Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC

Executable network of SARS-CoV-2-host interaction predicts drug combination treatments

The COVID-19 pandemic has pushed healthcare systems globally to a breaking point. The urgent need for effective and affordable COVID-19 treatments calls for repurposing combinations of approved drugs. The challenge is to identify which combinations are likely to be most effective and at what stages of the disease. Here, we present the first disease-stage executable signalling network model of SARS-CoV-2-host interactions used to predict effective repurposed drug combinations for treating early- and late stage severe disease. Using our executable model, we performed in silico screening of 9870 pairs of 140 potential targets and have identified nine new drug combinations. Camostat and Apilimod were predicted to be the most promising combination in effectively supressing viral replication in the early stages of severe disease and were validated experimentally in human Caco-2 cells. Our study further demonstrates the power of executable mechanistic modelling to enable rapid pre-clinical evaluation of combination therapies tailored to disease progression. It also presents a novel resource and expandable model system that can respond to further needs in the pandemic

A nurse-led, preventive, psychological intervention to reduce PTSD symptom severity in critically ill patients: the POPPI feasibility study and cluster RCT

BACKGROUND: High numbers of patients experience severe acute stress in critical care units. Acute stress has been linked to post-critical care psychological morbidity, including post-traumatic stress disorder (PTSD). Previously, a preventive, complex psychological intervention [Psychological Outcomes following a nurse-led Preventative Psychological Intervention for critically ill patients (POPPI)] was developed by this research team, to be led by nurses, to reduce the development of PTSD symptom severity at 6 months. OBJECTIVES: The objectives were to (1) standardise and refine the POPPI intervention, and, if feasible, (2) evaluate it in a cluster randomised clinical trial (RCT). DESIGN: Two designs were used – (1) two feasibility studies to test the delivery and acceptability (to patients and staff) of the intervention, education package and support tools, and to test the trial procedures (i.e. recruitment and retention), and (2) a multicentre, parallel-group, cluster RCT with a baseline period and staggered roll-out of the intervention. SETTING: This study was set in NHS adult, general critical care units. PARTICIPANTS: The participants were adult patients who were > 48 hours in a critical care unit, receiving level 3 care and able to consent. INTERVENTIONS: The intervention comprised three elements – (1) creating a therapeutic environment in critical care, (2) three stress support sessions for patients identified as acutely stressed and (3) a relaxation and recovery programme for patients identified as acutely stressed. MAIN OUTCOMES MEASURES: Primary outcome – patient-reported symptom severity using the PTSD Symptom Scale – Self Report (PSS-SR) questionnaire (to measure clinical effectiveness) and incremental costs, quality-adjusted life-years (QALYs) and net monetary benefit at 6 months (to measure cost-effectiveness). Secondary outcomes – days alive and free from sedation to day 30; duration of critical care unit stay; PSS-SR score of > 18 points; depression, anxiety and health-related quality of life at 6 months; and lifetime cost-effectiveness. RESULTS: (1) A total of 127 participants were recruited to the intervention feasibility study from two sites and 86 were recruited to the RCT procedures feasibility study from another two sites. The education package, support tools and intervention were refined. (2) A total of 24 sites were randomised to the intervention or control arms. A total of 1458 participants were recruited. Twelve sites delivered the intervention during the intervention period: > 80% of patients received two or more stress support sessions and all 12 sites achieved the target of > 80% of clinical staff completing the POPPI online training. There was, however, variation in delivery across sites. There was little difference between baseline and intervention periods in the development of PTSD symptom severity (measured by mean PSS-SR score) at 6 months for surviving patients in either the intervention or the control group: treatment effect estimate −0.03, 95% confidence interval (CI) −2.58 to 2.52; p = 0.98. On average, the intervention decreased costs and slightly improved QALYs, leading to a positive incremental net benefit at 6 months (£835, 95% CI −£4322 to £5992), but with considerable statistical uncertainty surrounding these results. There were no significant differences between the groups in any of the secondary outcomes or in the prespecified subgroup analyses. LIMITATIONS: There was a risk of bias because different consent processes were used and as a result of the lack of blinding, which was mitigated as far as possible within the study design. The intervention started later than anticipated. Patients were not routinely monitored for delirium. CONCLUSIONS: Among level 3 patients who stayed > 48 hours in critical care, the delivery of a preventive, complex psychological intervention, led by nurses, did not reduce the development of PTSD symptom severity at 6 months, when compared with usual care. FUTURE WORK: Prior to development and evaluation of subsequent psychological interventions, there is much to learn from post hoc analyses of the cluster RCT rich quantitative and qualitative data. TRIAL REGISTRATION: This trial is registered as ISRCTN61088114 and ISRCTN53448131. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 23, No. 30. See the NIHR Journals Library website for further project information

The central energy source of 70micron-selected galaxies: Starburst or AGN?

We present the first AGN census in a sample of 61 galaxies selected at 70microns, a wavelength which should strongly favour the detection of star-forming systems. For the purpose of this study we take advantage of deep Chandra X-ray and Spitzer infrared (3.6-160micron) data, as well as optical spectroscopy and photometry from the Deep Extragalactic Evolutionary Probe 2 (DEEP2) survey for the Extended Groth Strip (EGS) field. We investigate spectral line diagnostics ([OIII]/Hbeta and [NeIII]/[OII] ratios, Hdelta Balmer absorption line equivalent widths and the strength of the 4000Ang break), X-ray luminosities and spectral energy distributions (SEDs). We find that the 70micron sources are undergoing starburst episodes and are therefore characterised by a predominance of young stars. In addition, 13 per cent of the sources show AGN signatures and hence potentially host an AGN. When the sample is split into starbursts (SBs, 10^10<L_IR<10^11 L_solar), Luminous InfraRed Galaxies (LIRGs, 10^11<L_IR<10^12 L_solar) and UltraLuminous InfraRed Galaxies (ULIRGs,10^12<L_IR<10^13 L_solar), the AGN fraction becomes 0, 11 and 23 per cent respectively, showing an increase with total infrared luminosity. However, by examining the sources' panchromatic SEDs, we conclude that although the AGN is energetically important in 1 out of 61 objects, all 70micron-selected galaxies are primarily powered by star-formation.Comment: 20 pages, 14 figures, accepted for publication in MNRA

Providing psychological support to people in intensive care: development and feasibility study of a nurse-led intervention to prevent acute stress and long-term morbidity

OBJECTIVES: Adverse psychological outcomes, following stressful experiences in critical care, affect up to 50% of patients. We aimed to develop and test the feasibility of a psychological intervention to reduce acute stress and prevent future morbidity. DESIGN: A mixed-methods intervention development study, using two stages of the UK Medical Research Council framework for developing and testing complex interventions. Stage one (development) involved identifying an evidence base for the intervention, developing a theoretical understanding of likely processes of change and modelling change processes and outcomes. Stage two comprised two linked feasibility studies. SETTING: Four UK general adult critical care units. PARTICIPANTS: Stage one: former and current patients, and psychology, nursing and education experts. Stage two: current patients and staff. OUTCOMES: Feasibility and acceptability to staff and patients of content and delivery of a psychological intervention, assessed using quantitative and qualitative data. Estimated recruitment and retention rates for a clinical trial. RESULTS: Building on prior work, we standardised the preventative, nurse-led Provision Of Psychological support to People in Intensive Care (POPPI) intervention. We devised courses and materials to train staff to create a therapeutic environment, to identify patients with acute stress and to deliver three stress support sessions and a relaxation and recovery programme to them. 127 awake, orientated patients took part in an intervention feasibility study in two hospitals. Patient and staff data indicated the complex intervention was feasible and acceptable. Feedback was used to refine the intervention. 86 different patients entered a separate trial procedures study in two other hospitals, of which 66 (80% of surviving patients) completed questionnaires on post-traumatic stress, depression and health 5 months after recruitment. CONCLUSION: The 'POPPI' psychological intervention to reduce acute patient stress in critical care and prevent future psychological morbidity was feasible and acceptable. It was refined for evaluation in a cluster randomised clinical trial. TRIAL REGISTRATION NUMBER: ISRCTN61088114; Results

Wide-field optical imaging on ELAIS N1, ELAIS N2, First Look Survey and Lockman Hole: observations and source catalogues

We present u-, g-, r-, i- and z-band optical images and associated catalogues taken primarily with the Isaac Newton Telescope Wide Field Camera on the European Large Area ISO Survey (ELAIS) N1 and N2, First Look Survey and Lockman Hole fields comprising a total of 1000 h of integration time over 80 deg^2 and approximately 4.3 million objects. In this paper we outline the observations and data processing and characterize the completeness, reliability, photometric and astrometric accuracy of this data set. All images have been photometrically calibrated using the Sloan Digital Sky Survey and a uniform and homogeneous data set is composed over all the observed fields. Magnitude limits are u, g, r, i, z of 23.9, 24.5, 24.0, 23.3, 22.0 (AB, 5σ). These data have been used for optical identification of past and ongoing projects including the surveys ELAIS, Spitzer Wide-Area Infrared Extragalactic Survey, Spitzer Extragalactic Representative Volume Survey and Herschel Multi-tiered Extragalactic Survey

Restframe I-band Hubble diagram for type Ia supernovae up to redshift z ~0.5

We present a novel technique for fitting restframe I-band light curves on a data set of 42 Type Ia supernovae (SNe Ia). Using the result of the fit, we construct a Hubble diagram with 26 SNe from the subset at 0.01< z<0.1. Adding two SNe at z~0.5 yields results consistent with a flat Lambda-dominated``concordance universe'' ($\Omega_M,\Omega_\Lambda$)=(0.25,0.75). For one of these, SN 2000fr, new near infrared data are presented. The high redshift supernova NIR data are also used to test for systematic effects in the use of SNe Ia as distance estimators. A flat, Lambda=0, universe where the faintness of supernovae at z~0.5 is due to grey dust homogeneously distributed in the intergalactic medium is disfavoured based on the high-z Hubble diagram using this small data-set. However, the uncertainties are large and no firm conclusion may be drawn. We explore the possibility of setting limits on intergalactic dust based on B-I and B-V colour measurements, and conclude that about 20 well measured SNe are needed to give statistically significant results. We also show that the high redshift restframe I-band data points are better fit by light curve templates that show a prominent second peak, suggesting that they are not intrinsically underluminous.Comment: Accepted for publication in A&A (01/04/2005

Host Galaxy Extinction of SNIa: Co-evolution of ISM Structure and Extinction Law with Star-Formation

This paper presents a mechanism that may modify the extinction law for SNIa observed at higher redshift. Starting from the observations that (1) SNIa occur predominantly in spiral galaxies, (2) star-formation ejects ISM out of the plane of spirals, (3) star-formation alters the extinction properties of the dust in the ISM, and (4) there is substantially more star-formation at higher redshift, I propose that spiral galaxies have a dustier halo in the past than they do now. The ejected material's lower value of $R_V$ will lead to a lower average value ($\bar{R}_V$) for SNIa observed at higher redshift. Two relations in SNIa observations indicate evolution of the average $R_V$: the relation of observed $R_V$ with inclination of the host galaxy at low redshift and the matching of the distribution of extinction values ($A_V$) for SNIa in different redshift intervals. The inclination effect does point to a halo with lower $R_V$ values. In contrast, the distributions of $A_V$ values match best for a $\bar{R}_V(z)$ evolution that mimics the relation of SNIa dimming with redshift attributed to the cosmological constant. However, even in the worse case scenario, the evolution $\bar{R}_V$ can not fully explain the dimming of SNIa: host galaxy extinction law evolution is not a viable alternative to account for the dimming of SNIa. Future observations of SNIa --multi-color lightcurves and spectra-- will solve separately for values of $A_V$ and $R_V$ for each SNIa . Solving for evolution of $\bar{R}_V$ (and $A_V$) with redshift will be important for the coming generation of cosmological SNIa measurements and has the bonus science of insight into the distribution of dust-rich ISM in the host galaxies in the distant past.Comment: 7 pages, 5 figures, accepted by MNRA

APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability

Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution. Significance: We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors