Patients metabolize drugs differently. Personalized physiologically based pharmacokinetic (PBPK) models improve precision dosing Read the article

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Ann-Kristin Becker’s Bayesian network assesses the risk of developing the liver disease more accurately than common clinical scores.
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An interview with Ann-Kristin Becker, a PhD student at the Greifswald University Hospital, about how Bayesian networks can be used in systems biology to identify what variables are interdependent and to what degree
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LiSyM researchers Matthias König and Jan Grzegorzewski together with international collaborators introduce their open database PK-DB for pharmacokinetics data from clinical trials with many unique features. PK-DB represents the first open resource for storing pharmacokinetics data and corresponding patient-specific metadata in accordance with the FAIR (Findable, Accessible, Interoperable, and Reproducible) principles.
The database PK-DB-v0.9.3 (https://pk-db.com) consists of 512 studies containing 1457 groups, 6308 individuals, 1408 interventions, 73 017 outputs, 3148 time-courses and 37 scatters related to acetaminophen, caffeine, codeine, diazepam, glucose, midazolam, morphine, oxazepam, simvastatin or torasemide. It provides curated information for patient cohorts in clinical trials on patient characteristics, drug therapies and pharmacokinetic parameters. The standardized and machine-readable data can assist analyses undertaken in physiologically based pharmacokinetic, pharmacokinetic/pharmacodynamic or populated pharmacokinetic modeling.
The authors envisage that PK-DB will encourage better reporting of pharmacokinetics studies by providing a means for data representation and integration. Providing access to PK data in a central database will improve reusability of pharmacokinetics data. PK-DB will also facilitate data integration between clinical studies and computational models.
Publication: Jan Grzegorzewski, Janosch Brandhorst, Kathleen Green, Dimitra Eleftheriadou, Yannick Duport, Florian Barthorscht, Adrian Köller, Danny Yu Jia Ke, Sara De Angelis, Matthias König, PK-DB: pharmacokinetics database for individualized and stratified computational modeling, Nucleic Acids Research, , gkaa990, https://doi.org/10.1093/nar/gkaa990

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Many experimental results only reach patients through mathematical models. The computer scientist Dr. habil. Dirk Drasdo, an expert for simulations in the liver systems biology research network LiSyM, explains how models can contribute to medical advancements in acute and chronic liver disorders.
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Developing mathematical models of biological systems is very time consuming and challenging for scientists. Yet this is the only way for many experimental results to actually reach patients. The computer scientist Dr. habil. Dirk Drasdo from the systems biology research network LiSyM explains some of the technical issues involved when creating models. A simulations expert, Drasdo uses the liver model he has developed as an example to explain how chemistry, physics, biology, pharmacy, and medicine are transformed into mathematical equations and simulations.
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Genes have an effect on many diseases. According to Professor Dr. med. Frank Lammert, “The genetic profile plays an important role in NAFLD (nonalcoholic fatty liver disease).” Lammert, who is a member of the LiSyM research network, studies the gene variants that influence how susceptible people are to NAFLD. Other gene variants accelerate the course of the disease, or they increase the risk of complications. “How well therapies work also depends on genes,” Lammert explains, adding: “We need more large-scale clinical studies that combine patients’ clinical and molecular profiles with genetic data!” He believes this is the only way patients can benefit from the latest findings in genetic research.
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The World Gastroenterology Organization WGO and other health care associations identify the metabolic liver disease, NAFLD (nonalcoholic fatty liver disease), as a “growing public health problem.” As many as one in four people worldwide has a nonalcoholic fatty liver today. The number is even as high as 40% in the US and Europe, according to estimates from the European Association for the Study of the Liver (EASL). The organization believes that 12 million are affected in Germany.
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In Germany, as many as five million people suffer from liver diseases. The liver is a resilient and complex organ, and currently we do not understand enough, not even about its most basic functions. In a study funded by the Federal Ministry of Education and Research (BMBF), LiSyM team members in Dortmund at IfADo (Leibniz Research Centre for Working Environment and Human Factors) provide fundamentally new insights into the production and transport of bile through 'canaliculi' in the liver. Their results show that the canaliculi contain a stagnant fluid, and bile constituents pass through this fluid by diffusion. These findings overturn long-standing assumptions about how the liver secretes bile. Their results have been published in Hepatology.

"Our new findings require a scientific debate in liver research, which will lead to an adjustment of the doctrine to the new observation. It is to be hoped that this will lead to long-term progress in the treatment of liver diseases", summarizes Dr. Nachiket Vartak, junior group leader in the LiSyM research program.

Press release (English):
https://www.ifado.de/ifadoen/blog/2020/08/06/liver/

Press release (German):
https://www.ifado.de/2020/08/06/leber/

Explainer Video:
https://www.youtube.com/watch?v=W5uGZamqD4M&t=23s

Publication: Vartak, N. et al.: Intravital dynamic and correlative imaging reveals diffusion-dominated canalicular and flow-augmented ductular bile flux. Hepatology 2020. doi: 10.1002/hep.31422

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In collaboration with other key research partners, members of the LiSyM Network investigated the role played by MBOAT7 rs641738C>T – a variant of the MBOAT7 (membrane-bound O-acyltransferase domain containing 7) protein – in the origin and development of NAFLD (nonalcoholic fatty liver disease). They conclude that an MBOAT7 deficiency leads to the development of liver fibrosis without inflammation via a pathway that may be mediated by lipid signaling. Ultimately, this knowledge could lead to improved treatments of NAFLD.

Their study is based on the analysis of mice with hepatocyte-specific MBOAT7 deletion, of associations between the rs641738C>T genotype and liver inflammation and fibrosis in 846 NAFLD patients as well as genotype-specific liver lipidomes from 280 human biopsies.

See publication: https://gut.bmj.com/content/early/2020/06/25/gutjnl-2020-320853.long

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Human bodies are complex biological systems, with countless reactions taking place in every cell. These reactions are sometimes interconnected or have an impact on further processes. Furthermore, cells, tissue, and organs are closely connected. Professor Dr. med. Peter Jansen, director of the LiSyM research network, believes that the research of systems like these, which consist of multilayered processes, interactions, and dependencies, needs mathematical models.
Only models that simulate biological systems on computers make it possible to assemble the existing mass of heterogeneous data into dynamic reproductions in a meaningful way. Mathematical models enable systems researchers to deliver results more quickly and successfully. The idea that digital computers can play an essential role in this research is older than the machines themselves.
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In collaboration with international researchers, members of the Liver Systems Medicine research network have developed the technology and knowledge to generate 3D geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease, NAFLD. With these high definition models, cellular and tissue markers can be quantified to define how far NAFLD has progressed in individual patients and thereby improve medical diagnoses markedly.
To press release