A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability

The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hypomorphic Mre11 allele exhibit increased levels of oncogene-induced DNA damage, R-loop accumulation, and chromosomal instability with a characteristic copy number loss phenotype. Mre11 complex dysfunction is identified in a subset of human triple-negative breast cancers and is associated with increased sensitivity to DNA-damaging therapy and inhibitors of ataxia telangiectasia and Rad3 related (ATR) and poly (ADP-ribose) polymerase (PARP). Thus, deficiencies in the Mre11-dependent DDR drive proliferation and genome instability patterns in p53-deficient breast cancers and represent an opportunity for therapeutic exploitation

Real-time-capable prediction of temperature and density profiles in a tokamak using RAPTOR and a first-principle-based transport model

The RAPTOR code is a control-oriented core plasma profile simulator with various applications in control design and verification, discharge optimization and real-time plasma simulation. To date, RAPTOR was capable of simulating the evolution of poloidal flux and electron temperature using empirical transport models, and required the user to input assumptions on the other profiles and plasma parameters. We present an extension of the code to simulate the temperature evolution of both ions and electrons, as well as the particle density transport. A proof-of-principle neural-network emulation of the quasilinear gyrokinetic QuaLiKiz transport model is coupled to RAPTOR for the calculation of first-principle-based heat and particle turbulent transport. These extended capabilities are demonstrated in a simulation of a JET discharge. The multi-channel simulation requires ∼0.2 s to simulate 1 second of a JET plasma, corresponding to ∼20 energy confinement times, while predicting experimental profiles within the limits of the transport model. The transport model requires no external inputs except for the boundary condition at the top of the H-mode pedestal. This marks the first time that simultaneous, accurate predictions of Te, Tiand nehave been obtained using a first-principle-based transport code that can run in faster-than-real-time for present-day tokamaks

Comparison of runaway electron generation parameters in small, medium-sized and large tokamaks - A survey of experiments in COMPASS, TCV, ASDEX-Upgrade and JET

This paper presents a survey of the experiments on runaway electrons (RE) carried out recently in frames of EUROFusion Consortium in different tokamaks: COMPASS, ASDEX-Upgrade, TCV and JET. Massive gas injection (MGI) has been used in different scenarios for RE generation in small and medium-sized tokamaks to elaborate the most efficient and reliable ones for future RE experiments. New data on RE generated at disruptions in COMPASS and ASDEX-Upgrade was collected and added to the JET database. Different accessible parameters of disruptions, such as current quench rate, conversion rate of plasma current into runaways, etc have been analysed for each tokamak and compared to JET data. It was shown, that tokamaks with larger geometrical sizes provide the wider limits for spatial and temporal variation of plasma parameters during disruptions, thus extending the parameter space for RE generation. The second part of experiments was dedicated to study of RE generation in stationary discharges in COMPASS, TCV and JET. Injection of Ne/Ar have been used to mock-up the JET MGI runaway suppression experiments. Secondary RE avalanching was identified and quantified for the first time in the TCV tokamak in RE generating discharges after massive Ne injection. Simulations of the primary RE generation and secondary avalanching dynamics in stationary discharges has demonstrated that RE current fraction created via avalanching could achieve up to 70-75% of the total plasma current in TCV. Relaxations which are reminiscent the phenomena associated to the kinetic instability driven by RE have been detected in RE discharges in TCV. Macroscopic parameters of RE dominating discharges in TCV before and after onset of the instability fit well to the empirical instability criterion, which was established in the early tokamaks and examined by results of recent numerical simulations