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The ISBGroup Blog

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Here you can read about everything that's happening in the ISB Group.

Presentations at the VPH Virtual Physiological Human conference

3R and animal experiments, Events, News Posted on Sun, August 30, 2020 01:43:23

As usual, we have attended the Virtual Physiological Human conference, which this year was given as an eConference. This year, our group was represented with two oral presentations, and three poster presentations. The first oral presentation was held by Gunnar Cedersund, with the title: “Multi-organ and multi-level digital twin models enters the clinic”, and it was similar to the presentation already held at numerous earlier occasions, e.g. at Almedalen, in the Swedish Parliament, at NIH, etc.

Screen short from Peter Gennemark’s presentation at the VPH conference

The second presentation was of a new project: Belén Casas’ postdoc project on modelling of microphysiological systems. This project is financed by AstraZeneca, who are the ones who do the experiments, in collaboration with the company TissUse. This modelling has allowed us to both understand the available system better, and to create a first translation up to humans. This brings us one step closer to finding a workable replacement for animal experiments regarding research on type 2 diabetes and Nonalcoholic SteatoHepatitis (NASH) in the liver. The postdoc project has been supervised by Gunnar Cedersund and Peter Gennemark (AstraZeneca, but also adjoint associate professor in our group). Since Belen is now away on parental leave, Peter gave the presentation. The three final poster presentations were on digital twins and multi-level modelling (Tilda Herrgårdh), on modelling of fatty acid fluxes in the fat tissue (Kajsa Tunedal), and on a new model for exercise (Antonia Klingsäter). Apart from our own presentations, it was interesting to see that the new ASME V&V40 guidelines from FDA, on usage of modelling in certification, are getting more and more traction. Another interesting presentation was the keynote held by Tarique Hussain, who talked about how he has been using advanced modelling of the heart, to help guide treatment planning of complicated cases in child cardiology.

Screen short from the presentation by Tarique Hussain

Ph.D. defense of Markus Karlsson: MRI-based modelling of liver function

Events Posted on Thu, January 30, 2020 11:26:55
Markus preparing for his Ph.D. defense.

Today there is a new Ph.D. defense in ISB group: that of Markus Karlsson. Markus has been working with usage of magnetic resonance imaging techniques to characterize the liver, and the formal title of the Ph.D. thesis is: “Non-Invasive Characterization of Liver Disease – by multimodal quantitative magnetic resonance”. Various techniques have been tested, MRS-PDFF (to measure liver fat), T1 relaxation (to estimate fibrosis), R2* (to estimate iron in the liver), etc. In three of the papers (Paper 1,2 and 4), normal MRI analysis has been done in different patient cohorts, and in two of the papers (Paper 3 and 5), mathematical modelling has been done in collaboration with ISB group. More specifically:

Paper 1 established a relationship between R2* and MRS-PDFF, and saw that liver fat distorts the R2* signal with about one R2* unit per MRS-PDFF unit. This could be used to device a simpe correction method when using R2* to estimate liver iron levels.

Paper 2 looked at the relationship between T1 and liver fibrosis in a cohort of approximately 100 patients with various degrees of diffuse liver disease, ranging from no fibrosis to cirrhosis. In the literature, different degrees of connection between T1 and liver fibrosis have been reported, and this paper unfortunately supports the conclusion that there is low correlation.

Paper 3 was the main paper deviced by us:

Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort. Forsgren MF, Karlsson M, Dahlqvist Leinhard O, Dahlström N, Norén B, Romu T, Ignatova S, Ekstedt M, Kechagias S, Lundberg P, Cedersund G. PLoS Comput Biol. 2019 Jun 25;15(6):e1007157.

In this paper, the data consists of DCI-MRI data, i.e. dynamic MRI images which have been enhanced by the contrast agent gadoxetate, which has been injected into the arm at the beginning of the time-series. By combining this data with a previously developed compartment transport model, we could estimate reliable uptake rates into the liver for all patient groups. Furthermore, in this paper we also showed that these estimated uptake rates, only accesible using the model, serve as new useful biomarkers for estimating liver function and fibrosis. In this paper, we also demonstrated how nonlinear mixed-effects modelling could be used to simplify the currently used protocol, to save money and time in the clinic.

Paper 4 looked at the relationship between magnetic resonance cholangiopancreatography (MRCP) and liver function estimated using DCI-MRI.

Paper 5 again looks at modelling of DCI-MRI data, to characterize the transport rates in and out of hepatocytes. In this paper, we compare uptake rates in humans and rats, and in rats with different exposures to a drug which impacts liver function. This allows us to establish a translational framework, that can predict the likely effect of a drug in humans, based on these available data and new data for the effect of the drug in rats. This is useful for drug development, when one wants to estimate the likely effect of a drug in humans based on available pre-clinical and clinical evidence.

Opponent for the defense is Steven Sourbron, who has worked with similar uptake and perfusion modelling in many of the central organs for many years, and who is one of the leading authorities in the field. In the examination committee sits Sven Månsson (Malmö), Lennart Blomqvist (Stockholm) and Zoltan Szabo (Linköping), who have complementary radiological and clinical competence.

Seminar day on non-animal perspectives in biomedicine and drug development with 3R

3R and animal experiments, Events, Systems biology and science Posted on Tue, January 14, 2020 19:28:05

Today, parts of the group participated at a seminar day with the Swedish 3R center in stockholm, both with posters, presentations and in discussions.

The day consisted of presentations from people doing research that can/could lead to replacement of animal testing – specifically on organs on a chip and mathematical modelling – and a panel discussions. In the panel discussions, among other things, the capabilities of the presented research to replace animal testing was discussed, what they can replace, and what the hurdels of making that happen are. All in all, the day gave a clearer vision on where we are, where we couldget, and how to do it.

From the panel discussion. From left to right, Per Artursson, Uppsala University, Karin Stenkula, Lund University, Lotte Martoft, AstraZeneca, Peter Gennemark, AstraZeneca, and Gunnar Cedersund chairing the discussions.

Precise4Q meeting in Linköping

Events, News Posted on Tue, November 12, 2019 16:02:17

During 7th and 8th of the November, we have had meeting with our partners in the PRECISE4Q project here in Linköping. In PRECISE4Q, we are working wit developing hybrid models for a decision support for Stroke treatment together with scientists within health informatics, computer science, machine learning, medicine, etc.

During the meetings, we discussed our upcoming EU review (we are financed by EUs Horizon 2020 project), how we should move forward in general, and met with local scientists here in Linköping that are working with similar things.

Ellen’s master thesis defence

Events Posted on Wed, January 23, 2019 14:53:04

Today, Ellen
Lesshammar defended her master thesis project: ‘Mathematical modelling of TLR4-activated
macrophages in inflammation’. The project aimed to use a model-based approach to
investigate the synthesis and release of
cytokines from macrophages during inflammation and also when inflammatory
response is suppressed by anti-inflammatory drugs. The models Ellen constructed
have the potential of being further refined and extended to include other
aspects of inflammation and might thus hold the possibility to contribute to
the further understanding of inflammation and how it can be the root cause to
several common diseases.

The work was done here in the ISB-group but also at the
Linköping based company Wolfram MathCore. We would like to congratulate Ellen on a
job well done, and we wish her luck with all future endeavours!

Nicolas’s master thesis defence

Events Posted on Mon, December 03, 2018 14:56:21

Nicolas’s master thesis

Last week a member of our group held his master thesis defence. The
member in question was Nicolas who has been doing in his master thesis in our
group, as well as some work prior to that.

Nicolas hold a well-structured and informative presentation of his work
and defended his thesis in a great way.

Nicolas project aimed to characterize the metabolic fluxes of carbon-13
labelled metabolites throughout parts of the metabolic system. The fluxes were
determined from the structure of the metabolites in the end of the metabolic
system. By knowing the reactions in the system and the number of intermediate
products from the inserted labelled metabolites, one can determent the fluxes
between the reactions. This method is called metabolic flux analysis. Although
this is to hard math to do by hand, one can use mathematical modelling.

The second part of Nicolas project was to validate that his model could accurately
predict the quantities of the metabolic fluxes. However, today, there is no
established method for this kind of validation. Nicolas validated his model by the
model’s ability to predict a validation dataset, data that the model have not
seen before. By using this approach, one wish to see how the model react to new
data and judge the model quality by how true the model’s prediction of this
data is.

Additionally, the uncertainty of the predictions was analysed with a
profile likelihood analysis. With such predictions, one can place more trust in
fluxes determined by the model. Consequently, this allows for more challenging
issues to be tackled in the development process of new treatments.

With this we want to congratulate Nicolas on his completed master thesis
and wish good luck in the future.

3th national diabetes summit

Events Posted on Wed, November 21, 2018 12:16:27

On November 16th and 17th Gunnar, Elin, William, Tilda, Christian, Kajsa and Jonna attended the 3th national diabetes summit in Stockholm. During
this conference the Karolinska institute was the scene of many interesting conversations,
posters and presentations.

The program consisted of many interesting presentations
covering various aspects of diabetes research. Our group was represented with,
apart from a poster, a very nice talk by Elin. We have had many interesting conversations
with other researchers that may lead to some very nice collaborations. For me
personally the conference was a unique chance to see what kind of diabetes
research is performed in Sweden.

Since the end of November is approaching rapidly my time in
Sweden is almost coming to an end. I look back at a very nice time in Sweden were
I’ve learned a lot about modeling and applications of modeling to the liver.
And of course my new knowledge about things like Fika and warm meals during
lunch 😉

Regards, Jonna

Ph.D defence of Belén Casas

Events Posted on Fri, November 16, 2018 13:19:11

Last week we attended the Ph.D defence of Belén Casas, who has worked with our group during her research.

It was a pleasure to listen to the great presentation of her work and her defence. A short description about her work follows below.

Belén’s work aimed at improving the current diagnostic tools in the field of heart diseases. By analysing data gathered from using 4D flow-MRI (a technique with 3D time resolution and phase contrast magnetic resonance imaging) with mathematical models, Belén has developed tools that can be of help to improve a subject specific assessment of a patient’s cardiovascular function.

After a successful defence, there was a celebratory afterwork in Belén’s honour. We want to take our time to congratulate Belén to her well-deserved Ph.D title and wish her good luck in her future work.

Links to published articles
Briding the gap between measurment and modelling: a cardiovascular functional avatar

Non-invasive Assessment of Systolic and Diastolic Cardiac Function During Rest and Stress Conditions Using an Integrated Image-Modelling Approach

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