Monitored neutrino beams and the next generation of high precision cross section experiments

The main source of systematic uncertainty on neutrino cross section measurements at the GeV scale originates from the poor knowledge of the initial flux. The reduction of this uncertainty to 1% can be achieved through the monitoring of charged leptons produced in association with neutrinos. The goal of the ENUBET ERC project is to prove the feasibility of such a monitored neutrino beam. In this contribution, the final results of the ERC project, together with the complete assessment of the feasibility of its concept, are presented. An overview of the detector technology for a next generation of high precision neutrino-nucleus cross section measurements, to be performed with the ENUBET neutrino beam, is also given

Design and performance of the ENUBET monitored neutrino beam

The ENUBET project is aimed at designing and experimentally demonstrating the concept of monitored neutrino beams. These novel beams are enhanced by an instrumented decay tunnel, whose detectors reconstruct large-angle charged leptons produced in the tunnel and give a direct estimate of the neutrino flux at the source. These facilities are thus the ideal tool for high-precision neutrino cross-section measurements at the GeV scale because they offer superior control of beam systematics with respect to existing facilities. In this paper, we present the first end-to-end design of a monitored neutrino beam capable of monitoring lepton production at the single particle level. This goal is achieved by a new focusing system without magnetic horns, a 20 m normal-conducting transfer line for charge and momentum selection, and a 40 m tunnel instrumented with cost-effective particle detectors. Employing such a design, we show that percent precision in cross-section measurements can be achieved at the CERN SPS complex with existing neutrino detectors

Monitored neutrino beams: NP06/ENUBET

The main source of systematic uncertainty on neutrino cross section measurements at the GeV scale is represented by the poor knowledge of the initial flux. The goal of cutting down this uncertainty to 1% can be achieved through the monitoring of charged leptons produced in association with neutrinos, by properly instrumenting the decay region of a conventional narrow-band neutrino beam. The ENUBET project has been funded by the ERC in 2016 to prove the feasibility of such a monitored neutrino beam and is cast in the framework of the CERN Neutrino Platform (NP06) and the Physics Beyond Colliders initiative. This contribution reports the final design of the horn-less beamline able to deliver a meson yield large enough to perform a ve cross section measurement at 1% precision in about 3 years of data taking at CERN-SPS with a ProtoDUNE-like detector. The final configuration of the tunnel instrumentation and its implementation on a large-scale prototype, the Demonstrator, are also described. Finally the particle identification performance is presented together with the first assessment of the lepton monitoring impact in the reduction of the hadroproduction systematics on the neutrino flux

Status of the ENUBET Project

The ENUBET Collaboration is designing the first “monitored neutrino beam”: a beam with an unprecedented control of the flux, energy and flavor of neutrinos at source. In particular, ENUBET monitors the νe production mostly by the detection of large angle positrons from three body semileptonic decays of kaons: K+ → e+π0νe. In this paper, we present the status of the Project and the 2018-2019 advances on proton extraction, transfer line, particle identification in the decay tunnel and beam performance

Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype

BACKGROUND: Tumours contain hypoxic regions that select for an aggressive cell phenotype; tumour hypoxia induces metastasis-associated genes. Treatment refractory patients with metastatic cancer show increased numbers of circulating tumour cells (CTCs), which are also associated with disease progression. The aim of this study was to examine the as yet unknown relationship between hypoxia and CTCs. METHODS: We generated human MDA-MB-231 orthotopic xenografts and, using a new technology, isolated viable human CTCs from murine blood. The CTCs and parental MDA-MB-231 cells were incubated at 21 and 0.2% (hypoxia) oxygen, respectively. Colony formation was assayed and levels of hypoxia- and anoxia-inducible factors were measured. Xenografts generated from CTCs and parental cells were compared. RESULTS: MDA-MB-231 xenografts used to generate CTCs were hypoxic, expressing hypoxia factors: hypoxia-inducible factor1 alpha (HIF1alpha) and glucose transporter protein type 1 (GLUT1), and anoxia-induced factors: activating transcription factor 3 and 4 (ATF3 and ATF4). Parental MDA-MB-231 cells induced ATF3 in hypoxia, whereas CTCs expressed it constitutively. Asparagine synthetase (ASNS) expression was also higher in CTCs. Hypoxia induced ATF4 and the HIF1alpha target gene apelin in CTCs, but not in parental cells. Hypoxia induced lower levels of carbonic anhydrase IX (CAIX), GLUT1 and BCL2/adenovirus E1B 19-KD protein-interacting protein 3 (BNIP3) proteins in CTCs than in parental cells, supporting an altered hypoxia response. In chronic hypoxia, CTCs demonstrated greater colony formation than parental cells. Xenografts generated from CTCs were larger and heavier, and metastasised faster than MDA-MB-231 xenografts. CONCLUSION: CTCs show an altered hypoxia response and an enhanced aggressive phenotype in vitro and in vivo

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFN gamma-stimulated endothelial cells

IFN gamma enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFN gamma. We also assessed if NOD affects IFN gamma mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNF alpha and IFN gamma and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFN gamma stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFN gamma to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models

Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N–Terminal Peptide Binding

Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N–terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl–terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N–terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR–cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 ‘hotspot’ mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53–p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.JE Noll, J Jeffery, F Al-Ejeh, R Kumar, KK Khanna, DF Callen and PM Neilse