Interrogating the interconnected biological networks in liver diseases reveals the core components of a perturbed homeostatic system.

This thesis explores the interplay between genetics, environment, and immunological regulation in metabolic associated fatty liver disease (MAFLD), metabolic steatohepatitis (MeSH), and hepatocellular carcinoma (HCC), focusing on liver response to dietary exposome and bone marrow hematopoietic stem and progenitor cells (HSPCs) activity. Using weighted gene co-expression network analysis (WGCNA), we assessed mRNA expression in murine models and human datasets, identifying conserved metabolic and immunological programs and discrepancies in immune responses. The heightened immune response in certain mouse models, reflective of bone marrow HSPCs response, is found protective and consistent with human data, emphasizing the crucial role of immune system-tumorigenesis interplay. Investigating regulatory factors, we spotlight bile acids’ significance. Maintaining a robust immune response is linked to reduced liver tumor burden, with HSPC dietary response as a potential regulatory factor. While cholesterol homeostasis disruptions alone don’t stimulate HSPCs, when combined with disrupted bile acid homeostasis, they significantly impact HSPCs. Rescuing bile acid synthesis dampens HSPC activity, underscoring bile acids' regulatory role. Our findings provide valuable insights into the intricate regulatory networks governing liver disease, presenting potential new avenues for research, including exploring bile acid metabolism’s direct regulation of bone marrow HSPCs, assessing the long-term impact of HSPC stimulation, and investigating liver cholesterol homeostasis’s effect on immunotherapy response. This research suggests exploration of minimal therapeutics targeting sensitive targets and context-driven interpretation in animal model extrapolation. Overall, our experimental approach shows potential in aiding the development of effective treatments for liver diseases, paving the way for future studies in this field

Data mining techniques and breast cancer prediction : A case study of Libya.

Different forms of cancer have been widely studied and documented in various studies across the world. However, there have not been many similar studies in the developing countries - particularly those on the African continent (Parkin, et al., 2005). This thesis seeks to uncover the geo-demographic occurrence patterns of the disease by applying three Data mining Techniques, namely Logistic Regression (LR), Neural Networks (NNs) and Decision Trees (DTs), to learn the underlying rules in the overall behaviour of breast cancer. The data, 3,057 observations on 29 variables obtained from four cancer treatment centres in Libya (2004-2008), were interrogated using multiple K-folds cross validation. The predictive strategy yielded a list of breast cancer predictor factors ordered according to their importance in predicting the disease. Comparison between our results and those obtainable from conventional LR, NN and DT models shows that our strategy out-performs the conventional variable selection. It is expected that the findings from this thesis will provide an input into comparative geo-ethnic studies of cancer and provide informed intervention guidelines in the prevention and cure of the disease, not only in Libya but also in other parts of the world

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40