| 1. |
- Simonsson, Christian, et al.
(författare)
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A unified framework for prediction of liver steatosis dynamics in response to different diet and drug interventions
- 2024
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Ingår i: Clinical Nutrition. - : CHURCHILL LIVINGSTONE. - 0261-5614 .- 1532-1983. ; 43:6, s. 1532-1543
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Tidskriftsartikel (refereegranskat)abstract
- Background & aims: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder, characterized by the accumulation of excess fat in the liver, and is a driving factor for various severe liver diseases. These multi -factorial and multi-timescale changes are observed in different clinical studies, but these studies have not been integrated into a uni fied framework. In this study, we aim to present such a uni fied framework in the form of a dynamic mathematical model. Methods: For model training and validation, we collected data for dietary or drug -induced interventions aimed at reducing or increasing liver fat. The model was formulated using ordinary differential equations (ODEs) and the mathematical analysis, model simulation, model formulation and the model parameter estimation were all performed in MATLAB. Results: Our mathematical model describes accumulation of fat in the liver and predicts changes in lipid fluxes induced by both dietary and drug interventions. The model is validated using data from a wide range of drug and dietary intervention studies and can predict both short-term (days) and long-term (weeks) changes in liver fat. Importantly, the model computes the contribution of each individual lipid flux to the total liver fat dynamics. Furthermore, the model can be combined with an established bodyweight model, to simulate even longer scenarios (years), also including the effects of insulin resistance and body weight. To help prepare for corresponding eHealth applications, we also present a way to visualize the simulated changes, using dynamically changing lipid droplets, seen in images of liver biopsies. Conclusion: In conclusion, we believe that the minimal model presented herein might be a useful tool for future applications, and to further integrate and understand data regarding changes in dietary and drug induced changes in ectopic TAG in the liver. With further development and validation, the minimal model could be used as a disease progression model for steatosis. (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 2. |
- Herrgårdh, Tilda, et al.
(författare)
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A multi-scale digital twin for adiposity-driven insulin resistance in humans : diet and drug effects
- 2023
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Ingår i: Diabetology & Metabolic Syndrome. - : BioMed Central (BMC). - 1758-5996. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The increased prevalence of insulin resistance is one of the major health risks in society today. Insulin resistance involves both short-term dynamics, such as altered meal responses, and long-term dynamics, such as the development of type 2 diabetes. Insulin resistance also occurs on different physiological levels, ranging from disease phenotypes to organ-organ communication and intracellular signaling. To better understand the progression of insulin resistance, an analysis method is needed that can combine different timescales and physiological levels. One such method is digital twins, consisting of combined mechanistic mathematical models. We have previously developed a model for short-term glucose homeostasis and intracellular insulin signaling, and there exist long-term weight regulation models. Herein, we combine these models into a first interconnected digital twin for the progression of insulin resistance in humans.METHODS: The model is based on ordinary differential equations representing biochemical and physiological processes, in which unknown parameters were fitted to data using a MATLAB toolbox. RESULTS: The interconnected twin correctly predicts independent data from a weight increase study, both for weight-changes, fasting plasma insulin and glucose levels, and intracellular insulin signaling. Similarly, the model can predict independent weight-change data in a weight loss study with the weight loss drug topiramate. The model can also predict non-measured variables.CONCLUSIONS: The model presented herein constitutes the basis for a new digital twin technology, which in the future could be used to aid medical pedagogy and increase motivation and compliance and thus aid in the prevention and treatment of insulin resistance.
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| 3. |
- Silfvergren, Oscar, et al.
(författare)
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Digital twin predicting diet response before and after long-term fasting
- 2022
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Ingår i: PloS Computational Biology. - : Public Library of Science. - 1553-734X .- 1553-7358. ; 18:9
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Tidskriftsartikel (refereegranskat)abstract
- Today, there is great interest in diets proposing new combinations of macronutrient compositions and fasting schedules. Unfortunately, there is little consensus regarding the impact of these different diets, since available studies measure different sets of variables in different populations, thus only providing partial, non-connected insights. We lack an approach for integrating all such partial insights into a useful and interconnected big picture. Herein, we present such an integrating tool. The tool uses a novel mathematical model that describes mechanisms regulating diet response and fasting metabolic fluxes, both for organ-organ crosstalk, and inside the liver. The tool can mechanistically explain and integrate data from several clinical studies, and correctly predict new independent data, including data from a new study. Using this model, we can predict non-measured variables, e.g. hepatic glycogen and gluconeogenesis, in response to fasting and different diets. Furthermore, we exemplify how such metabolic responses can be successfully adapted to a specific individuals sex, weight, height, as well as to the individuals historical data on metabolite dynamics. This tool enables an offline digital twin technology.
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| 4. |
- Simonsson, Christian, 1992-
(författare)
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Mathematical Modelling of MASLD ‐ Towards Digital Twins in Liver Disease
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Unhealthy dieting and a sedentary lifestyle are causing an increased prevalence of obesity related complications. One such complication is metabolic dysfunction-associated steatotic liver disease (MASLD) the manifestation of metabolic dysregulation and insulin resistance in the liver. Today, MASLD effect a third of the world’s population. One of the main characteristics of MASLD is accumulation of ectopic lipids in the liver, also denoted steatosis. Steatosis is not inherently dangerous but is an indication of metabolic dysregulation, and long-term MASLD can progress into severe conditions such as chronic hepatic inflammation denoted metabolic dysfunction-associated steatohepatitis (MASH), liver scarring (cirrhosis), and primary liver cancer (hepatocellular carcinoma, HCC). Moreover, these conditions can be further aggravated by alcohol consumption. The increase in potential patients with MASLD will have an enormous burden on future healthcare. Thus, future healthcare has a need for innovative solutions to lessen this burden. Such solutions should be capable of personalized and preventive measures, cost-effective high throughput screening methods, and frameworks integrating all available patient data, for all stages of MASLD. Today, some of these methodologies already exist, however there is still a need for ways to integrate different liver biomarkers into a user-friendly framework, with strong personalization and predictive capabilities. For this purpose, data-driven mathematical modelling is of use. Data-driven mathematical models has proven useful for such integration in other disease areas such as stroke. In this thesis, I have created and explored several mathematical models aimed at exploring different aspects of MASLD, as well as developed several models using data from example: our own collected magnetic resonance imaging (MRI) data from patients suffering from chronic liver disease or HCC, and pre-clinical mouse data of insulin resistance progression. The studies presented in this thesis investigate diet-driven insulin resistance development, steatosis development and screening, as well as lifestyle interventions for alcohol and dietary habits, and liver function evaluation at late-stage liver disease. Thus, this thesis presents a possible fundament to create a so-called digital twin of MASLD – a highly personalized model capable of making predictions based on lifestyle.
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| 5. |
- Abadpour, S., et al.
(författare)
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Inhibition of the prostaglandin D-2-GPR44/DP2 axis improves human islet survival and function
- 2020
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 63, s. 1355-1367
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D-2 (PGD(2)) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD(2) or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1 beta. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD(2) or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1 beta in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3 beta signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-alpha and growth-regulated oncogene-alpha/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.
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| 6. |
- Almquist, Joachim, et al.
(författare)
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Model-Based Analysis Reveals a Sustained and Dose-Dependent Acceleration of Wound Healing by VEGF-A mRNA (AZD8601)
- 2020
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Ingår i: CPT. - : WILEY. - 2163-8306. ; 9:7, s. 384-394
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Tidskriftsartikel (refereegranskat)abstract
- Intradermal delivery of AZD8601, an mRNA designed to produce vascular endothelial growth factor A (VEGF-A), has previously been shown to accelerate cutaneous wound healing in a murine diabetic model. Here, we develop population pharmacokinetic and pharmacodynamic models aiming to quantify the effect of AZD8601 injections on the dynamics of wound healing. A dataset of 584 open wound area measurements from 131 mice was integrated from 3 independent studies encompassing different doses, dosing timepoints, and number of doses. Evaluation of several candidate models showed that wound healing acceleration is not likely driven directly by time-dependent VEGF-A concentration. Instead, we found that administration of AZD8601 induced a sustained acceleration of wound healing depending on the accumulated dose, with a dose producing 50% of the maximal effect of 92 mu g. Simulations with this model showed that a single dose of 200 mu g AZD8601 can reduce the time to reach 50% wound healing by up to 5 days.
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| 7. |
- Arjmandi, Hamidreza, et al.
(författare)
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Diffusive Molecular Communication with a Spheroidal Receiver for Organ-on-Chip Systems
- 2023
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Ingår i: ICC 2023 - IEEE INTERNATIONAL CONFERENCE ON COMMUNICATIONS. - : IEEE. - 9781538674628 - 9781538674635 ; , s. 4464-4469
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Konferensbidrag (refereegranskat)abstract
- Realistic models of the components and processes are required for molecular communication (MC) systems. In this paper, a spheroidal receiver structure is proposed for MC that is inspired by the 3D cell cultures known as spheroids being widely used in organ-on-chip systems. A simple diffusive MC system is considered where the spheroidal receiver and a point source transmitter are in an unbounded fluid environment. The spheroidal receiver is modeled as a porous medium for diffusive signaling molecules, then its boundary conditions and effective diffusion coefficient are characterized. It is revealed that the spheroid amplifies the diffusion signal, but also disperses the signal which reduces the information communication rate. Furthermore, we analytically formulate and derive the concentration Green's function inside and outside the spheroid in terms of infinite series-forms that are confirmed by a particle-based simulator (PBS).
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| 8. |
- Boianelli, Alessandro, et al.
(författare)
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Cross-Species Translation of Biophase Half-Life and Potency of GalNAc-Conjugated siRNAs
- 2022
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Ingår i: Nucleic Acid Therapeutics. - : Mary Ann Liebert. - 2159-3337 .- 2159-3345. ; 32:6, s. 507-512
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Tidskriftsartikel (refereegranskat)abstract
- Small interfering RNAs (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal for in vivo study design and human dose prediction. However, the literature is sparse on translational data for this modality, and pharmacokinetics in the liver is seldom measured. To overcome these difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in various species and applied the kinetic-pharmacodynamic modeling approach to estimate the biophase (liver) half-life and the potency. Our analysis indicates that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and 1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8 times longer in human than in mouse, and generally 1-3 times longer in human than in monkey. The analysis indicates that the siRNAs are more potent in human than in mouse and monkey.
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| 9. |
- Casas Garcia, Belén, et al.
(författare)
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Integrated experimental-computational analysis of a HepaRG liver-islet microphysiological system for human-centric diabetes research
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- Microphysiological systems (MPS) are powerful tools for emulating human physiology and replicating disease progression in vitro. MPS could be better predictors of human outcome than current animal models, but mechanistic interpretation and in vivo extrapolation of the experimental results remain significant challenges. Here, we address these challenges using an integrated experimental-computational approach. This approach allows for in silico representation and predictions of glucose metabolism in a previously reported MPS with two organ compartments (liver and pancreas) connected in a closed loop with circulating medium. We developed a computational model describing glucose metabolism over 15 days of culture in the MPS. The model was calibrated on an experiment-specific basis using data from seven experiments, where HepaRG single-liver or liver-islet cultures were exposed to both normal and hyperglycemic conditions resembling high blood glucose levels in diabetes. The calibrated models reproduced the fast (i.e. hourly) variations in glucose and insulin observed in the MPS experiments, as well as the long-term (i.e. over weeks) decline in both glucose tolerance and insulin secretion. We also investigated the behaviour of the system under hypoglycemia by simulating this condition in silico, and the model could correctly predict the glucose and insulin responses measured in new MPS experiments. Last, we used the computational model to translate the experimental results to humans, showing good agreement with published data of the glucose response to a meal in healthy subjects. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders.
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| 10. |
- Gennemark, Peter, et al.
(författare)
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An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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