wings and the rotor as well as a variation in the sense of rotation of the propeller are numerically studied to allow finding mitigation means to reduce the interactions in the final RACER configuration. The noise from rotor and propeller emitted by the complete RACER configuration for various flight conditions is analyzed and the analysis of acoustic scattering of propeller noise by the RACER configuration is conducted