Bayesian modelling of time series data (BayModTS)-a FAIR workflow to process sparse and highly variable data.

MOTIVATION: Systems biology aims to better understand living systems through mathematical modelling of experimental and clinical data. A pervasive challenge in quantitative dynamical modelling is the integration of time series measurements, which often have high variability and low sampling resolution. Approaches are required to utilize such information while consistently handling uncertainties. RESULTS: We present BayModTS (Bayesian modelling of time series data), a new FAIR (findable, accessible, interoperable, and reusable) workflow for processing and analysing sparse and highly variable time series data. BayModTS consistently transfers uncertainties from data to model predictions, including process knowledge via parameterized models. Further, credible differences in the dynamics of different conditions can be identified by filtering noise. To demonstrate the power and versatility of BayModTS, we applied it to three hepatic datasets gathered from three different species and with different measurement techniques: (i) blood perfusion measurements by magnetic resonance imaging in rat livers after portal vein ligation, (ii) pharmacokinetic time series of different drugs in normal and steatotic mice, and (iii) CT-based volumetric assessment of human liver remnants after clinical liver resection. AVAILABILITY AND IMPLEMENTATION: The BayModTS codebase is available on GitHub at https://github.com/Systems-Theory-in-Systems-Biology/BayModTS. The repository contains a Python script for the executable BayModTS workflow and a widely applicable SBML (systems biology markup language) model for retarded transient functions. In addition, all examples from the paper are included in the repository. Data and code of the application examples are stored on DaRUS: https://doi.org/10.18419/darus-3876. The raw MRI ROI voxel data were uploaded to DaRUS: https://doi.org/10.18419/darus-3878. The steatosis metabolite data are published on FairdomHub: 10.15490/fairdomhub.1.study.1070.1.

Cross-species variability in lobular geometry and cytochrome P450 hepatic zonation: insights into CYP1A2, CYP2D6, CYP2E1 and CYP3A4.

There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.

[Liver transplantation in aged patients]. / Lebertransplantation bei alten Patient:innen.

Due to the demographic changes and the increasing incidence of chronic, especially nutritively toxic liver diseases, the number of patients over 65 years of age with indications for liver transplantation is rising considerably. Patient age alone is not a contraindication for organ transplantation; however, in order to ensure the postoperative outcome, a structured interdisciplinary assessment is necessary, especially in older potential organ recipients. With knowledge of comorbidities, individualized prehabilitation enables the perioperative risk to be minimized. The postoperative morbidity in aged patients appears to be comparable to that of younger patients, especially after careful evaluation. Overall, there is a clear survival advantage compared with the best conservative treatment for liver disease. In addition to the perioperative procedure, differences in follow-up care and long-term outcome should also be considered. In this context, predominantly the pharmacological peculiarities, such as polypharmacy and the mutual influence of immunosuppression and comorbidities, have to be taken into account. In addition to old organ recipients, livers from old donors (so-called marginal organs) increasingly play a crucial role in transplantation medicine due to the organ shortage. These are more susceptible to ischemia reperfusion injury and thus put the recipient at a higher risk for delayed or lack of organ function recovery. New ethical issues are raised by the increasing age of donors and recipients, complicating decision making about organ acceptance or rejection for the transplantation physician.

[Multimodal therapy for liver metastases of colorectal carcinoma in curative intention]. / Multimodale Therapie bei Lebermetastasen kolorektaler Karzinome in kurativer Intention.

Depending on the patient's constitution, the biological conditions of the primary tumor, the metastases and the liver function and perfusion, a variety of therapeutic options are available. The basis of metastatic surgery of the liver is partial liver resection. Multimodal therapies with local and systemic approaches are used in functionally or oncologically borderline situations. They are intended to improve long-term success and allow curative treatment in more patients. In recent years, for isolated lesions that cannot be removed by partial liver resection, an R0 situation is achieved in selected patients by liver transplantation with good long-term success. The large number of treatment options and the increasing individualization of therapy require treatment planning in the interdisciplinary tumor board. Also, in view of promising studies, for example, in the field of liver transplantation as well as regional therapy methods, the range of treatment options has not yet been exhausted.