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Dear Editor, In this study, measurement of target inhibition of lysyl oxidase-like 2 (LOXL2) in a high throughput manner from tissue lysates and blood was achieved by the tailored design of an activity-based probe (ABP), PXS-5878. Lysyl oxidases are a family of five enzymes critically responsible for the formation of cross-linked collagen and elastin, the hallmarks of fibrosis and stroma.1,2 One member in particular, LOXL2, has excellent pre-clinical target validation, is upregulated in various fibrotic diseases and cancer,3 and acts as a biomarker for disease severity and progression in humans.4,5 Despite overwhelming target rationale, the failure of the LOXL2 antibody simtuzumab to achieve positive clinical endpoints6,7 has undoubtedly hampered progress in the field and cast doubt over the validity of LOXL2 inhibition as a viable therapeutic approach. SEE PDF] In clinical studies with simtuzumab, the humanised version of AB0023, target engagement in human blood was not measured, triggering uncertainty about the lack of efficacy in humans.

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε‐amino group of lysine or hydroxylysine on collagen side‐chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS‐5153A, a novel mechanism based, fast‐acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS‐5153A dose‐dependently reduced LOXL2‐mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet‐induced, PXS‐5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS‐5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.

The INO collaboration is designing a cosmic muon veto detector (CMVD) to cover the mini-ICAL detector which is operational at the IICHEP transit campus, Madurai in South India. The aim of the CMVD is to study the feasibility of building an experiment to record rare events at a shallow depth of around 100 m, and use plastic scintillators to veto atmospheric muons from those produced by the rare interactions within the target mass of the detector. The efficiency of such a veto detector should be better than 99.99% and false positive rate of less than \\(10^{-5}\\). The CMVD is being built using extruded plastic scintillator (EPS) strips to detect and tag atmospheric muons. More than 700 EPS strips are required to build the CMVD. Two EPS strips are pasted together to make a di-counter (DC) and wavelength shifting fibres are embedded inside the EPS strips to trap the scintillation light generated by a passing cosmic ray muon and transmit it as secondary photons to the Silicon Photo-Multipliers (SiPMs) mounted at the two ends of the DCs. Since the efficiency requirement of the veto detector is rather high, it is imperative to thoroughly test each and every component used for building the CMVD. A cosmic ray muon telescope has been setup using the DCs to qualify all the DCs that will be fabricated. In this paper we will discuss the details of the design and fabrication of the DCs, and the cosmic muon setup and the electronics used for their testing and the test results.