Global energy minimisation of arterial trees with application to embolic stroke

Computer generation of optimal arterial trees has previously been limited to the production of locally optimal configurations. The application of a global optimisation algorithm allows for the generation of vasculatures with consistent structure. Comparison of this structure to that of in-vivo vasculatures allows the determination of to what extent the vascular structure is the result of energy minimisation. In this thesis an algorithm capable of generation globally optimal vascular trees in geometries derived from medical imaging is developed. We begin by outlining a small set of constraints which capture physiological principles guiding the organisation of arterial trees. The constraints are then used to produce an algorithm capable of finding the minimal energy configuration of a given arterial tree. The algorithm is used to produce both coronary and cerebral vasculature, and the latter is generated in geometries segmented from MRI data of a human brain. The trees are compared both morphologically and structurally to those found in-vivo. The morphological comparisons for the coronary vasculature show excellent agreement with experiment. The positions of the larger coronary arteries in the generated trees agree extremely well with experiment, suggesting that structure of the coronary vasculature is the result of energy minimisation. The generated cerebral vasculature approximates the vascular territories of the major cerebral arteries, however the morphological comparisons show that the structure of the cerebral arteries is likely not the result of energy minimisation. The cerebral vasculatures is used to extend a statistical model of embolic stroke to include the effects of branching asymmetry, and an analytic approximation to the statistical model of embolic stroke is developed and validated. It is found that branching asymmetry produces an overall reduction in the level of blockage occuring during an embolic event

CCD QE in the Soft X-ray Range

e2v has previously provided back-illuminated CCDs for several solar observation projects, resulting in a number of key articles on CCD QE in the soft X-ray region. To update these, e2v has arranged for tests on X-ray optimised EMCCDs at a synchrotron. These have shown QE of at least 45% from 40 eV to 2000 eV, with Enhanced process devices having significantly higher QE than Basic process. The measured values were similar to data published from the SDO SXI mission, showing that the e2v process has been stable over many years. The soft X-ray QE measurements show a reasonable fit to the simple layer model for energies > 600 eV. For energies < 100 eV, measurements show slightly lower QE than the model prediction for both Basic and Enhanced processes. For energies 100 eV to 600 eV, measurements show a reasonable fit to the model for the Basic process, but less improvement from the Enhanced process than the model predicts. Comparing the ~80% typical QE for UV-optimised CCDs at 385 nm with the 45% QE measured at 120 eV in this study, there is a discrepancy in QE for two photon energies with the same absorption length measured on CCDs from the same back-thinning process (one type with AR coating, one type without)

Development of a globally optimised model of the cerebral arteries

The cerebral arteries are difficult to reproduce from first principles, featuring interwoven territories, and intricate layers of grey and white matter with differing metabolic demand. The aim of this study was to identify the ideal configuration of arteries required to sustain an entire brain hemisphere based on minimisation of the energy required to supply the tissue. The 3D distribution of grey and white matter within a healthy human brain was first segmented from Magnetic Resonance Images. A novel simulated annealing algorithm was then applied to determine the optimal configuration of arteries required to supply brain tissue. The model is validated through comparison of this ideal, entirely optimised, brain vasculature with the known structure of real arteries. This establishes that the human cerebral vasculature is highly optimised; closely resembling the most energy efficient arrangement of vessels. In addition to local adherence to fluid dynamics optimisation principles, the optimised vasculature reproduces global brain perfusion territories with well defined boundaries between anterior, middle and posterior regions. This validated brain vascular model and algorithm can be used for patient-specific modelling of stroke and cerebral haemodynamics, identification of sub-optimal conditions associated with vascular disease, and optimising vascular structures for tissue engineering and artificial organ design

Simulated annealing approach to vascular structure with application to the coronary arteries

Do the complex processes of angiogenesis during organism development ultimately lead to a near optimal coronary vasculature in the organs of adult mammals? We examine this hypothesis using a powerful and universal method, built on physical and physiological principles, for the determination of globally energetically optimal arterial trees. The method is based on simulated annealing, and can be used to examine arteries in hollow organs with arbitrary tissue geometries. We demonstrate that the approach can generate in silico vasculatures which closely match porcine anatomical data for the coronary arteries on all length scales, and that the optimized arterial trees improve systematically as computational time increases. The method presented here is general, and could in principle be used to examine the arteries of other organs. Potential applications include improvement of medical imaging analysis and the design of vascular trees for artificial organs

The role of vascular complexity on optimal junction exponents

We examine the role of complexity on arterial tree structures, determining globally optimal vessel arrangements using the Simulated AnneaLing Vascular Optimization algorithm, a computational method which we have previously used to reproduce features of cardiac and cerebral vasculatures. In order to progress computational methods for growing arterial networks, deeper understanding of the stability of computational arterial growth algorithms to complexity, variations in physiological parameters (such as metabolic costs for maintaining and pumping blood), and underlying assumptions regarding the value of junction exponents is needed. We determine the globally optimal structure of two-dimensional arterial trees; analysing how physiological parameters affect tree morphology and optimal bifurcation exponent. We find that considering the full complexity of arterial trees is essential for determining the fundamental properties of vasculatures. We conclude that optimisation-based arterial growth algorithms are stable against uncertainties in physiological parameters, while optimal bifurcation exponents (a key parameter for many arterial growth algorithms) are affected by the complexity of vascular networks and the boundary conditions dictated by organs

Monte Carlo simulations of hyper-velocity particulate mechanics within silicon micropore optics

The focal planes of X-ray astronomy missions are at risk of particulate impacts from both micrometeoroids and orbital debris due to the open aperture of the narrow-angle incidence optics. Silicon micro-pore optics (sMPOs) have seen significant development due to their wide-angle observing capabilities and are planned for use in future X-ray space missions such as SMILE and THESEUS. Although previous space missions have seen sporadic and disruptive events in detectors which are attributed to particulate impacts, the number of particulates that can traverse the new sMPO and affect detector performance is not currently known, preventing the quantification of damage on focal planes. Work carried out on nested shell X-ray optics suggested that hyper-velocity particulates could scatter from the polished inner-mirrors and be focused on the focal plane of an instrument. By assuming that this basic scattering mechanic is present in sMPO, along with the natural clear path from space to the focal plane, the overall transmission rate of particulates through such an optic can be calculated using the Monte Carlo simulation methodology. By using the simulation presented here, along with known micrometeoroid flux models and so-called damage equations, the risk to focal planes of large-scale space missions due to hyper-velocity particulate impacts can for the first time be quantified. As such, the work presented here has many applications and uses across a wide range of fields

Three-dimensional simulations of embolic stroke and an equation for sizing emboli from imaging

Stroke simulations are needed to run in-silico trials, develop hypotheses for clinical studies and to interpret ultrasound monitoring and radiological imaging. We describe proof-of-concept three-dimensional stroke simulations, carrying out in silico trials to relate lesion volume to embolus diameter and calculate probabilistic lesion overlap maps, building on our previous Monte Carlo method. Simulated emboli were released into an in silico vasculature to simulate 1000 s of strokes. Infarct volume distributions and probabilistic lesion overlap maps were determined. Computer-generated lesions were assessed by clinicians and compared with radiological images. The key result of this study is development of a three-dimensional simulation for embolic stroke and its application to an in silico clinical trial. Probabilistic lesion overlap maps showed that the lesions from small emboli are homogeneously distributed throughout the cerebral vasculature. Mid-sized emboli were preferentially found in posterior cerebral artery (PCA) and posterior region of the middle cerebral artery (MCA) territories. For large emboli, MCA, PCA and anterior cerebral artery (ACA) lesions were comparable to clinical observations, with MCA, PCA then ACA territories identified as the most to least probable regions for lesions to occur. A power law relationship between lesion volume and embolus diameter was found. In conclusion, this article showed proof-of-concept for large in silico trials of embolic stroke including 3D information, identifying that embolus diameter could be determined from infarct volume and that embolus size is critically important to the resting place of emboli. We anticipate this work will form the basis of clinical applications including intraoperative monitoring, determining stroke origins, and in silico trials for complex situations such as multiple embolisation

Mitigating the effects of particle background on the Athena Wide Field Imager

The Wide Field Imager (WFI) flying on Athena will usher in the next era of studying the hot and energetic Universe. Among Athena’s ambitious science programs are observations of faint, diffuse sources limited by statistical and systematic uncertainty in the background produced by high-energy cosmic ray particles. These particles produce easily identified “cosmic-ray tracks” along with less easily identified signals produced by secondary photons or x-rays generated by particle interactions with the instrument. Such secondaries produce identical signals to the x-rays focused by the optics and cannot be filtered without also eliminating these precious photons. As part of a larger effort to estimate the level of unrejected background and mitigate its effects, we here present results from a study of background-reduction techniques that exploit the spatial correlation between cosmic-ray particle tracks and secondary events. We use Geant4 simulations to generate a realistic particle background signal, sort this into simulated WFI frames, and process those frames in a similar way to the expected flight and ground software to produce a realistic WFI observation containing only particle background. The technique under study, self-anti-coincidence (SAC), then selectively filters regions of the detector around particle tracks, turning the WFI into its own anti-coincidence detector. We show that SAC is effective at improving the systematic uncertainty for observations of faint, diffuse sources, but at the cost of statistical uncertainty due to a reduction in signal. If sufficient pixel pulse-height information is telemetered to the ground for each frame, then this technique can be applied selectively based on the science goals, providing flexibility without affecting the data quality for other science. The results presented here are relevant for any future silicon-based pixelated x-ray imaging detector and could allow the WFI and similar instruments to probe to truly faint x-ray surface brightness

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.We thank all members of the Brain Metastasis Group and A. Chalmers, E. Wagner, O. Fernández-Capetillo, R. Ciérvide and A. Hidalgo for critical discussion of the manuscript; the CNIO Core Facilities for their excellent assistance; and Fox Chase Cancer Center Transgenic Facility for generation of S100A9 mice. We thank EuCOMM repository for providing S100A9 targeted embryonic stem cells. We also thank J. Massagué (MSKCC) for some of the BrM cell lines and M. Bosenberg (Yale) for the YUMM1.1 cell line. Samples from patients included in this study that provided by the Girona Biomedical Research Institute (IDIBGI) (Biobanc IDIBGI, B.0000872) are integrated into the Spanish National Biobanks Network and in the Xarxa de Bancs de Tumors de Catalunya (XBTC) financed by the Pla Director d’Oncologia de Catalunya. All patients consented to the storage of these samples in the biobank and for their use in research projects. This study was funded by MINECO (SAF2017-89643-R) (M.V.), Fundació La Marató de TV3 (201906-30-31-32) (J.B.-B., M.V. and A.C.), Fundación Ramón Areces (CIVP19S8163) (M.V.) and CIVP20S10662 (E.O.P.), Worldwide Cancer Research (19-0177) (M.V. and E.C.-J.M.), Cancer Research Institute (Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC (Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), ERC CoG (864759) (M.V.), Portuguese Foundation for Science and Technology (SFRH/bd/100089/2014) (C.M.), Boehringer-Ingelheim Fonds MD Fellowship (L.M.), La Caixa International PhD Program Fellowship-Marie Skłodowska-Curie (LCF/BQ/DI17/11620028) (P.G.-G.), La Caixa INPhINIT Fellowship (LCF/BQ/DI19/11730044) (A.P.-A.), MINECO-Severo Ochoa PhD Fellowship (BES-2017-081995) (L.A.-E.) and an AECC postdoctoral fellowship (POSTD19016PRIE) (N.P.). M.V. is an EMBO YIP member (4053). Additional support was provided by Gertrud and Erich Roggenbuck Stiftung (M.M.), Science Foundation Ireland Frontiers for the Future Award (19/FFP/6443) (L.Y.), Science Foundation Ireland Strategic Partnership Programme, Precision Oncology Ireland (18/SPP/3522) (L.Y.), Breast Cancer Now Fellowship Award with the generous support of Walk the Walk (2019AugSF1310) (D.V.), Science Foundation Ireland (20/FFP-P/8597) (D.V.), Paradifference Foundation (C.F.-T.), “la Caixa” Foundation (ID 100010434) (A.I.), European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement 847648 (CF/BQ/PI20/11760029) (A.I.), Champalimaud Centre for the Unknown (N.S.), Lisboa Regional Operational Programme (Lisboa 2020) (LISBOA01-0145-FEDER-022170) (N.S.), NCI (R01 CA227629; R01 CA218133) (S.I.G.), Fundació Roses Contra el Càncer (J.B.-B.), Ministerio de Universidades FPU Fellowship (FPU 18/00069) (P.T.), MICIN-Agencia Estatal de Investigación Fellowships (PRE2020-093032 and BES-2017-080415) (P.M. and E. Cintado, respectively), Ministerio de Ciencia, Innovación y Universidades-E050251 (PID2019-110292RB-I00) (J.L.T.), FCT (PTDC/MED-ONC/32222/2017) (C.C.F.), Fundação Millennium bcp (C.C.F.), private donations (C.C.F.) and the Foundation for Applied Cancer Research in Zurich (E.L.R. and M.W.)