Human Immunocompetent Model of Neuroendocrine Liver Metastases Recapitulates Patient-Specific Tumour Microenvironment.

Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune checkpoint receptors in the culture supernatants proves that these immunomodulators are actively produced by LM-NEN and suggests that this process is epithelium-dependent. This model can be employed to investigate these pathways and provides a powerful platform for mechanistic, immunological and pre-clinical studies.

Agent-based modelling of iron cycling bacteria provides a framework for testing alternative environmental conditions and modes of action.

Iron-reducing and iron-oxidizing bacteria are of interest in a variety of environmental and industrial applications. Such bacteria often co-occur at oxic-anoxic gradients in aquatic and terrestrial habitats. In this paper, we present the first computational agent-based model of microbial iron cycling, between the anaerobic ferric iron (Fe3+)-reducing bacteria Shewanella spp. and the microaerophilic ferrous iron (Fe2+)-oxidizing bacteria Sideroxydans spp. By including the key processes of reduction/oxidation, movement, adhesion, Fe2+-equilibration and nanoparticle formation, we derive a core model which enables hypothesis testing and prediction for different environmental conditions including temporal cycles of oxic and anoxic conditions. We compared (i) combinations of different Fe3+-reducing/Fe2+-oxidizing modes of action of the bacteria and (ii) system behaviour for different pH values. We predicted that the beneficial effect of a high number of iron-nanoparticles on the total Fe3+ reduction rate of the system is not only due to the faster reduction of these iron-nanoparticles, but also to the nanoparticles' additional capacity to bind Fe2+ on their surfaces. Efficient iron-nanoparticle reduction is confined to pH around 6, being twice as high than at pH 7, whereas at pH 5 negligible reduction takes place. Furthermore, in accordance with experimental evidence our model showed that shorter oxic/anoxic periods exhibit a faster increase of total Fe3+ reduction rate than longer periods.

Modeling the energy metabolism in immune cells.

In this review, we summarize and briefly discuss various approaches to modeling the metabolism in human immune cells, with a focus on energy metabolism. These approaches include metabolic reconstruction, elementary modes, and flux balance analysis, which are often subsumed under constraint-based modeling. Further approaches are evolutionary game theory and kinetic modeling. Many immune cells such as macrophages show the Warburg effect, meaning that glycolysis is upregulated upon activation. We outline a minimal model for explaining that effect using optimization. The effect of a confrontation with pathogen cells on immunometabolism is highlighted. Models describing the differences between M1 and M2 macrophages, ROS production in neutrophils, and tryptophan metabolism are discussed. Obstacles and future prospects are outlined.

Precision-cut liver slices: a versatile tool to advance liver research.

Human precision-cut liver slices represent a robust and versatile ex vivo model which retains the complex and multi-cellular histoarchitecture of the hepatic environment. As such, they represent an ideal model to investigate the mechanisms of liver injury and for the identification of novel therapeutic targets. Schematic overview to highlight the utility of precision-cut liver slices as a relevant and versatile ex-vivo model of liver disease. Top panel; Precision cut liver slices (PCLS) exposed to ethanol develop mega-mitochondria, a classical hallmark of Alcoholic Liver Disease (ALD). Right panel; PCLS from liver tumours can be used as a model for liver cancer and can be used to investigate cancer-immune cell interactions by co-culturing with matched immune cells. Bottom panel; Exposure to a mixture of oleic and linoleic acids can simulate Non-Alcoholic Fatty Liver Disease (NAFLD). Left panel; PCLS can be infected with Hepatitis B and C virus and used as a model to study viral infection and replication.

Modelling the host-pathogen interactions of macrophages and Candida albicans using Game Theory and dynamic optimization.

The release of fungal cells following macrophage phagocytosis, called non-lytic expulsion, is reported for several fungal pathogens. On one hand, non-lytic expulsion may benefit the fungus in escaping the microbicidal environment of the phagosome. On the other hand, the macrophage could profit in terms of avoiding its own lysis and being able to undergo proliferation. To analyse the causes of non-lytic expulsion and the relevance of macrophage proliferation in the macrophage-Candida albicans interaction, we employ Evolutionary Game Theory and dynamic optimization in a sequential manner. We establish a game-theoretical model describing the different strategies of the two players after phagocytosis. Depending on the parameter values, we find four different Nash equilibria and determine the influence of the systems state of the host upon the game. As our Nash equilibria are a direct consequence of the model parameterization, we can depict several biological scenarios. A parameter region, where the host response is robust against the fungal infection, is determined. We further apply dynamic optimization to analyse whether macrophage mitosis is relevant in the host-pathogen interaction of macrophages and C. albicans For this, we study the population dynamics of the macrophage-C. albicans interactions and the corresponding optimal controls for the macrophages, indicating the best macrophage strategy of switching from proliferation to attacking fungal cells.

Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells.

The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.