Off-label in-silico flow diverter performance assessment in posterior communicating artery aneurysms.

Background: The posterior communicating artery (PComA) is among the most common intracranial aneurysm locations, but flow diverter (FD) treatment with the widely used pipeline embolization device (PED) remains an off-label treatment that is not well understood. PComA aneurysm flow diversion is complicated by the presence of fetal posterior circulation (FPC), which has an estimated prevalence of 4-29% and is more common in people of black (11.5%) than white (4.

Reduced order modelling of intracranial aneurysm flow using proper orthogonal decomposition and neural networks.

Reduced order modelling (ROMs) methods, such as proper orthogonal decomposition (POD), systematically reduce the dimensionality of high-fidelity computational models and potentially achieve large gains in execution speed. Machine learning (ML) using neural networks has been used to overcome limitations of traditional ROM techniques when applied to nonlinear problems, which has led to the recent development of reduced order models augmented by machine learning (ML-ROMs). However, the performance of ML-ROMs is yet to be widely evaluated in realistic applications and questions remain regarding the optimal design of ML-ROMs.

Accelerated simulation methodologies for computational vascular flow modelling.

Vascular flow modelling can improve our understanding of vascular pathologies and aid in developing safe and effective medical devices. Vascular flow models typically involve solving the nonlinear Navier-Stokes equations in complex anatomies and using physiological boundary conditions, often presenting a multi-physics and multi-scale computational problem to be solved. This leads to highly complex and expensive models that require excessive computational time.

Aldehyde oxidase 1 activity and protein expression in human, rabbit, and pig ocular tissues.

Aldehyde oxidase (AOX) is a cytosolic drug-metabolizing enzyme which has attracted increasing attention in drug development due to its high hepatic expression, broad substrate profile and species differences. In contrast, there is limited information on the presence and activity of AOX in extrahepatic tissues including ocular tissues. Because several ocular drugs are potential substrates for AOX, we performed a comprehensive analysis of the AOX1 expression and activity profile in seven ocular tissues from humans, rabbits, and pigs.

Hemodynamics of thrombus formation in intracranial aneurysms: An observational study.

How prevalent is spontaneous thrombosis in a population containing all sizes of intracranial aneurysms? How can we calibrate computational models of thrombosis based on published data? How does spontaneous thrombosis differ in normo- and hypertensive subjects? We address the first question through a thorough analysis of published datasets that provide spontaneous thrombosis rates across different aneurysm characteristics. This analysis provides data for a subgroup of the general population of aneurysms, namely, those of large and giant size (>10 mm). Based on these observed spontaneous thrombosis rates, our computational modeling platform enables the first observational study of spontaneous thrombosis prevalence across a broader set of aneurysm phenotypes.

Virtual high-resolution MR angiography from non-angiographic multi-contrast MRIs: synthetic vascular model populations for in-silico trials.

Despite success on multi-contrast MR image synthesis, generating specific modalities remains challenging. Those include Magnetic Resonance Angiography (MRA) that highlights details of vascular anatomy using specialised imaging sequences for emphasising inflow effect. This work proposes an end-to-end generative adversarial network that can synthesise anatomically plausible, high-resolution 3D MRA images using commonly acquired multi-contrast MR images (e.

Extrahepatic in vitro metabolism of peptides; comparison of human kidney and intestinal S9 fraction, human plasma and proximal tubule cells, using cyclosporine A, leuprorelin, and cetrorelix as model compounds.

Peptide therapeutics showcase number of advantages compared to the traditional small molecule drugs, e,g. they usually have higher affinity to target and lower toxicity profiles. Endogenous peptides are mostly cleared from the body through renal clearance or proteolytic hydrolysis.

Activity and Expression of Carboxylesterases and Arylacetamide Deacetylase in Human Ocular Tissues.

As a multitissue organ, the eye possesses unique anatomy and physiology, including differential expression of drug-metabolizing enzymes. Several hydrolytic enzymes that play a major role in drug metabolism and bioactivation of prodrugs have been detected in ocular tissues, but data on their quantitative expression is scarce. Also, many ophthalmic drugs are prone to hydrolysis.

In-silico trial of intracranial flow diverters replicates and expands insights from conventional clinical trials.

The cost of clinical trials is ever-increasing. In-silico trials rely on virtual populations and interventions simulated using patient-specific models and may offer a solution to lower these costs. We present the flow diverter performance assessment (FD-PASS) in-silico trial, which models the treatment of intracranial aneurysms in 164 virtual patients with 82 distinct anatomies with a flow-diverting stent, using computational fluid dynamics to quantify post-treatment flow reduction.

Stromal interaction molecule 1 (STIM1) knock down attenuates invasion and proliferation and enhances the expression of thyroid-specific proteins in human follicular thyroid cancer cells.

Stromal interaction molecule 1 (STIM1) and the ORAI1 calcium channel mediate store-operated calcium entry (SOCE) and regulate a multitude of cellular functions. The identity and function of these proteins in thyroid cancer remain elusive. We show that STIM1 and ORAI1 expression is elevated in thyroid cancer cell lines, compared to primary thyroid cells.

Calcium Signaling in the Thyroid: Friend and Foe.

Calcium signaling participates in a vast number of cellular processes, ranging from the regulation of muscle contraction, cell proliferation, and mitochondrial function, to the regulation of the membrane potential in cells. The actions of calcium signaling are, thus, of great physiological significance for the normal functioning of our cells. However, many of the processes that are regulated by calcium, including cell movement and proliferation, are important in the progression of cancer.

Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues.

Hydrolytic reactions constitute an important pathway of drug metabolism and a significant route of prodrug activation. Many ophthalmic drugs and prodrugs contain ester groups that greatly enhance their permeation across several hydrophobic barriers in the eye before the drugs are either metabolized or released, respectively, hydrolysis. Thus, the development of ophthalmic drug therapy requires the thorough profiling of substrate specificities, activities, and expression levels of ocular esterases.

Highly integrated workflows for exploring cardiovascular conditions: Exemplars of precision medicine in Alzheimer's disease and aortic dissection.

For precision medicine to be implemented through the lens of in silico technology, it is imperative that biophysical research workflows offer insight into treatments that are specific to a particular illness and to a particular subject. The boundaries of precision medicine can be extended using multiscale, biophysics-centred workflows that consider the fundamental underpinnings of the constituents of cells and tissues and their dynamic environments. Utilising numerical techniques that can capture the broad spectrum of biological flows within complex, deformable and permeable organs and tissues is of paramount importance when considering the core prerequisites of any state-of-the-art precision medicine pipeline.

Population-specific modelling of between/within-subject flow variability in the carotid arteries of the elderly.

Computational fluid dynamics models are increasingly proposed for assisting the diagnosis and management of vascular diseases. Ideally, patient-specific flow measurements are used to impose flow boundary conditions. When patient-specific flow measurements are unavailable, mean values of flow measurements across small cohorts are used as normative values.

Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca handling in HeLa cells.

Sphingosine kinase 1 (SK1) converts sphingosine to the bioactive lipid sphingosine 1-phosphate (S1P). S1P binds to G-protein-coupled receptors (S1PR) to regulate cellular events, including Ca signaling. The SK1/S1P axis and Ca signaling both play important roles in health and disease.

A computational model for prediction of clot platelet content in flow-diverted intracranial aneurysms.

Treatment of intracranial aneurysms with flow-diverting stents is a safe and minimally invasive technique. The goal is stable embolisation that facilitates stent endothelialisation, and elimination of the aneurysm. However, it is not fully understood why some aneurysms fail to develop a stable clot even with sufficient levels of flow reduction.

Pharmacokinetics of intra-articular vitamin D analogue calcipotriol in sheep and metabolism in human synovial and mesenchymal stromal cells.

Calcipotriol (MC903) is a side chain analogue of the biologically active 1,25-dihydroxyvitamin D [1,25(OH)D]. Due to its anti-inflammatory and anti-proliferative effects on stromal cells, calcipotriol is a promising candidate for the local treatment of arthritis. In this preliminary work, we studied the pharmacokinetics and safety of calcipotriol after an IV (0.

Oxysterol-binding protein related-proteins (ORPs) 5 and 8 regulate calcium signaling at specific cell compartments.

Oxysterol-binding protein related-protein 5 and 8 (ORP5/8) localize to the membrane contact sites (MCS) of the endoplasmic reticulum (ER) and the mitochondria, as well as to the ER-plasma membrane (PM) MCS. The MCS are emerging as important regulators of cell signaling events, including calcium (Ca) signaling. ORP5/8 have been shown to interact with phosphatidylinositol-4,5-bisphosphate (PIP) in the PM, and to modulate mitochondrial respiration and morphology.

Sphingosine 1-phosphate attenuates MMP2 and MMP9 in human anaplastic thyroid cancer C643 cells: Importance of S1P2.

In anaplastic thyroid cancer C643 cells, sphingosine 1-phosphate (S1P) attenuates migration by activating the S1P2 receptor and the Rho-ROCK pathway. In the present study, we show that stimulating C643 cells with S1P decreases the expression, secretion and activity of matrix metalloproteinase-2 (MMP2), and to a lesser extent MMP9. Using receptor-specific antagonists, and S1P2 siRNA, we showed that the inhibition of expression of MMP2 is mediated through S1P2.

Subject-specific multi-poroelastic model for exploring the risk factors associated with the early stages of Alzheimer's disease.

There is emerging evidence suggesting that Alzheimer's disease is a vascular disorder, caused by impaired cerebral perfusion, which may be promoted by cardiovascular risk factors that are strongly influenced by lifestyle. In order to develop an understanding of the exact nature of such a hypothesis, a biomechanical understanding of the influence of lifestyle factors is pursued. An extended poroelastic model of perfused parenchymal tissue coupled with separate workflows concerning subject-specific meshes, permeability tensor maps and cerebral blood flow variability is used.

Screening for Cognitive Impairment by Model-Assisted Cerebral Blood Flow Estimation.

Objective: Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disease; a major health concern in the ageing population with an estimated prevalence of 46 million dementia cases worldwide. Early diagnosis is therefore crucial so mitigating treatments can be initiated at an early stage. Cerebral hypoperfusion has been linked with blood-brain barrier dysfunction in the early stages of AD, and screening for chronic cerebral hypoperfusion in individuals has been proposed for improving the early diagnosis of AD.

Uncertainty quantification of wall shear stress in intracranial aneurysms using a data-driven statistical model of systemic blood flow variability.

Adverse wall shear stress (WSS) patterns are known to play a key role in the localisation, formation, and progression of intracranial aneurysms (IAs). Complex region-specific and time-varying aneurysmal WSS patterns depend both on vascular morphology as well as on variable systemic flow conditions. Computational fluid dynamics (CFD) has been proposed for characterising WSS patterns in IAs; however, CFD simulations often rely on deterministic boundary conditions that are not representative of the actual variations in blood flow.

Virtual endovascular treatment of intracranial aneurysms: models and uncertainty.

Virtual endovascular treatment models (VETMs) have been developed with the view to aid interventional neuroradiologists and neurosurgeons to pre-operatively analyze the comparative efficacy and safety of endovascular treatments for intracranial aneurysms. Based on the current state of VETMs in aneurysm rupture risk stratification and in patient-specific prediction of treatment outcomes, we argue there is a need to go beyond personalized biomechanical flow modeling assuming deterministic parameters and error-free measurements. The mechanobiological effects associated with blood clot formation are important factors in therapeutic decision making and models of post-treatment intra-aneurysmal biology and biochemistry should be linked to the purely hemodynamic models to improve the predictive power of current VETMs.

Improved hybrid/GPU algorithm for solving cardiac electrophysiology problems on Purkinje networks.

Cardiac Purkinje fibers provide an important pathway to the coordinated contraction of the heart. We present a numerical algorithm for the solution of electrophysiology problems across the Purkinje network that is efficient enough to be used in in silico studies on realistic Purkinje networks with physiologically detailed models of ion exchange at the cell membrane. The algorithm is on the basis of operator splitting and is provided with 3 different implementations: pure CPU, hybrid CPU/GPU, and pure GPU.