The impact of the Hippo pathway and cell metabolism on pathological complete response in locally advanced Her2+ breast cancer: the TRISKELE multicenter prospective study

The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies

New Working Point for CERN Proton Synchrotron

The LHC High-luminosity project requests high brightness and intensity beams from the CERN Proton Synchrotron (PS). The generation of such beams is limited due to resonance effects at injection. The impact of resonances can be minimized by performing appropriate correction with dedicated magnets and by optimizing the tune working point. Currently the tune working point at injection is naturally set by the quadrupolar component generated by the one hundred combined function normal conducting magnets installed in the PS, and slightly corrected by low energy quadrupole magnets. In this paper, a study is presented exploiting the use of the available five auxiliary individually powered circuits to adjust the quadrupolar and higher-order multipole components for changing the tune integer at injection. Due to the non-linear contribution of each circuit to the magnetic field distribution a finite-element magnetic model was prepared to predict the required currents in the auxiliary coils. The magnetic model was benchmarked with magnetic measurements and then tested in the PS machine during dedicated machine development times