Hypoxia up-regulates SERPINB3 through HIF-2\u3b1 in human liver cancer cells.

SERPINB3 is a cysteine-proteases inhibitor up-regulated in a significant number of cirrhotic patients carrying hepatocellular carcinoma (HCC) and recently proposed as a prognostic marker for HCC early recurrence. SERPINB3 has been reported to stimulate proliferation, inhibit apoptosis and, similar to what reported for hypoxia, to trigger epithelial-to-mesenchymal transition (EMT) and increased invasiveness in liver cancer cells. This study has investigated whether SERPINB3 expression is regulated by hypoxia-related mechanisms in liver cancer cells. Exposure of HepG2 and Huh7 cells to hypoxia up-regulated SERPINB3 transcription, protein synthesis and release in the extracellular medium. Hypoxia-dependent SERPINB3 up-regulation was selective (no change detected for SERPINB4) and operated through hypoxia inducible factor (HIF)-2\u3b1 (not HIF-1\u3b1) binding to SERPINB3 promoter, as confirmed by chromatin immuno-precipitation assay and silencing experiments employing specific siRNAs. HIF-2\u3b1-mediated SERPINB3 up-regulation under hypoxic conditions required intracellular generation of ROS. Immuno-histochemistry (IHC) and transcript analysis, performed in human HCC specimens, revealed co-localization of the two proteins in liver cancer cells and the existence of a positive correlation between HIF-2\u3b1 and SERPINB3 transcript levels, respectively. Hypoxia, through HIF-2\u3b1-dependent and redox-sensitive mechanisms, up-regulates the transcription, synthesis and release of SERPINB3, a molecule with a high oncogenic potential

GPU-based Real-time Triggering in the NA62 Experiment

Over the last few years the GPGPU (General-Purpose computing on Graphics Processing Units) paradigm represented a remarkable development in the world of computing. Computing for High-Energy Physics is no exception: several works have demonstrated the effectiveness of the integration of GPU-based systems in high level trigger of different experiments. On the other hand the use of GPUs in the low level trigger systems, characterized by stringent real-time constraints, such as tight time budget and high throughput, poses several challenges. In this paper we focus on the low level trigger in the CERN NA62 experiment, investigating the use of real-time computing on GPUs in this synchronous system. Our approach aimed at harvesting the GPU computing power to build in real-time refined physics-related trigger primitives for the RICH detector, as the the knowledge of Cerenkov rings parameters allows to build stringent conditions for data selection at trigger level. Latencies of all components of the trigger chain have been analyzed, pointing out that networking is the most critical one. To keep the latency of data transfer task under control, we devised NaNet, an FPGA-based PCIe Network Interface Card (NIC) with GPUDirect capabilities. For the processing task, we developed specific multiple ring trigger algorithms to leverage the parallel architecture of GPUs and increase the processing throughput to keep up with the high event rate. Results obtained during the first months of 2016 NA62 run are presented and discussed

Mutant p53 improves cancer cells\u2019 resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6

Missense mutations in the TP53 gene are frequent in human cancers, giving rise to mutant p53 proteins that can acquire oncogenic properties. Gain of function mutant p53 proteins can enhance tumour aggressiveness by promoting cell invasion, metastasis and chemoresistance. Accumulating evidences indicate that mutant p53 proteins can also modulate cell homeostatic processes, suggesting that missense p53 mutation may increase resistance of tumour cells to intrinsic and extrinsic cancer-related stress conditions, thus offering a selective advantage. Here we provide evidence that mutant p53 proteins can modulate the Unfolded Protein Response (UPR) to increase cell survival upon Endoplasmic Reticulum (ER) stress, a condition to which cancer cells are exposed during tumour formation and progression, as well as during therapy. Mechanistically, this action of mutant p53 is due to enhanced activation of the pro-survival UPR effector ATF6, coordinated with inhibition of the pro-apoptotic UPR effectors JNK and CHOP. In a triple-negative breast cancer cell model with missense TP53 mutation, we found that ATF6 activity is necessary for viability and invasion phenotypes. Together, these findings suggest that ATF6 inhibitors might be combined with mutant p53-targeting drugs to specifically sensitise cancer cells to endogenous or chemotherapy-induced ER stress

Performance of the NA62 trigger system

The NA62 experiment at CERN targets the measurement of the ultra-rare K+ ->pi+ nu nu decay, and carries out a broad physics programme that includes probes for symmetry violations and searches for exotic particles. Data were collected in 2016–2018 using a multi-level trigger system, which is described highlighting performance studies based on 2018 data

Externalities and the nucleolus

In most economic applications, externalities prevail: the worth of a coalition depends on how the other players are organized. We show that there is a unique natural way of extending the nucleolus from (coalitional) games without externalities to games with externalities. This is in contrast to the Shapley value and the core for which many different extensions have been proposed

Physics beyond the standard model with kaons at NA62

The NA62 experiment at CERN Super Proton Synchrotron was designed to measure BR(K+ \u2192 \u3c0+\u3bdv\u304) with an in-fight technique, never used before for this measurement. This decay is characterised by a very precise prediction in the Standard Model. Its branching ratio, which is expected to be less than 10-10, is one of the best candidates to indicate indirect effects of new physics beyond SM at the highest mass scales. NA62 result on K+ \u2192 \u3c0+\u3bdv\u304 from the full 2016 data set is described. Also a search for an invisible dark photon A\u2032 has been performed, exploiting the efficient photon-veto capability and high resolution tracking of the NA62. The signal stems from the chain K+ \u2192 \u3c0+\u3c00 followed by \u3c00 \u2192 A\u2032\u3b3. No significant statistical excess has been identified. Upper limits on the dark photon coupling to the ordinary photon as a function of the dark photon mass have been set, improving on the previous limits over the mass range 60 - 110 MeV/c2

Search for π⁰ decays to invisible particles

The NA62 experiment at the CERN SPS reports a study of a sample of 4 × 109 tagged π0 mesons from K+ → π+π0(γ), searching for the decay of the π0 to invisible particles. No signal is observed in excess of the expected background fluctuations. An upper limit of 4.4 × 10−9 is set on the branching ratio at 90% confidence level, improving on previous results by a factor of 60. This result can also be interpreted as a model- independent upper limit on the branching ratio for the decay K+ → π+X, where X is a particle escaping detection with mass in the range 0.110–0.155 GeV/c2 and rest lifetime greater than 100 ps. Model-dependent upper limits are obtained assuming X to be an axion-like particle with dominant fermion couplings or a dark scalar mixing with the Standard Model Higgs boson

Searches for lepton number violating K+ decays

The NA62 experiment at CERN reports a search for the lepton number violating decays K+→π−e+e+ and K+→π−μ+μ+ using a data sample collected in 2017. No signals are observed, and upper limits on the branching fractions of these decays of 2.2 x 10^-10 and 4.2 x 10^-11 are obtained, respectively, at 90% confidence level. These upper limits improve on previously reported measurements by factors of 3 and 2, respectively