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Fusion performance in tokamaks depends on the core and edge regions as well as on their nonlinear feedbacks. The achievable degree of edge confinement under the constraints of power handling in presence of a metallic wall is still an open question. Therefore, any improvement in the core temperature and density peaking is crucial for achieving target performance. This has motivated further progress in understanding core turbulent transport mechanisms, to help scenario development in present devices and improve predictive tools for ITER operations. In the last two decades, detailed experiments and their interpretation via the gyrokinetic theory of turbulent transport have led to a satisfactory level of understanding of the heat, particle, and momentum transport channels and of their mutual interactions. This paper presents some highlights of the progress, which stems from joint work of several devices and theory groups, in Europe and worldwide within the International Tokamak Physics Activities framework. On the other hand, the achievement of predictive capabilities of plasma profiles via integrated modeling, which also accounts for the nonlinear interactions inherent to the multi-channel nature of transport, is a priority in view of ITER. This requires using faster, reduced models, and the extent to which they capture the complex physics described by nonlinear gyrokinetics must be carefully evaluated. Present quasi-linear models match well experiments in baseline scenarios, and thus offer reliable predictions for the ITER reference scenario, but have issues in advanced scenarios. Some of these challenges are examined and discussed. In the longer term, advances in high performance computing will continue to drive physics discovery through increasingly complex gyrokinetic simulations, allowing also further development of reduced models. The development of neural network surrogate models is another recent advance that bridges the gap towards physics-based fast models for optimization and control applications. [ABSTRACT FROM AUTHOR]

Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)