Design and operation of the air-cooled beam dump for the extraction line of CERN's Proton Synchrotron Booster (PSB)

A new beam dump has been designed, built, installed and operated to withstand the future proton beam extracted from the Proton Synchrotron Booster (PSB) in the framework of the LHC Injector Upgrade (LIU) Project at CERN, consisting of up to 1E14 protons per pulse at 2 GeV, foreseen after the machine upgrades planned for CERN's Long Shutdown 2 (2019-2020). In order to be able to efficiently dissipate the heat deposited by the primary beam, the new dump was designed as a cylindrical block assembly, made out of a copper alloy and cooled by forced airflow. In order to determine the energy density distribution deposited by the beam in the dump, Monte Carlo simulations were performed using the FLUKA code, and thermo-mechanical analyses were carried out by importing the energy density into ANSYS. In addition, Computational Fluid Dynamics (CFD) simulations of the airflow were performed in order to accurately estimate the heat transfer convection coefficient on the surface of the dump. This paper describes the design process, highlights the constraints and challenges of integrating a new dump for increased beam power into the existing facility and provides data on the operation of the dump

Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer

Altres ajuts: This work has been supported by the Community of Madrid (grant S2010/BMD-2303 to GMB), the Breast Cancer Research Foundation (BCRF) to JA. Alba Mota is a predoctoral student supported by a FPU fellowship (Spanish Ministry of Education, Culture and Sport). David Sarrio is a postdoctoral researcher funded by the AECC Scientific Foundation.Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer

Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer

Altres ajuts: This work has been supported by the Community of Madrid (grant S2010/BMD-2303 to GMB), the Breast Cancer Research Foundation (BCRF) to JA. Alba Mota is a predoctoral student supported by a FPU fellowship (Spanish Ministry of Education, Culture and Sport). David Sarrio is a postdoctoral researcher funded by the AECC Scientific Foundation.Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer

Controversies around epithelial–mesenchymal plasticity in cancer metastasis

Experimental evidence accumulated over decades has implicated epithelial–mesenchymal plasticity (EMP), which collectively encompasses epithelial–mesenchymal transition and the reverse process of mesenchymal–epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial–mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents.See 'additional link' for access to a free to read version of the article.</p