A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeting drugs normalise the tumour vasculature and improve access for chemotherapy. However, excessive VEGF inhibition fails to improve clinical outcome, and successive treatment cycles lead to incremental extracellular matrix (ECM) deposition, which limits perfusion and drug delivery. We show here, that low-dose VEGF inhibition augmented with PDGF-R inhibition leads to superior vascular normalisation without incremental ECM deposition thus maintaining access for therapy. METHODS: Collagen IV expression was analysed in response to VEGF inhibition in liver metastasis of colorectal cancer (CRC) patients, in syngeneic (Panc02) and xenograft tumours of human colorectal cancer cells (LS174T). The xenograft tumours were treated with low (0.5 mg kg(−1) body weight) or high (5 mg kg(−1) body weight) doses of the anti-VEGF antibody bevacizumab with or without the tyrosine kinase inhibitor imatinib. Changes in tumour growth, and vascular parameters, including microvessel density, pericyte coverage, leakiness, hypoxia, perfusion, fraction of vessels with an open lumen, and type IV collagen deposition were compared. RESULTS: ECM deposition was increased after standard VEGF inhibition in patients and tumour models. In contrast, treatment with low-dose bevacizumab and imatinib produced similar growth inhibition without inducing detrimental collagen IV deposition, leading to superior vascular normalisation, reduced leakiness, improved oxygenation, more open vessels that permit perfusion and access for therapy. CONCLUSIONS: Low-dose bevacizumab augmented by imatinib selects a mature, highly normalised and well perfused tumour vasculature without inducing incremental ECM deposition that normally limits the effectiveness of VEGF targeting drugs

The RICH detector of the NA62 experiment at CERN

The RICH detector of the NA62 experiment is one of the key detectors to achieve the muon rejection needed in the search for the {K + } to {pi + }nu bar nu decay, performed by NA62. Since R({K + } to {mu + }nu ) is higher than BR({K + } to {pi + }nu bar nu ) by more than 9 orders of magnitude, it represents one of the most relevant background contributions. Its rejection is performed with kinematic reconstruction of the event and identification of the charged particles in the final state (pions against muons). The Ring Imaging Cherenkov detector (RICH) gives a muon rejection higher than a factor 100 in the momentum range 15-35 GeV/c, and measures the track crossing time with a resolution better than 100 ps. It is also exploited to provide trigger for charged particles. In this contribution the RICH detector will be described, together with its basic performance, the mirrors alignment procedure and its usage in {K + } to {pi + }nu bar nu search

NA62 results on Dark Sector searches

NA62 is a precision physics experiment studying charged kaons and their decayproducts with an unprecedented accuracy (measurement of the K + → π + ννbranching ratio of the order of 10 −11), allowing indirect probes of new physicsscales up to O(100) TeV. NA62 experiment also searches directly for weaklyinteracting particles of up to O(100) MeV masses in kaon decays and up to O(1)GeV masses when running in the beam dump mode. For both modes of directsearches, NA62 has been collecting data since 2021 after a successful 2016-18run 1. Past results and future prospects are presented in this talk