A statistical model of the penetrating arterioles and venules in the human cerebral cortex

ObjectiveModels of the cerebral microvasculature are required at many different scales in order to understand the effects of microvascular topology on CBF. There are, however, no data-driven models at the arteriolar/venular scale. In this paper, we develop a data-driven algorithm based on available data to generate statistically accurate penetrating arterioles and venules. MethodsA novel order-based density-filling algorithm is developed based on the statistical data including bifurcating angles, LDRs, and area ratios. Three thousand simulations are presented, and the results validated against morphological data. These are combined with a previous capillary network in order to calculate full vascular network parameters. ResultsStatistically accurate penetrating trees were successfully generated. All properties provided a good fit to experimental data. The k exponent had a median of 2.5 and an interquartile range of 1.75-3.7. CBF showed a standard deviation ranging from andplusmn;18% to andplusmn;34% of the mean, depending on the penetrating vessel diameter. ConclusionsSmall CBF variations indicate that the topology of the penetrating vessels plays only a small part in the large regional variations of CBF seen in the brain. These results open up the possibility of efficient oxygen and blood flow simulations at MRI voxel scales which can be directly validated against MRI data.</p

A distributed optimization method for the geographically distributed data centres problem

The geographically distributed data centres problem (GDDC) is a naturally distributed resource allocation problem. The problem involves allocating a set of virtual machines (VM) amongst the data centres (DC) in each time period of an operating horizon. The goal is to optimize the allocation of workload across a set of DCs such that the energy cost is minimized, while respecting limitations on data centre capacities, migrations of VMs, etc. In this paper, we propose a distributed optimization method for GDDC using the distributed constraint optimization (DCOP) framework. First, we develop a new model of the GDDC as a DCOP where each DC operator is represented by an agent. Secondly, since traditional DCOP approaches are unsuited to these types of large-scale problem with multiple variables per agent and global constraints, we introduce a novel semi-asynchronous distributed algorithm for solving such DCOPs. Preliminary results illustrate the benefits of the new method

The Ageing Brain: Investigating the Role of Age in Changes to the Human Cerebral Microvasculature With an in silico Model

Ageing causes extensive structural changes to the human cerebral microvasculature, which have a significant effect on capillary bed perfusion and oxygen transport. Current models of brain capillary networks in the literature focus on healthy adult brains and do not capture the effects of ageing, which is critical when studying neurodegenerative diseases. This study builds upon a statistically accurate model of the human cerebral microvasculature based on ex-vivo morphological data. This model is adapted for “healthy” ageing using in-vivo measurements from mice at three distinct age groups—young, middle-aged, and old. From this new model, blood and molecular exchange parameters are calculated such as permeability and surface-area-to-volume ratio, and compared across the three age groups. The ability to alter the model vessel-by-vessel is used to create a continuous gradient of ageing. It was found that surface-area-to-volume ratio reduced in old age by 6% and permeability by 24% from middle-age to old age, and variability within the networks also increased with age. The ageing gradient indicated a threshold in the ageing process around 75 years old, after which small changes have an amplified effect on blood flow properties. This gradient enables comparison of studies measuring cerebral properties at discrete points in time. The response of middle aged and old aged capillary beds to micro-emboli showed a lower robustness of the old age capillary bed to vessel occlusion. As the brain ages, there is thus increased vulnerability of the microvasculature—with a “tipping point” beyond which further remodeling of the microvasculature has exaggerated effects on the brain. When developing in-silico models of the brain, age is a very important consideration to accurately assess risk factors for cognitive decline and isolate early biomarkers of microvascular health.</jats:p

Age-based sensitivity analysis on cardiac hemodynamics using lumped-parameter modelling

Age is a major risk for heart failure, which is associated with the reduction in ventricular compliance, increase in arterial stiffening, and increase in systemic vascular resistance. In this study, a lumped-parameter model is used to investigate the effect of aging on the possibility of heart failure occurrence. Model parameters including the systemic and pulmonary arterial compliance and resistance, and the left ventricular elastance are calculated for different ages using a ratio-based method. These parameters are then used in the lumped-parameter model. Our findings show that as age increases, there is a leftward and a rightward shift in the left ventricle and right ventricle pressure-volume loops, respectively. For the left ventricle, there is a decrease in stroke volume and an increase in ventricular pressure as the age increases. This correlates with the occurrence of arterial hypertension in the older population. Meanwhile, the right ventricular pressure is maintained as the population gets older, despite the increase in the stroke volume. This is possibly due to the shift in intraventricular septum that causes an enlargement of the right ventricle as the age increases. This study provides understanding on the effect of age on the occurrence of heart failure.This study demonstrates the relationship of aging with cardiac hemodynamics, which provides the potential risk of heart failure occurrence. Although there are many risk factors that can cause heart failure, aging has been strongly associated with its occurrence. Understanding how age affects heart failure can help to differentiate them from other effects such as dietary, gender, and early cardiovascular diseases including arrhythmia and myocardial infarction

Tumour Cells Express Functional Lymphatic Endothelium-Specific Hyaluronan Receptor In Vitro and In Vivo: Lymphatic Mimicry Promotes Oral Oncogenesis?

Lymphatic metastasis represents the main route of tumour cell dissemination in oral squamous cell carcinoma (OSCC). Yet, there are no FDA-approved therapeutics targeting cancer-related lymphangiogenesis to date. The lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), a specific lymphatic marker, is associated with poor survival in OSCC patients. In this study, we present a potential novel mechanism of lymphatic metastasis in OSCC—lymphatic mimicry (LM), a process whereby tumour cells form cytokeratin+/LYVE-1+, but podoplanin-negative, mosaic endothelial-like vessels. LM was detected in one-third (20/57; 35.08%) of randomly selected OSCC patients. The LM-positive patients had shorter overall survival (OS) compared to LM-negative group albeit not statistically significant. Highly-metastatic tumour cells formed distinct LM structures in vitro and in vivo. Importantly, the siRNA-mediated knockdown of LYVE-1 not only impaired tumour cell migration but also blunted their capacity to form LM-vessels in vitro and reduced tumour metastasis in vivo. Together, our findings uncovered, to our knowledge, a previously unknown expression and function of LYVE-1 in OSCC, whereby tumour cells could induce LM formation and promote lymphatic metastasis. Finally, more detailed studies on LM are warranted to better define this phenomenon in the future. These studies could benefit the development of targeted therapeutics for blocking tumour-related lymphangiogenesis.Peer reviewe

Mathematical modelling of haemorrhagic transformation within a multiscale microvasculature network

Abstract Objective. Haemorrhagic transformation (HT) is one of the most common complications after ischaemic stroke, caused by damage to the blood–brain barrier (BBB) that could be the result of stroke progression or a complication of stroke treatment with reperfusion therapy. The aim of this study is to develop further a previous simple HT mathematical model into an enlarged multiscale microvasculature model in order to investigate the effects of HT on the surrounding tissue and vasculature. In addition, this study investigates the relationship between tissue displacement and vascular geometry. Approach. By modelling tissue displacement, capillary compression, hydraulic conductivity in tissue and vascular permeability, we establish a mathematical model to describe the change of intracranial pressure (ICP) surrounding the damaged vascular bed after HT onset, applied to a 3D multiscale microvasculature. The use of a voxel-scale model then enables us to compare our HT simulation with available clinical imaging data for perfusion and cerebral blood volume ( C B V ) in the multiscale microvasculature network. Main results. We showed that the haematoma diameter and the maximum tissue displacement are approximately proportional to the diameter of the breakdown vessel. Based on the voxel-scale model, we found that perfusion reduces by approximately 13 – 17 % and C B V reduces by around 20 – 25 % after HT onset due to the effect of capillary compression caused by increased interstitial pressure. The results are in good agreement with the limited experimental data. Significance. This model, by enabling us to bridge the gap between the microvascular scale and clinically measurable parameters, providing a foundation for more detailed validation and understanding of HT in patients.</jats:p

The effect of fascin 1 inhibition on head and neck squamous cell carcinoma cells

Fascin 1 plays important pro-metastatic roles in head and neck carcinoma (HNSCC) migration, invasion, and metastasis. However, limited advancement in targeting metastasis remains a major obstacle in improving HNSCC patients' survival. Therefore, we assessed the therapeutic potential of fascin 1 targeted inhibition and its potential prognostic value in HNSCC patients. Using in vitro and in vivo approaches, we investigated the effect of compound G2, a novel fascin 1 inhibitor, on HNSCC cells migration, invasion, and metastasis. High-throughput screening (HTS) was used to assess cytotoxic activity of compound G2 alone or combined with irradiation. We also evaluated the prognostic potential of fascin 1 in HNSCC patients. Interestingly, compound G2 reduced carcinoma cells migration and invasion in vitro and inhibited metastasis in vivo. Moreover, HTS revealed a modest cytotoxic activity of the compound G2 on HNSCC cell lines. Irradiation did not synergistically enhance the compound G2-mediated cytotoxic activity. Survival analyses showed that high fascin 1 immunoexpression, at the tumor invasive front, was associated with cancer-specific mortality in the advanced stages of HNSCC. Collectively, our findings suggest that fascin 1 represents a promising anti-metastatic therapeutic target and a useful prognostic marker in patients with HNSCC. Novel anti-metastatic agents could provide a valuable addition to cancer therapy.Peer reviewe

Initial blood pressure and adverse cardiac events following acute ischaemic stroke: An individual patient data pooled analysis from the VISTA database.

BackgroundAdverse cardiac events following ischaemic stroke (stroke-heart syndrome, SHS) pose a clinical challenge. We investigated the association between initial blood pressure at stroke presentation and the risk of SHS.MethodsWe utilised data from the Virtual International Stroke Trials Archive (VISTA). We defined SHS as the incidence of cardiac complications within 30 days post-ischaemic stroke. These presentations included acute coronary syndrome encompassing myocardial injury, heart failure/left ventricular dysfunction, atrial fibrillation/flutter, other arrhythmia/electrocardiogram abnormalities, and cardiorespiratory arrest. Using Cox proportional hazards models, we assessed the risk trajectories for developing SHS and its presentations associated with initial blood pressure. We also explored the risk trajectories for 90-day mortality related to initial blood pressure.ResultsFrom 16,095 patients with acute ischaemic stroke, 14,965 (mean age 69 ± 12 years; 55% male) were analysed. Of these, 1774 (11.8%) developed SHS. The risk of SHS and initial blood pressure showed a U-shaped relationship. The lowest blood pressures (⩽130 mmHg systolic and ⩽55 mmHg diastolic) were associated with the highest risks (adjusted hazard ratio [95%confidence interval]: 1.40 [1.21-1.63]; p p p = 0.017 for systolic blood pressure >190 mmHg), whereas other presentations exhibited the highest risk at lower pressures. The 90-day mortality risk also followed a U-shaped distribution, with greater risks observed at high blood pressure thresholds.ConclusionsThere is a U-shaped relationship between initial blood pressure at ischaemic stroke presentation and the risk of subsequent SHS