An exceptionally potent inhibitor of human CD73

The research described in this manuscript was fully funded by Arcus Biosciences, Inc. a publicly traded biotechnology company.We recently reported the initiation of a Phase I clinical trial with AB680, a potent human CD73 inhibitor, being developed for the treatment of solid tumors (NCT03677973). We undertook a detailed kinetic analysis of the interaction between human CD73 and AB680 to determine the mode of inhibition. We found AB680 to be a reversible, slow-onset competitive inhibitor of human CD73 with a Ki of 5 pM. Clinical candidates of this potency are uncommon and deserve special consideration during lead optimization.PostprintPeer reviewe

Demarginalizing Interdisciplinarity in IS Research: Interdisciplinary Research in Marginalization

This paper reports on the second Workshop of a World University Network (WUN) Research Development Funded project on “The trans-nationalization of Indigenous movements: The role of digital technologies” at the University of Southampton, UK. The workshop explored interdisciplinarity and how interdisciplinary collaboration can help scholars study complex social phenomenon, such as the ways in which marginalized Indigenous communities use and shape digital technologies (such as social media) to enhance their cause. The workshop brought together scholars from diverse disciplines to engage in a critical debate. In addition to scholars from information systems, scholars from history, political science, geography, literature, arts, and anthropology came together to discuss how marginalized Indigenous communities can use digital media. The workshop highlighted the need for more interdisciplinary research and called for more critical approaches to bring such marginalized topics to the forefront of research in information systems. We consider three broad areas of inquiry in this paper: demarginalizing methodology for interdisciplinary research, interdisciplinary perspectives for demarginalization, and interdisciplinary contexts for demarginalization

The Hubble Space Telescope Wide Field Camera 3 Early Release Science data: Panchromatic Faint Object Counts for 0.2-2 microns wavelength

We describe the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) Early Release Science (ERS) observations in the Great Observatories Origins Deep Survey (GOODS) South field. The new WFC3 ERS data provide calibrated, drizzled mosaics in the UV filters F225W, F275W, and F336W, as well as in the near-IR filters F098M (Ys), F125W (J), and F160W (H) with 1-2 HST orbits per filter. Together with the existing HST Advanced Camera for Surveys (ACS) GOODS-South mosaics in the BViz filters, these panchromatic 10-band ERS data cover 40-50 square arcmin at 0.2-1.7 {\mu}m in wavelength at 0.07-0.15" FWHM resolution and 0.090" Multidrizzled pixels to depths of AB\simeq 26.0-27.0 mag (5-{\sigma}) for point sources, and AB\simeq 25.5-26.5 mag for compact galaxies. In this paper, we describe: a) the scientific rationale, and the data taking plus reduction procedures of the panchromatic 10-band ERS mosaics; b) the procedure of generating object catalogs across the 10 different ERS filters, and the specific star-galaxy separation techniques used; and c) the reliability and completeness of the object catalogs from the WFC3 ERS mosaics. The excellent 0.07-0.15" FWHM resolution of HST/WFC3 and ACS makes star- galaxy separation straightforward over a factor of 10 in wavelength to AB\simeq 25-26 mag from the UV to the near-IR, respectively.Comment: 51 pages, 71 figures Accepted to ApJS 2011.01.2

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

<p>Abstract</p> <p>Background</p> <p>The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment.</p> <p>Methods</p> <p>Prostate CD90⁺stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder.</p> <p>Results</p> <p>The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes.</p> <p>Conclusion</p> <p>CD90⁺prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development.</p

An in vitro collagen perfusion wound biofilm model; with applications for antimicrobial studies and microbial metabolomics

BackgroundThe majority of in vitro studies of medically relevant biofilms involve the development of biofilm on an inanimate solid surface. However, infection in vivo consists of biofilm growth on, or suspended within, the semi-solid matrix of the tissue, whereby current models do not effectively simulate the nature of the in vivo environment. This paper describes development of an in vitro method for culturing wound associated microorganisms in a system that combines a semi-solid collagen gel matrix with continuous flow of simulated wound fluid. This enables culture of wound associated reproducible steady state biofilms under conditions that more closely simulate the dynamic wound environment. To demonstrate the use of this model the antimicrobial kinetics of ceftazidime, against both mature and developing Pseudomonas aeruginosa biofilms, was assessed. In addition, we have shown the potential application of this model system for investigating microbial metabolomics by employing selected ion flow tube mass spectrometry (SIFT-MS) to monitor ammonia and hydrogen cyanide production by Pseudomonas aeruginosa biofilms in real-time. ResultsThe collagen wound biofilm model facilitates growth of steady-state reproducible Pseudomonas aeruginosa biofilms under wound like conditions. A maximum biofilm density of 1010 cfu slide-1 was achieved by 30 hours of continuous culture and maintained throughout the remainder of the experiment. Treatment with ceftazidime at a clinically relevant dose resulted in a 1.2 – 1.6 log reduction in biofilm density at 72 hours compared to untreated controls. Treatment resulted in loss of complex biofilm architecture and morphological changes to bacterial cells, visualised using confocal microscopy. When monitoring the biofilms using SIFT-MS, ammonia and hydrogen cyanide levels peaked at 12 hours at 2273 ppb (±826.4) and 138 ppb (±49.1) respectively and were detectable throughout experimentation. ConclusionsThe collagen wound biofilm model has been developed to facilitate growth of reproducible biofilms under wound-like conditions. We have successfully used this method to: (1) evaluate antimicrobial efficacy and kinetics, clearly demonstrating the development of antimicrobial tolerance in biofilm cultures; (2) characterise volatile metabolite production by P. aeruginosa biofilms, demonstrating the potential use of this method in metabolomics studies