Modelling the impact of clot fragmentation on the microcirculation after thrombectomy

Many ischaemic stroke patients who have a mechanical removal of their clot (thrombectomy) do not get reperfusion of tissue despite the thrombus being removed. One hypothesis for this ‘no-reperfusion’ phenomenon is micro-emboli fragmenting off the large clot during thrombectomy and occluding smaller blood vessels downstream of the clot location. This is impossible to observe in-vivo and so we here develop an in-silico model based on in-vitro experiments to model the effect of micro-emboli on brain tissue. Through in-vitro experiments we obtain, under a variety of clot consistencies and thrombectomy techniques, micro-emboli distributions post-thrombectomy. Blood flow through the microcirculation is modelled for statistically accurate voxels of brain microvasculature including penetrating arterioles and capillary beds. A novel micro-emboli algorithm, informed by the experimental data, is used to simulate the impact of micro-emboli successively entering the penetrating arterioles and the capillary bed. Scaled-up blood flow parameters–permeability and coupling coefficients–are calculated under various conditions. We find that capillary beds are more susceptible to occlusions than the penetrating arterioles with a 4x greater drop in permeability per volume of vessel occluded. Individual microvascular geometries determine robustness to micro-emboli. Hard clot fragmentation leads to larger micro-emboli and larger drops in blood flow for a given number of micro-emboli. Thrombectomy technique has a large impact on clot fragmentation and hence occlusions in the microvasculature. As such, in-silico modelling of mechanical thrombectomy predicts that clot specific factors, interventional technique, and microvascular geometry strongly influence reperfusion of the brain. Micro-emboli are likely contributory to the phenomenon of no-reperfusion following successful removal of a major clot.

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Modelling the impact of clot fragmentation on the microcirculation after thrombectomy

10.1101/2020.11.30.403808 ◽

2020 ◽

Author(s):

Wahbi K. El-Bouri ◽

Andrew MacGowan ◽

Tamás I. Józsa ◽

Matthew J. Gounis ◽

Stephen J. Payne

Keyword(s):

Blood Flow ◽

Ischaemic Stroke ◽

Computational Model ◽

In Silico ◽

Large Scale ◽

In Vitro Experiments ◽

Mechanical Removal ◽

The Impact ◽

The Brain

1AbstractMany ischaemic stroke patients who have a mechanical removal of their clot (thrombectomy) do not get reperfusion of tissue despite the thrombus being removed. One hypothesis for this ‘no-reperfusion’ phenomenon is micro-emboli fragmenting off the large clot during thrombectomy and occluding smaller blood vessels downstream of the clot location. This is impossible to observe in-vivo and so we here develop an in-silico model based on in-vitro experiments to model the effect of micro-emboli on brain tissue. Through in-vitro experiments we obtain, under a variety of clot consistencies and thrombectomy techniques, micro-emboli distributions post-thrombectomy. Blood flow through the microcirculation is modelled for statistically accurate voxels of brain microvasculature including penetrating arterioles and capillary beds. A novel micro-emboli algorithm, informed by the experimental data, is used to simulate the impact of micro-emboli successively entering the penetrating arterioles and the capillary bed. Scaled-up blood flow parameters – permeability and coupling coefficients – are calculated under various conditions. We find that capillary beds are more susceptible to occlusions than the penetrating arterioles with a 4x greater drop in permeability per volume of vessel occluded. Individual microvascular geometries determine robustness to micro-emboli. Hard clot fragmentation leads to larger micro-emboli and larger drops in blood flow for a given number of micro-emboli. Thrombectomy technique has a large impact on clot fragmentation and hence occlusions in the microvasculature. As such, in-silico modelling of mechanical thrombectomy predicts that clot specific factors, interventional technique, and microvascular geometry strongly influence reperfusion of the brain. Micro-emboli are likely contributory to the phenomenon of no-reperfusion following successful removal of a major clot.2Author summaryAfter an ischaemic stroke - one where a clot blocks a major artery in the brain - patients can undergo a procedure where the clot is removed mechanically with a stent - a thrombectomy. This reopens the blocked vessel, yet some patients don’t achieve blood flow returning to their tissue downstream. One hypothesis for this phenomenon is that the clot fragments into smaller clots (called micro-emboli) which block smaller vessels downstream. However, this can’t be measured in patients due to the inability of clinical imaging resolving the micro-scale. We therefore develop a computational model here, based on experimental thrombectomy data, to quantify the impact of micro-emboli on blood flow in the brain after the removal of a clot. With this model, we found that micro-emboli are a likely contributor to the no-reflow phenomenon after a thrombectomy. Individual blood vessel geometries, clot composition, and thrombectomy technique all impacted the effect of micro-emboli on blood flow and should be taken into consideration to minimise the impact of micro-emboli in the brain. Furthermore, the computational model developed here allows us to now build large-scale models of blood flow in the brain, and hence simulate stroke and the impact of micro-emboli on the entire brain.

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Andean Berry (Vaccinium meridionale Swartz) Juice in Combination With Aspirin Modulated Apoptotic Signaling in Colon Cancer In Vitro and In Vivo

Current Developments in Nutrition ◽

10.1093/cdn/nzab036_003 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 261-261

Author(s):

Sandra Arango-Varela ◽

Ivan Luzardo ◽

Maria Maldonado-Celis

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

In Silico ◽

Aberrant Crypt Foci ◽

Apoptotic Signaling ◽

Polyphenolic Composition ◽

Apoptotic Effects ◽

The Impact

Abstract Objectives This research aimed to assess the impact of Andean Berry (Vaccinium meridionale Swartz) juice (ABJ) in combination with Aspirin in the apoptotic signaling in colon cancer in vitro and in vivo. We hypothesized that ABJ + Aspirin would produce the most effective anti-proliferative and pro-apoptotic effects in vitro and in vivo. Methods The polyphenolic composition of ABJ was carried out by HPLC-DAD. ABJ (0–30% v/v), Aspirin (0–20 mM), and their mixture were evaluated for their pro-apoptotic effects in human SW480 colorectal cancer cells, followed by human apoptosis proteomic and bioinformatic analysis and in silico docking potential between ABJ components and selected pro-apoptotic targets. For the in vivo assays, colorectal cancer was induced with two injections (separated 1 week each) of azoxymethane (AOM: 15 mg/kg body weight, BW), and treatments were evaluated for its chemopreventive and chemoprotective effects. Hence, 30 male and female Balb/c mice were randomly divided in 5 groups: negative control (basal diet, BD); and four AOM-induced groups: positive control (BD), Aspirin (25 mg/kg BW + BD), ABJ (30% v/v in drinking water ABJ + BD), and ABJ + Aspirin (30% v/v ABJ + 25 mg/kg BW Aspirin + BD). Macroscopic and histopathological parameters were evaluated in vivo. Results The mixture displayed the highest antiproliferative effects (+46%), arrested cell cycle at the G2/M phase, decreased cloning efficiency, but reduced Caspase 3/7 activity, suggesting an alternative apoptotic pathway, compared to untreated SW480 cells. Several pro-apoptotic (cytochrome C, TNFRSF1A, Bax, and Bad) and anti-apoptotic (Hsp70/Hsp32) proteins were decreased. ABJ flavonoids (rutin and kaempferol) exhibited the highest in silico affinity with proteins like TRAILR2 or Catalase. Both chemopreventive and chemoprotective approaches showed similar body/liver weight outcomes, but the mixture displayed the strongest aberrant crypt foci reduction in vivo. The chemopreventive approach was more effective in protecting the colon from AOM. Conclusions Results suggested the potential of ABJ to reduce Aspirin use in the alleviation of colorectal cancer markers in vitro and in vivo, modulating alternate pro-apoptotic signaling. Funding Sources The funding provided by COLCIENCIAS and DGAPA-CTIC-UNAM is appreciated.

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Relationship between capillary blood flow parameters measured in vivo and microrheologic parameters of blood measured in vitro in arterial hypertension and coronary heart disease

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2021-20-1-17-24 ◽

2021 ◽

Vol 20 (1) ◽

pp. 17-24

Author(s):

I. M. Kadanova ◽

A. I. Neznanov ◽

A. Е. Lugovtsov ◽

Yu. I. Gurfinkel ◽

A. A. Pigurenko ◽

...

Keyword(s):

Coronary Heart Disease ◽

Blood Flow ◽

Heart Disease ◽

Capillary Blood ◽

Control Group ◽

Aggregation Index ◽

Flow Parameters ◽

Rbc Aggregation

Introduction. Blood microcirculation and its microrheologic properties are impaired in cardiovascular diseases. Microrheologic properties are characterized by the red blood cells (RBC) ability to aggregate and disaggregate. Therefore, the correlation studies between RBC aggregation and microcirculation disorders in pathologies are of interest for the development of theoretical concepts related to blood flow and for clinical practice.Aim. To analyze the correlation between capillary blood flow parameters measured in vivo and microrheologic blood parameters measured in vitro in patients suffering arterial hypertension (AH) and coronary heart disease (CHD).Materials and methods. We studied 3 groups of people: patients suffering AH, patients suffering AH+CHD and healthy donors. The characteristic aggregation time and aggregation index were measured in vitro by laser aggregometry. Analysis of capillary blood velocity (CBV) and assessment of the presence and absence of RBC aggregates in the nail bed capillaries were performed in vivo using vital digital capillaroscopy (VDC).Results. RBC aggregation for groups of patients suffering AH and AH+CHD was increased compared to the control group. Thus, in these patients groups, the characteristic aggregation time significantly decreases by an average of (38±13) %. Comparison of the results obtained using in vitro and in vivo methods showed the aggregation index for individuals with high CBV was significantly lower than for individuals with low CBV. The tendency is that the number of aggregates in the capillaries increases with a decrease in CBV.Conclusion. RBC aggregation is increased in groups of patients suffering AH and AH+CHD compared to the control group. The correlation between parameters measured in vitro and in vivo is evident for patients divided into subgroups according to parameters measured using the VDC. The obtained results allow us to conclude that the used methods are applicable in clinical practice.

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Therapeutic Ultrasound Increases Myocardial Blood Flow in Ischemic Myocardium and Cardiac Endothelial Cells: Results of In Vivo and In Vitro Experiments

Journal of the American Society of Echocardiography ◽

10.1016/j.echo.2019.05.012 ◽

2019 ◽

Vol 32 (9) ◽

pp. 1151-1160 ◽

Cited By ~ 3

Author(s):

Brian Mott ◽

Azzdine Y. Ammi ◽

D. Elizabeth Le ◽

Catherine Davis ◽

Igor V. Dykan ◽

...

Keyword(s):

Endothelial Cells ◽

Blood Flow ◽

Myocardial Blood Flow ◽

Therapeutic Ultrasound ◽

Ischemic Myocardium ◽

In Vitro Experiments

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Harnessing tumor immunity with chemotherapy: Mathematical modeling for decision-making in combinatorial regimen with immune-oncology drugs.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e14095 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e14095-e14095

Author(s):

Vesna Cuplov ◽

Guillaume Sicard ◽

Dominique Barbolosi ◽

Joseph Ciccolini ◽

Fabrice Barlesi

Keyword(s):

Mathematical Modeling ◽

T Cells ◽

In Silico ◽

Checkpoint Inhibitors ◽

Cytotoxic T Cells ◽

Model Parameters ◽

In Vivo Experiments ◽

The Impact

e14095 Background: Combining chemotherapy and immune checkpoint inhibitors (ICI) is challenging due to the near-infinite choice of dosing, scheduling and sequencing between drugs. The aim of this work is to develop a phenomenological model that describes the synergistic effect between cytotoxics and immune check point inhibitors in patients with cancer. Methods: Inspired from literature, we have developed an integrative mathematical model that includes tumor cells, cytotoxic T cells (CTLs) and regulatory T cells (TREGs) plus pharmacokinetics (PK) inputs. Loss in tumor mass is due to combined effect of direct chemotherapy-induced cytotoxicity and CTLs immune response, which is in turn inhibited by the tumor and mitigated by TREGs in the tumor micro-environment. The model describes as well the impact of chemotherapy-induced lymphodepletion on immune tolerance, whereas ICIs protect CTLs against tumor inhibition. Identification of model’s parameters and simulations of various scheduling were performed using Mlxplore software and a Python standalone code. In vitro and in vivo experiments using lung cancer models generate experimental data to adjust model parameters. Results: Complex interplays between cytotoxics and immune cells were best described by a 10-parameters model so as to ensure better identifiability. PK/PD relationships were integrated using compartmental modeling. In silico simulations show how changes in dosing and scheduling impact efficacy endpoints, an observation in line with data from the literature. Ongoing in vitro and in vivo experiments with pemetrexed-cisplatin doublet and anti-PD1 pembrolizumab help optimizing the model’s parameters in a self-learning loop. Conclusions: This work is at the frontier between mathematical modeling and experimental therapeutics with ICIs. In silico modeling and simulations could help narrow down the treatment choices and define optimal combinations prior to running clinical trials. Such model will help identify optimal dosing and scheduling, so as to achieve better synergism and efficacy.

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In Silico Experiments in Scientific Papers on Molecular Biology

Science & Technology Studies ◽

10.23987/sts.55262 ◽

2011 ◽

Vol 24 (2) ◽

pp. 23-42

Author(s):

Sabrina Moretti

Keyword(s):

Molecular Biology ◽

In Silico ◽

In Vitro Experiments ◽

Technical Object ◽

Experimental Conditions ◽

Biological Phenomena ◽

Scientific Papers

This article explores the role of the so-called in silico experiments used in molecular biology. It is based on the analysis of some papers that present scientific applications which rely on in silico experiments. By means of this study I found two basic ways of viewing them. According to the first view, the in silico experiment is a computer program that realizes some specific operations: it constitutes some particular experimental conditions, which allow us to investigate biological phenomena, and which complement those present in in vivo and in vitro experiments. According to the second view, in silico experimentation has a different meaning, which corresponds more closely to the meaning of “simulation”: its identity is linked to that of the “model” used to construct such simulation. The authors of the analysed papers never express an intention to standardize a model, so its meaning remains contingent, and cannot be turned into a technical object.

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LPS-stimulated Macrophage Exosomes Inhibit Inflammation by Activating the Nrf2 / HO-1 Defense Pathway and Promote Wound Healing in Diabetic Rats

10.21203/rs.3.rs-78864/v1 ◽

2020 ◽

Author(s):

Daoyong Li ◽

Chao Wu ◽

He Tian ◽

Liang Mao ◽

Zhanshan Gao ◽

...

Keyword(s):

Wound Healing ◽

Effective Treatment ◽

Diabetic Rats ◽

In Vitro Experiments ◽

Endothelial Cell Function ◽

Promote Wound Healing ◽

The Impact ◽

Wound Tissue

Abstract Background:Impaired wound healing is one of the important complications of diabetes. However, the specific pathogenesis is still unclear, and there is no effective treatment. Macrophages pretreated with chemical or biological factors may increase the biological activity of macrophage-derived exosomes, which is expected to become a new effective treatment method. The purpose of this study was to investigate whether the exosomes secreted by macrophages pretreated with lipopolysaccharide (LPS) have better anti-inflammatory and angiogenic abilities in the treatment of diabetic wound healing and their underlying molecular mechanisms.Methods:In this study, macroscopical, biochemical, histological, immunofluorescence and molecular biology methods were used to evaluate the potential protective mechanism and effect of lipopolysaccharide stimulated macrophage exosomes (LPS-Exos) on wound healing in streptozotocin induced hyperglycemia rats.In the in vivo experiment, the percentages of wound closure and contraction were compared and analyzed on the 7th, 14th, and 21st day after treatment by grouping treatments with different concentrations of LPS-Exos.At the same time, hematoxylin and eosin staining (HE), Masson staining, immunofluorescence staining and Western blotting (WB) were used for histological analysis of the wound tissue on the 14th day after injury to evaluate the impact of different treatment methods on wound healing.In in vitro experiments, the ability of endothelial cells related to proliferation, migration, tube formation and the expression of vascular endothelial growth factor (VEGF) were tested.At the same time, in vivo and in vitro experiments, the effect of Nrf2/HO-1 signaling pathway on LPS-Exos in inhibiting inflammation and promoting angiogenesis was evaluated by using exosome-specific inhibitors.Results:LPS-Exos reduced the content of ROS and MDA in the wound tissue of hyperglycemic rats, increased the activity of SOD and the production of GSH-Px, activated the Nrf2/HO-1 pathway, inhibited the expression of inflammation-related proteins, and promoted blood vessels generate. The group given exosome inhibitors reversed this phenomenon.Conclusions: LPS-Exos may activate the Nrf2/HO-1 defense pathway, improve endothelial cell function, inhibit oxidative damage and inflammation, and promote wound healing in diabetic rats, thereby having the potential to treat diabetic skin defects.

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Trends in In Silico Approaches to the Prediction of Biologically Active Peptides in Meat and Meat Products as an Important Factor for Preventing Food-Related Chronic Diseases

Applied Sciences ◽

10.3390/app112311236 ◽

2021 ◽

Vol 11 (23) ◽

pp. 11236

Author(s):

Paulina Kęska ◽

Waldemar Gustaw ◽

Joanna Stadnik

Keyword(s):

Chronic Diseases ◽

Research Methods ◽

In Silico ◽

Meat Products ◽

Biologically Active ◽

Research Areas ◽

New Research ◽

The Impact

The increasing awareness of modern consumers regarding the nutritional and health value of food has changed their preferences, as well their requirements, for food products, including meat and meat products. Expanding the knowledge on the impact of food on human health is currently one of the most important research areas for scientists worldwide, and it is also of interest to consumers who want to consciously compose their daily diets. New research methods, such as in silico techniques, offer solutions to these new challenges. These research methods are preferred over food evaluation, e.g., from meat, because of their advantages, such as low costs, shorter analysis times, and general availability (e.g., online databases), and are often used to design in vitro and, subsequently, in vivo tests. This review focuses on the possible use of in silico computerized methods to assess the potential of food as a source of these health-relevant biomolecules by using examples from the literature on meat and meat products. This review also provides information and important suggestions for analyzing peptides in terms of assessing their best sources, and screening those resistant to digestive factors and that show biological activity. The information provided in this review could contribute to the development of new sources of foods as biomolecules important for preventing or treating food-related chronic diseases, such as obesity, hypertension, and diabetes.

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Ischaemia and insulin, but not ischaemia and contraction, act synergistically in stimulating muscle glucose uptake in vivo in humans

Clinical Science ◽

10.1042/cs20080087 ◽

2008 ◽

Vol 116 (2) ◽

pp. 157-164 ◽

Cited By ~ 1

Author(s):

Marlies Bosselaar ◽

Paul Smits ◽

Cees J. Tack

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Muscle Contraction ◽

Glucose Uptake ◽

Muscle Blood Flow ◽

In Vitro Models ◽

Skeletal Muscle Glucose Uptake ◽

The Impact

Ischaemia, like muscle contraction, has been reported to induce skeletal muscle glucose uptake in in vitro models. This stimulating effect appears independent of insulin and is probably mediated by activation of AMPK (AMP-activated protein kinase). In the present study, we hypothesized that in vivo in humans ischaemia- and insulin-induced glucose uptake are additive, and that the combined impact of ischaemia and contraction on glucose uptake is of a similar magnitude when each is applied separately. We assessed the effects of ischaemia with and without euglycaemic–hyperinsulinaemia (clamp; protocol 1) and with and without muscle contraction (protocol 2) on muscle FGU (forearm glucose uptake) in healthy subjects. Furthermore, we assessed the impact of ischaemia on FBF (forearm blood flow; plethysmography). In protocol 1, ischaemia increased FGU from 0.6±0.1 at baseline to 5.5±1.9 μmol·min−1·dl−1, and insulin increased FGU to 1.6±0.3 μmol·min−1·dl−1 (P<0.05 for both). The combination of ischaemia+insulin increased FGU to 15.5±2.2 μmol·min−1·dl−1 (P<0.05 compared with each stimulus alone). Maximal FBF obtained after ischaemia was similar with and without hyperinsulinaemia. In protocol 2, isometric contraction increased FGU from 0.3±0.1 to 2.7±0.8 μmol·min−1·dl−1 (P<0.05), but FGU was not significantly different from ischaemia compared with ischaemia+contraction. However, combined ischaemia+contraction resulted in a greater increase in FBF. In summary, ischaemia and insulin independently stimulate skeletal muscle glucose uptake in vivo in humans, whereas ischaemia and contraction do not. The observed differential effects of these stimuli on glucose uptake appear to be unrelated to changes in muscle blood flow.

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