A model based approach for the characterisation of radiolabelled antibodies in radioimmunotherapy

Radioimmunotherapy (RIT) utilises antibodies directed against tumour associated antigens to carry a therapeutic dose of radiation to the tumour. Using RIT, model tumours have been successfully treated and yet clinical responses have been limited by poor tumour localisation. In an attempt to overcome this, many new antibodies have been developed. Measuring the gross tumour localisation and tumour to normal tissue ratio in animal models has generally been used to assess the potential clinical use of these antibodies. However, these measurements assume all the energy from the electron emitted from the radionuclide is deposited in the source organ, and also ignore the effects of dose-rate and cell proliferation during treatment. In addition, they do not consider the effects of heterogeneous dose deposition and response within the tissues. The principal purpose of this thesis is to develop a more accurate measure of the biological effect of radiolabelled antibodies in a mouse xenograft in order to select the optimal radionuclide/antibody combination for more effective therapy in man. A structural model has been developed from mouse data to facilitate more accurate absorbed dose calculations by accounting for organ size, shape, and position relative to surrounding organs. In addition, the linear-quadratic model, conventionally used in external beam radiotherapy, has been adapted for use in RIT to account for the effects of dose-rate and proliferation during treatment. To characterise heterogeneity of dose deposition and response in tumours, images of tumour morphology and radiolabelled antibody distribution were registered. The images were obtained through digitisation of stained histological sections and storage phosphor plate technology. All data was collected using a wide range of antibodies labelled with 131I and 90Y. These models show that multivalent, tumour-specific antibodies, with intermediate clearance rates, deliver the most effective dose to xenografts. Antibody affinity and avidity facilitate the prolonged retention in radiosensitive areas of tumour where most of the dose is deposited. In addition, a significantly greater activity of 131I can be injected before causing the equivalent bone marrow toxicity. Furthermore, when antibodies are labelled with 90Y, a significant amount of the electron energy escapes the source organ and is absorbed in surrounding tissue. Nevertheless, the results clearly show that radionuclide and antibody should be matched in order to deliver optimum therapy

Pulmonary 18F-FDG uptake helps refine current risk stratification in idiopathic pulmonary fibrosis (IPF).

PURPOSE: There is a lack of prognostic biomarkers in idiopathic pulmonary fibrosis (IPF) patients. The objective of this study is to investigate the potential of 18F-FDG-PET/ CT to predict mortality in IPF. METHODS: A total of 113 IPF patients (93 males, 20 females, mean age ± SD: 70 ± 9 years) were prospectively recruited for 18F-FDG-PET/CT. The overall maximum pulmonary uptake of 18F-FDG (SUVmax), the minimum pulmonary uptake or background lung activity (SUVmin), and target-to-background (SUVmax/ SUVmin) ratio (TBR) were quantified using routine region-of-interest analysis. Kaplan-Meier analysis was used to identify associations of PET measurements with mortality. We also compared PET associations with IPF mortality with the established GAP (gender age and physiology) scoring system. Cox analysis assessed the independence of the significant PET measurement(s) from GAP score. We investigated synergisms between pulmonary 18F-FDG-PET measurements and GAP score for risk stratification in IPF patients. RESULTS: During a mean follow-up of 29 months, there were 54 deaths. The mean TBR ± SD was 5.6 ± 2.7. Mortality was associated with high pulmonary TBR (p = 0.009), low forced vital capacity (FVC; p = 0.001), low transfer factor (TLCO; p  4.9 was 24 months. Combining PET data with GAP data ("PET modified GAP score") refined the ability to predict mortality. CONCLUSIONS: A high pulmonary TBR is independently associated with increased risk of mortality in IPF patients

Anti-inflammatory therapy with nebulised dornase alfa in patients with severe COVID-19 pneumonia A Randomised Clinical Trial

SARS-CoV2 infection causes severe, life-threatening pneumonia. Hyper-inflammation, coagulopathy and lymphopenia are associated with pathology and poor outcomes in these patients. Cell-free (cf) DNA is prominent in COVID-19 patients, amplifies inflammation and promotes coagulopathy and immune dysfunction. We hypothesized that cf-DNA clearance by nebulised dornase alfa may reduce inflammation and improve disease outcomes. Here, we evaluated the efficacy of nebulized dornase alfa in patients hospitalised with severe COVID-19 pneumonia. In this randomised controlled single-centre phase 2 proof-of-concept trial, we recruited adult patients admitted to hospital that exhibited stable oxygen saturation (≥94%) on supplementary oxygen and a C-reactive protein (CRP) level ≥30mg/L post dexamethasone treatment. Participants were randomized at a 3:1 ratio to receive twice-daily nebulised dornase alfa in addition to best available care (BAC) or BAC alone for seven days or until hospital discharge. A 2:1 ratio of historical controls to treated individuals (HC, 2:1) were included as the primary endpoint comparators. The primary outcome was a reduction in systemic inflammation measured by blood CRP levels over 7 days post-randomisation, or to discharge if sooner. Secondary and exploratory outcomes included time to discharge, time on oxygen, D-dimer levels, lymphocyte counts and levels of circulating cf-DNA. We screened 75 patients and enrolled 39 participants out of which 30 in dornase alfa arm, and 9 in BAC group. We also matched the recruited patients in the treated group (N=30) to historical controls in the BAC group (N=60). For the the primary outcome, 30 patients in the dornase alfa were compared to 69 patients in the BAC group. Dornase alfa treatment reduced CRP by 33% compared to the BAC group at 7-days (P=0.01). The dornase alfa group least squares mean CRP was 23.23 mg/L (95% CI 17.71 to 30.46) and the BAC group 34.82 mg/L (95% CI 28.55 to 42.47). A significant difference was also observed when only randomised participants were compared. Furthermore, compared to the BAC group, the chance of live discharge was increased by 63% in the dornase alfa group (HR 1.63, 95% CI 1.01 to 2.61, P=0.03), lymphocyte counts were improved (least-square mean: 1.08 vs 0.87, P=0.02) and markers of coagulopathy such as D-dimer were diminished (least-square mean: 570.78 vs 1656.96μg/mL, P=0.004). Moreover, the dornase alfa group exhibited lower circulating cf-DNA levels that correlated with CRP changes over the course of treatment. No differences were recorded in the rates and length of stay in the ICU or the time on oxygen between the groups. Dornase alfa was well-tolerated with no serious adverse events reported. In this proof-of-concept study in patients with severe COVID-19 pneumonia, treatment with nebulised dornase alfa resulted in a significant reduction in inflammation, markers of immune pathology and time to discharge. The effectiveness of dornase alfa in patients with acute respiratory infection and inflammation should be investigated further in larger trials

The genome of the venomous snail Lautoconus ventricosus shed light on the origin of conotoxin diversity

Background: Venoms are deadly weapons to subdue prey or deter predators that have evolved independently in many animal lineages. The genomes of venomous animals are essential to understand the evolutionary mechanisms involved in the origin and diversification of venoms. Results: Here, we report the chromosome-level genome of the venomous Mediterranean cone snail, Lautoconus ventricosus (Caenogastropoda: Conidae). The total size of the assembly is 3.59 Gb; it has high contiguity (N50 = 93.53 Mb) and 86.6 Mb of the genome assembled into the 35 largest scaffolds or pseudochromosomes. On the basis of venom gland transcriptomes, we annotated 262 complete genes encoding conotoxin precursors, hormones, and other venom-related proteins. These genes were scattered in the different pseudochromosomes and located within repetitive regions. The genes encoding conotoxin precursors were normally structured into 3 exons, which did not necessarily coincide with the 3 structural domains of the corresponding proteins. Additionally, we found evidence in the L. ventricosus genome for a past whole-genome duplication event by means of conserved gene synteny with the Pomacea canaliculata genome, the only one available at the chromosome level within Caenogastropoda. The whole-genome duplication event was further confirmed by the presence of a duplicated hox gene cluster. Key genes for gastropod biology including those encoding proteins related to development, shell formation, and sex were located in the genome. Conclusions: The new high-quality L. ventricosus genome should become a reference for assembling and analyzing new gastropod genomes and will contribute to future evolutionary genomic studies among venomous animals.This work was funded by the Spanish Ministry of Science and Innovation (CGL2016-75255-C2-1-P [AEI/FEDER, UE] and PID2019-103947GB-C22/AEI/10.13039/501100011033 to R.Z.; BES-2017-081195 to J.R.P.-B.; BES-2014-069575 to S.A.; IJCI-2016-29566 to I.I.). I.I. acknowledges the support from the European Research Council during the latest stages of the project (Grant Agreement No. 852725; ERC-StG "TerreStriAL" to Jan de Vries, University of Goettingen)

Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression

Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples — including Xist, which orchestrates X chromosome inactivation — has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here we discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. We explore these principles to highlight biological challenges in gene regulation, in which lncRNAs are well-suited to perform roles that cannot be carried out by DNA elements or protein regulators alone, such as acting as spatial amplifiers of regulatory signals in the nucleus

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure