@article {771,
	title = {Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer.},
	journal = {Int J Mol Sci},
	volume = {24},
	year = {2023},
	month = {2023 Apr 18},
	abstract = {<p>The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role in regulating signaling pathways. To assess the potential role of metabolites in the regulation of signaling pathways, both metabolic and signaling pathway activities of Breast invasive Carcinoma (BRCA) have been modeled using mechanistic models. Gaussian Processes, powerful machine learning methods, were used in combination with SHapley Additive exPlanations (SHAP), a recent methodology that conveys causality, to obtain potential causal relationships between the production of metabolites and the regulation of signaling pathways. A total of 317 metabolites were found to have a strong impact on signaling circuits. The results presented here point to the existence of a complex crosstalk between signaling and metabolic pathways more complex than previously was thought.</p>},
	issn = {1422-0067},
	doi = {10.3390/ijms24087450},
	author = {Cubuk, Cankut and Loucera, Carlos and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin}
}
@article {403,
	title = {A comparison of mechanistic signaling pathway activity analysis methods.},
	journal = {Brief Bioinform},
	volume = {20},
	year = {2019},
	month = {2019 09 27},
	pages = {1655-1668},
	abstract = {<p>Understanding the aspects of cell functionality that account for disease mechanisms or drug modes of action is a main challenge for precision medicine. Classical gene-based approaches ignore the modular nature of most human traits, whereas conventional pathway enrichment approaches produce only illustrative results of limited practical utility. Recently, a family of new methods has emerged that change the focus from the whole pathways to the definition of elementary subpathways within them that have any mechanistic significance and to the study of their activities. Thus, mechanistic pathway activity (MPA) methods constitute a new paradigm that allows recoding poorly informative genomic measurements into cell activity quantitative values and relate them to phenotypes. Here we provide a review on the MPA methods available and explain their contribution to systems medicine approaches for addressing challenges in the diagnostic and treatment of complex diseases.</p>},
	keywords = {Algorithms, Humans, Postmortem Changes, Signal Transduction, Systems biology, Transcriptome},
	issn = {1477-4054},
	doi = {10.1093/bib/bby040},
	author = {Amadoz, Alicia and Hidalgo, Marta R and Cubuk, Cankut and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin}
}
@article {1198,
	title = {Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.},
	journal = {Stress (Amsterdam, Netherlands)},
	year = {2016},
	month = {2016 Mar 7},
	pages = {1-11},
	abstract = {Chronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus.},
	keywords = {Adipose tissue, insulin, IRS1, IRS2, metabolic syndrome, obesity, pathway analysis},
	issn = {1607-8888},
	doi = {10.3109/10253890.2016.1151491},
	url = {http://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists20},
	author = {Sanghez, Valentina and Cubuk, Cankut and Sebasti{\'a}n-Leon, Patricia and Carobbio, Stefania and Dopazo, Joaquin and Vidal-Puig, Antonio and Bartolomucci, Alessandro}
}
