Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer

UNLABELLED: The cGAS-STING pathway serves a critical role in anticancer therapy. Particularly, response to immunotherapy is likely driven by both active cGAS-STING signaling that attracts immune cells, and by the presence of cancer neoantigens that presents as targets for cytotoxic T cells. Chromosomal instability (CIN) is a hallmark of cancer, but also leads to an accumulation of cytosolic DNA that in turn results in increased cGAS-STING signaling. To avoid triggering the cGAS-STING pathway, it is commonly disrupted by cancer cells, either through mutations in the pathway or through transcriptional silencing. Given its effect on the immune system, determining the cGAS-STING activation status prior to treatment initiation is likely of clinical relevance. Here, we used combined expression data from 2,307 tumors from five cancer types from The Cancer Genome Atlas to define a novel cGAS-STING activity score based on eight genes with a known role in the pathway. Using unsupervised clustering, four distinct categories of cGAS-STING activation were identified. In multivariate models, the cGAS-STING active tumors show improved prognosis. Importantly, in an independent bladder cancer immunotherapy-treated cohort, patients with low cGAS-STING expression showed limited response to treatment, while patients with high expression showed improved response and prognosis, particularly among patients with high CIN and more neoantigens. In a multivariate model, a significant interaction was observed between CIN, neoantigens, and cGAS-STING activation. Together, this suggests a potential role of cGAS-STING activity as a predictive biomarker for the application of immunotherapy. SIGNIFICANCE: The cGAS-STING pathway is induced by CIN, triggers inflammation and is often deficient in cancer. We provide a tool to evaluate cGAS-STING activity and demonstrate clinical significance in immunotherapy response

How large should whales be?

The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.Comment: 7 pages, 3 figures, 2 data table

The non-Abelian gauge theory of matrix big bangs

We study at the classical and quantum mechanical level the time-dependent Yang-Mills theory that one obtains via the generalisation of discrete light-cone quantisation to singular homogeneous plane waves. The non-Abelian nature of this theory is known to be important for physics near the singularity, at least as far as the number of degrees of freedom is concerned. We will show that the quartic interaction is always subleading as one approaches the singularity and that close enough to t=0 the evolution is driven by the diverging tachyonic mass term. The evolution towards asymptotically flat space-time also reveals some surprising features.Comment: 29 pages, 8 eps figures, v2: minor changes, references added: v3 small typographical changes

Serum 25-hydroxyvitamin D and cognitive decline in the very old: the Newcastle 85+ Study.

This is the final version of the article. Available from Wiley via the DOI in this record.BACKGROUND AND PURPOSE: Studies investigating the association between 25-hydroxyvitamin D [25(OH)D] and cognition in the very old (85+) are lacking. METHODS: Cross-sectional (baseline) and prospective data (up to 3 years follow-up) from 775 participants in the Newcastle 85+ Study were analysed for global (measured by the Standardized Mini-Mental State Examination) and attention-specific (measured by the attention battery of the Cognitive Drug Research test) cognitive performance in relation to season-specific 25(OH)D quartiles. RESULTS: Those in the lowest and highest season-specific 25(OH)D quartiles had an increased risk of impaired prevalent (1.66, 95% confidence interval 1.06-2.60, P = 0.03; 1.62, 95% confidence interval 1.02-2.59, P = 0.04, respectively) but not incident global cognitive functioning or decline in functioning compared with those in the middle quartiles adjusted for sociodemographic, health and lifestyle confounders. Random effects models showed that participants belonging to the lowest and highest 25(OH)D quartiles, compared with those in the middle quartiles, had overall slower (log-transformed) attention reaction times for Choice Reaction Time (lowest, β = 0.023, P = 0.01; highest, β = 0.021, P = 0.02), Digit Vigilance Task (lowest, β = 0.009, P = 0.05; highest, β = 0.01, P = 0.02) and Power of Attention (lowest, β = 0.017, P = 0.02; highest, β = 0.022, P = 0.002) and greater Reaction Time Variability (lowest, β = 0.021, P = 0.02; highest, β = 0.02, P = 0.03). The increased risk of worse global cognition and attention amongst those in the highest quartile was not observed in non-users of vitamin D supplements/medication. CONCLUSION: Low and high season-specific 25(OH)D quartiles were associated with prevalent cognitive impairment and poorer overall performance in attention-specific tasks over 3 years in the very old, but not with global cognitive decline or incident impairment.This work was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University (AG). The Newcastle 85+ Study has been funded by the Medical Research Council, Biotechnology and Biological Sciences Research Council and the Dunhill Medical Trust. Additional work has also been funded by the British Heart Foundation, Unilever Corporate Research, Newcastle University and National Health Service (NHS) North of Tyne (Newcastle Primary Care Trust). The views expressed in this paper are those of the authors and not necessarily those of the National Health Service, UK. We acknowledge the operational support of NHS North of Tyne, the local general practitioners and their staff, the research nurses, laboratory technicians, data management and clerical team, as well as many colleagues for their expert advice. Thanks are due especially to the study participants

Endovascular control of haemorrhagic urological emergencies: an observational study

BACKGROUND: Transarterial embolisation (TAE) is an effective method in control of haemorrhage irrespective of the nature of urological emergency. As the technique and technology have evolved, it is now possible to perform highly selective embolisation. The aim of this study was to critically appraise feasibility and efficacy of therapeutic TAE in control of haemorrhagic urological emergencies using selective and non-selective embolisation. Specifically, we aimed to assess the impact of timing of embolisation on the requirement of blood transfusion and long-term morphological and functional follow-up of embolised organs. METHODS: This is a single institutional observational study carried out between March 1992 and March 2006. Records of all patients who underwent selective and non-selective angioembolisation to control bleeding in urological emergencies were reviewed. Data on success rate, periprocedural complications, timing of embolisation, requirement of blood transfusion and the long-term morphological and functional outcomes of embolised organs was recorded. RESULTS: Fourteen patients underwent endovascular control of bleeding as a result of trauma, iatrogenic injury and spontaneous perinephric haemorrhage during a period of 14 years. All these patients would have required emergency open surgery without the option of embolisation procedure. The mean time between the first presentation and embolisation was 22 hours (range 30 minutes to 60 hours). Mean pre-embolisation transfusion requirement was 6.8 units (range 0–22 units). None of the patients with successful embolisation required post-procedural blood transfusion. Permanent haemostasis was achieved in all but one patient, who required emergency nephrectomy. There were no serious procedure related post-embolisation complications. CONCLUSION: Endovascular control using transarterial angioembolisation is an effective method for managing haematuria or haemorrhage in urological emergencies. Wherever and whenever indicated, this option should be considered early in the management of these cases

Experimental Measurement of the Berry Curvature from Anomalous Transport

Geometrical properties of energy bands underlie fascinating phenomena in a wide-range of systems, including solid-state materials, ultracold gases and photonics. Most famously, local geometrical characteristics like the Berry curvature can be related to global topological invariants such as those classifying quantum Hall states or topological insulators. Regardless of the band topology, however, any non-zero Berry curvature can have important consequences, such as in the semi-classical evolution of a wave packet. Here, we experimentally demonstrate for the first time that wave packet dynamics can be used to directly map out the Berry curvature. To this end, we use optical pulses in two coupled fibre loops to study the discrete time-evolution of a wave packet in a 1D geometrical "charge" pump, where the Berry curvature leads to an anomalous displacement of the wave packet under pumping. This is both the first direct observation of Berry curvature effects in an optical system, and, more generally, the proof-of-principle demonstration that semi-classical dynamics can serve as a high-resolution tool for mapping out geometrical properties

Optimal cut-off criteria for duplex ultrasound for the diagnosis of restenosis in stented carotid arteries: Review and protocol for a diagnostic study

Background: Carotid angioplasty with stenting is a relatively new, increasingly used, less-invasive treatment for the treatment of symptomatic carotid artery stenosis. It is being evaluated in ongoing and nearly finished randomized trials. An important factor in the evaluation of stents is the occurrence of in-stent restenosis. An un-stented carotid artery is likely to have a more elastic vessel wall than a stented one, even if stenosis is present. Therefore, duplex ultrasound cut-off criteria for the degrees of an in-stent stenosis, based on blood velocity parameters, are probably different from the established cut-offs used for un-stented arteries. Routine criteria can not be applied to stented arteries but new criteria need to be established for this particular purpose. Methods/Design: Current literature was systematically reviewed. From the selected studies, the following data were extracted: publication year, population size, whether the study was prospective, which reference test was used, and if there was an indication for selection bias and for verification bias in particular. Previous studies often were retrospective, or the reference test (DSA or CTA) was carried out only when a patient was suspected of having restenosis at DUS, which may result in verification bias. Results: In general, the cut-off values are higher than those reported for unstented arteries. Previous studies often were retrospective, or the reference test (DSA or CTA) was carried out only when a patient was suspected of having restenosis at DUS, which may result in verification bias. Discussion: To address the deficiencies of the existing studies, we propose a prospective cohort study nested within the International Carotid Stenting Study (ICSS), an international multi-centre trial in which over 1,700 patients have been randomised between stenting and CEA. In this cohort we will enrol a minimum of 300 patients treated with a stent. All patients undergo regular DUS examination at the yearly follow-up visit according to the ICSS protocol. To avoid verification bias, an additional computed tomography angiography (CTA) will be performed as a reference test in all consecutive patients, regardless of the degree of stenosis on the initial DUS test

Linking urban aerosol fluxes in street canyons to larger scale emissions

In this study we investigate ultrafine particle (UFP) fluxes using a first order eddy viscosity turbulence closure Computational Fluid Dynamics (CFD) model and determine the different factors that influence emissions of UFP into the urban boundary layer. Both vertical turbulent fluxes as well as the fluxes due to mean circulatory flow are shown to contribute to the overall ventilation characteristics of street canyons. We then derive a simple parameterised numerical prediction model for canyon top UFP venting which is then compared with tower based micrometeorological flux measurements obtained during the REPARTEE & CityFlux field experiments

Interventions to Promote Cancer Awareness and Early Presentation: Systematic Review

Low cancer awareness contributes to delay in presentation for cancer symptoms and may lead to delay in cancer diagnosis. The aim of this study was to review the evidence for the effectiveness of interventions to raise cancer awareness and promote early presentation in cancer to inform policy and future research. We searched bibliographic databases and reference lists for randomised controlled trials of interventions delivered to individuals, and controlled or uncontrolled studies of interventions delivered to communities. We found some evidence that interventions delivered to individuals modestly increase cancer awareness in the short term and insufficient evidence that they promote early presentation. We found limited evidence that public education campaigns reduce stage at presentation of breast cancer, malignant melanoma and retinoblastoma

Towards a large-scale quantum simulator on diamond surface at room temperature

Strongly-correlated quantum many-body systems exhibits a variety of exotic phases with long-range quantum correlations, such as spin liquids and supersolids. Despite the rapid increase in computational power of modern computers, the numerical simulation of these complex systems becomes intractable even for a few dozens of particles. Feynman's idea of quantum simulators offers an innovative way to bypass this computational barrier. However, the proposed realizations of such devices either require very low temperatures (ultracold gases in optical lattices, trapped ions, superconducting devices) and considerable technological effort, or are extremely hard to scale in practice (NMR, linear optics). In this work, we propose a new architecture for a scalable quantum simulator that can operate at room temperature. It consists of strongly-interacting nuclear spins attached to the diamond surface by its direct chemical treatment, or by means of a functionalized graphene sheet. The initialization, control and read-out of this quantum simulator can be accomplished with nitrogen-vacancy centers implanted in diamond. The system can be engineered to simulate a wide variety of interesting strongly-correlated models with long-range dipole-dipole interactions. Due to the superior coherence time of nuclear spins and nitrogen-vacancy centers in diamond, our proposal offers new opportunities towards large-scale quantum simulation at room temperatures