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1.  Metabolomics enables precision medicine: “A White Paper, Community Perspective” 
Metabolomics  2016;12(9):149.
Introduction: Background to metabolomics
Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or “-omics” level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person’s metabolic state provides a close representation of that individual’s overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates.
Objectives of White Paper—expected treatment outcomes and metabolomics enabling tool for precision medicine
We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject’s response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient’s metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine.
Conclusions: Key scientific concepts and recommendations for precision medicine
Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its “Precision Medicine and Pharmacometabolomics Task Group”, with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.
doi:10.1007/s11306-016-1094-6
PMCID: PMC5009152  PMID: 27642271
Metabolomics; Metabonomics; Pharmacometabolomics; Pharmacometabonomics; Precision medicine; Personalized medicine
2.  Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition 
Pharmacological research  2015;102:218-234.
Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimise its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and Reactive Oxygen Species production were analysed in A549 cells. FOXO3a subcellular localisation was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24 h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin.
doi:10.1016/j.phrs.2015.09.009
PMCID: PMC4850087  PMID: 26375988
Methylseleninic acid; Selenium; FOXO; Akt; PI3K; Cisplatin
3.  HepatoDyn: A Dynamic Model of Hepatocyte Metabolism That Integrates 13C Isotopomer Data 
PLoS Computational Biology  2016;12(4):e1004899.
The liver performs many essential metabolic functions, which can be studied using computational models of hepatocytes. Here we present HepatoDyn, a highly detailed dynamic model of hepatocyte metabolism. HepatoDyn includes a large metabolic network, highly detailed kinetic laws, and is capable of dynamically simulating the redox and energy metabolism of hepatocytes. Furthermore, the model was coupled to the module for isotopic label propagation of the software package IsoDyn, allowing HepatoDyn to integrate data derived from 13C based experiments. As an example of dynamical simulations applied to hepatocytes, we studied the effects of high fructose concentrations on hepatocyte metabolism by integrating data from experiments in which rat hepatocytes were incubated with 20 mM glucose supplemented with either 3 mM or 20 mM fructose. These experiments showed that glycogen accumulation was significantly lower in hepatocytes incubated with medium supplemented with 20 mM fructose than in hepatocytes incubated with medium supplemented with 3 mM fructose. Through the integration of extracellular fluxes and 13C enrichment measurements, HepatoDyn predicted that this phenomenon can be attributed to a depletion of cytosolic ATP and phosphate induced by high fructose concentrations in the medium.
Author Summary
Despite the key role of hepatocytes in carbohydrate and lipid homeostasis, available dynamic models of hepatocyte metabolism tend to be limited to a single pathway and/or are based on assumptions of constant concentrations of key metabolites involved in redox and energy metabolism (ATP, NAD, NADPH etc.). Furthermore, most dynamic models are unable to integrate information from 13C based experiments. 13C based experiments allow us to infer the relative activity of alternative pathways and hence are highly useful for indicating flux distributions. To overcome these limitations, we developed HepatoDyn, a dynamic model of hepatic metabolism. HepatoDyn uses a large metabolic network including key pathways such as glycolysis, the Krebs cycle, the pentose phosphate pathway and fatty acid metabolism, and dynamically models the concentrations of metabolites involved in the redox and energy metabolism of hepatocytes. In addition, the model was coupled to the label propagation module of the package IsoDyn, allowing it to integrate data from 13C based experiments to assist in the parametrization process. These features make HepatoDyn a powerful tool for studying the dynamics of hepatocyte metabolism.
doi:10.1371/journal.pcbi.1004899
PMCID: PMC4849781  PMID: 27124774
4.  Maslinic Acid, a Natural Triterpene, Induces a Death Receptor-Mediated Apoptotic Mechanism in Caco-2 p53-Deficient Colon Adenocarcinoma Cells 
PLoS ONE  2016;11(1):e0146178.
Maslinic acid (MA) is a natural triterpene present in high concentrations in the waxy skin of olives. We have previously reported that MA induces apoptotic cell death via the mitochondrial apoptotic pathway in HT29 colon cancer cells. Here, we show that MA induces apoptosis in Caco-2 colon cancer cells via the extrinsic apoptotic pathway in a dose-dependent manner. MA triggered a series of effects associated with apoptosis, including the cleavage of caspases -8 and -3, and increased the levels of t-Bid within a few hours of its addition to the culture medium. MA had no effect on the expression of the Bax protein, release of cytochrome-c or on the mitochondrial membrane potential. This suggests that MA triggered the extrinsic apoptotic pathway in this cell type, as opposed to the intrinsic pathway found in the HT29 colon-cancer cell line. Our results suggest that the apoptotic mechanism induced in Caco-2 may be different from that found in HT29 colon-cancer cells, and that in Caco-2 cells MA seems to work independently of p53. Natural antitumoral agents capable of activating both the extrinsic and intrinsic apoptotic pathways could be of great use in treating colon-cancer of whatever origin.
doi:10.1371/journal.pone.0146178
PMCID: PMC4709006  PMID: 26751572
5.  ChainRank, a chain prioritisation method for contextualisation of biological networks 
BMC Bioinformatics  2016;17:17.
Background
Advances in high throughput technologies and growth of biomedical knowledge have contributed to an exponential increase in associative data. These data can be represented in the form of complex networks of biological associations, which are suitable for systems analyses. However, these networks usually lack both, context specificity in time and space as well as the distinctive borders, which are usually assigned in the classical pathway view of molecular events (e.g. signal transduction). This complexity and high interconnectedness call for automated techniques that can identify smaller targeted subnetworks specific to a given research context (e.g. a disease scenario).
Results
Our method, named ChainRank, finds relevant subnetworks by identifying and scoring chains of interactions that link specific network components. Scores can be generated from integrating multiple general and context specific measures (e.g. experimental molecular data from expression to proteomics and metabolomics, literature evidence, network topology). The performance of the novel ChainRank method was evaluated on recreating selected signalling pathways from a human protein interaction network. Specifically, we recreated skeletal muscle specific signaling networks in healthy and chronic obstructive pulmonary disease (COPD) contexts. The analysis showed that ChainRank can identify main mediators of context specific molecular signalling. An improvement of up to factor 2.5 was shown in the precision of finding proteins of the recreated pathways compared to random simulation.
Conclusions
ChainRank provides a framework, which can integrate several user-defined scores and evaluate their combined effect on ranking interaction chains linking input data sets. It can be used to contextualise networks, identify signaling and regulatory path amongst targeted genes or to analyse synthetic lethality in the context of anticancer therapy. ChainRank is implemented in R programming language and freely available at https://github.com/atenyi/ChainRank.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0864-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-015-0864-x
PMCID: PMC4700624  PMID: 26729273
Biological networks; Protein-protein interaction; Data integration; Filtering; Computational biology; Bioinformatics; Systems biology; COPD
6.  COordination of Standards in MetabOlomicS (COSMOS): facilitating integrated metabolomics data access 
Metabolomics  2015;11(6):1587-1597.
Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative ‘coordination of standards in metabolomics’ (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities’ participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards.
doi:10.1007/s11306-015-0810-y
PMCID: PMC4605977  PMID: 26491418
Metabolomics; Metabonomics; Data standards; Data exchange; e-Infrastructure; Coordination and data sharing community
7.  Sampling with poling-based flux balance analysis: optimal versus sub-optimal flux space analysis of Actinobacillus succinogenes 
BMC Bioinformatics  2015;16(1):49.
Background
Flux balance analysis is traditionally implemented to identify the maximum theoretical flux for some specified reaction and a single distribution of flux values for all the reactions present which achieve this maximum value. However it is well known that the uncertainty in reaction networks due to branches, cycles and experimental errors results in a large number of combinations of internal reaction fluxes which can achieve the same optimal flux value.
Results
In this work, we have modified the applied linear objective of flux balance analysis to include a poling penalty function, which pushes each new set of reaction fluxes away from previous solutions generated. Repeated poling-based flux balance analysis generates a sample of different solutions (a characteristic set), which represents all the possible functionality of the reaction network. Compared to existing sampling methods, for the purpose of generating a relatively “small” characteristic set, our new method is shown to obtain a higher coverage than competing methods under most conditions.
The influence of the linear objective function on the sampling (the linear bias) constrains optimisation results to a subspace of optimal solutions all producing the same maximal fluxes. Visualisation of reaction fluxes plotted against each other in 2 dimensions with and without the linear bias indicates the existence of correlations between fluxes. This method of sampling is applied to the organism Actinobacillus succinogenes for the production of succinic acid from glycerol.
Conclusions
A new method of sampling for the generation of different flux distributions (sets of individual fluxes satisfying constraints on the steady-state mass balances of intermediates) has been developed using a relatively simple modification of flux balance analysis to include a poling penalty function inside the resulting optimisation objective function. This new methodology can achieve a high coverage of the possible flux space and can be used with and without linear bias to show optimal versus sub-optimal solution spaces. Basic analysis of the Actinobacillus succinogenes system using sampling shows that in order to achieve the maximal succinic acid production CO2 must be taken into the system. Solutions involving release of CO2 all give sub-optimal succinic acid production.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0476-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-015-0476-5
PMCID: PMC4350952  PMID: 25887116
Flux sampling; Optimisation; Flux balance analysis
8.  Biomedical research in a Digital Health Framework 
Journal of Translational Medicine  2014;12(Suppl 2):S10.
This article describes a Digital Health Framework (DHF), benefitting from the lessons learnt during the three-year life span of the FP7 Synergy-COPD project. The DHF aims to embrace the emerging requirements - data and tools - of applying systems medicine into healthcare with a three-tier strategy articulating formal healthcare, informal care and biomedical research. Accordingly, it has been constructed based on three key building blocks, namely, novel integrated care services with the support of information and communication technologies, a personal health folder (PHF) and a biomedical research environment (DHF-research). Details on the functional requirements and necessary components of the DHF-research are extensively presented. Finally, the specifics of the building blocks strategy for deployment of the DHF, as well as the steps toward adoption are analyzed. The proposed architectural solutions and implementation steps constitute a pivotal strategy to foster and enable 4P medicine (Predictive, Preventive, Personalized and Participatory) in practice and should provide a head start to any community and institution currently considering to implement a biomedical research platform.
doi:10.1186/1479-5876-12-S2-S10
PMCID: PMC4255881  PMID: 25472554
Biomedical Research; Chronic care; Clinical Decision Support Systems; Integrated Health Care Systems; Patient Decision Support Systems; Personal Health Folder
9.  Workforce preparation: the Biohealth computing model for Master and PhD students 
Journal of Translational Medicine  2014;12(Suppl 2):S11.
The article addresses the strategic role of workforce preparation in the process of adoption of Systems Medicine as a driver of biomedical research in the new health paradigm. It reports on relevant initiatives, like CASyM, fostering Systems Medicine at EU level. The chapter focuses on the BioHealth Computing Program as a reference for multidisciplinary training of future systems-oriented researchers describing the productive interactions with the Synergy-COPD project.
doi:10.1186/1479-5876-12-S2-S11
PMCID: PMC4255883  PMID: 25472654
Biomedical Research; Education; Integrated Health Care Systems; Master; PhD; Professionals; Systems Medicine; Training
10.  Predictive medicine: outcomes, challenges and opportunities in the Synergy-COPD project 
Journal of Translational Medicine  2014;12(Suppl 2):S12.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a major challenge for healthcare. Heterogeneities in clinical manifestations and in disease progression are relevant traits in COPD with impact on patient management and prognosis. It is hypothesized that COPD heterogeneity results from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering.
Objectives
To assess the potential of systems medicine to better understand non-pulmonary determinants of COPD heterogeneity. To transfer acquired knowledge to healthcare enhancing subject-specific health risk assessment and stratification to improve management of chronic patients.
Method
Underlying mechanisms of skeletal muscle dysfunction and of co-morbidity clustering in COPD patients were explored with strategies combining deterministic modelling and network medicine analyses using the Biobridge dataset. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was done (ICD9-CM data from Medicare, 13 million people). A targeted network analysis using the two studies: skeletal muscle dysfunction and co-morbidity clustering explored shared pathways between them.
Results
(1) Evidence of abnormal regulation of pivotal skeletal muscle biological pathways and increased risk for co-morbidity clustering was observed in COPD; (2) shared abnormal pathway regulation between skeletal muscle dysfunction and co-morbidity clustering; and, (3) technological achievements of the projects were: (i) COPD Knowledge Base; (ii) novel modelling approaches; (iii) Simulation Environment; and, (iv) three layers of Clinical Decision Support Systems.
Conclusions
The project demonstrated the high potential of a systems medicine approach to address COPD heterogeneity. Limiting factors for the project development were identified. They were relevant to shape strategies fostering 4P Medicine for chronic patients. The concept of Digital Health Framework and the proposed roadmap for its deployment constituted relevant project outcomes.
doi:10.1186/1479-5876-12-S2-S12
PMCID: PMC4255885  PMID: 25472742
chronic diseases; co-morbidities; chronic obstructive pulmonary disease; information and communication technologies; modelling; network medicine; training
11.  Synergy-COPD: a systems approach for understanding and managing chronic diseases 
Journal of Translational Medicine  2014;12(Suppl 2):S2.
Chronic diseases (CD) are generating a dramatic societal burden worldwide that is expected to persist over the next decades. The challenges posed by the epidemics of CD have triggered a novel health paradigm with major consequences on the traditional concept of disease and with a profound impact on key aspects of healthcare systems.
We hypothesized that the development of a systems approach to understand CD together with the generation of an ecosystem to transfer the acquired knowledge into the novel healthcare scenario may contribute to a cost-effective enhancement of health outcomes. To this end, we designed the Synergy-COPD project wherein the heterogeneity of chronic obstructive pulmonary disease (COPD) was addressed as a use case representative of CD.
The current manuscript describes main features of the project design and the strategies put in place for its development, as well the expected outcomes during the project life-span. Moreover, the manuscript serves as introductory and unifying chapter of the different papers associated to the Supplement describing the characteristics, tools and the objectives of Synergy-COPD
doi:10.1186/1479-5876-12-S2-S2
PMCID: PMC4255903  PMID: 25472826
Chronic Diseases; Chronic Obstructive Pulmonary Disease; COPD; Integrated Care; ICT; Systems Medicine; Predictive Medicine; Telemedicine
12.  Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management 
Journal of Translational Medicine  2014;12(Suppl 2):S3.
Background and hypothesis
Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.
Objective and method
To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.
Results
(1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.
Conclusions
The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.
doi:10.1186/1479-5876-12-S2-S3
PMCID: PMC4255905  PMID: 25472887
Chronic diseases; COPD; Disease heterogeneity; Integrated Care; Predictive Medicine; Redox disequilibrium; Systems Medicine; VO2max
13.  Systems Medicine: from molecular features and models to the clinic in COPD 
Journal of Translational Medicine  2014;12(Suppl 2):S4.
Background and hypothesis
Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice.
Objective and method
Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework.
Results
In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice.
Conclusions
The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.
doi:10.1186/1479-5876-12-S2-S4
PMCID: PMC4255907  PMID: 25471042
Chronic diseases; COPD; Disease heterogeneity; Systems Medicine; Predictive Modeling; Co-morbidity
14.  The COPD Knowledge Base: enabling data analysis and computational simulation in translational COPD research 
Journal of Translational Medicine  2014;12(Suppl 2):S6.
Background
Previously we generated a chronic obstructive pulmonary disease (COPD) specific knowledge base (http://www.copdknowledgebase.eu) from clinical and experimental data, text-mining results and public databases. This knowledge base allowed the retrieval of specific molecular networks together with integrated clinical and experimental data.
Results
The COPDKB has now been extended to integrate over 40 public data sources on functional interaction (e.g. signal transduction, transcriptional regulation, protein-protein interaction, gene-disease association). In addition we integrated COPD-specific expression and co-morbidity networks connecting over 6 000 genes/proteins with physiological parameters and disease states. Three mathematical models describing different aspects of systemic effects of COPD were connected to clinical and experimental data. We have completely redesigned the technical architecture of the user interface and now provide html and web browser-based access and form-based searches. A network search enables the use of interconnecting information and the generation of disease-specific sub-networks from general knowledge. Integration with the Synergy-COPD Simulation Environment enables multi-scale integrated simulation of individual computational models while integration with a Clinical Decision Support System allows delivery into clinical practice.
Conclusions
The COPD Knowledge Base is the only publicly available knowledge resource dedicated to COPD and combining genetic information with molecular, physiological and clinical data as well as mathematical modelling. Its integrated analysis functions provide overviews about clinical trends and connections while its semantically mapped content enables complex analysis approaches. We plan to further extend the COPDKB by offering it as a repository to publish and semantically integrate data from relevant clinical trials. The COPDKB is freely available after registration at http://www.copdknowledgebase.eu.
doi:10.1186/1479-5876-12-S2-S6
PMCID: PMC4255911  PMID: 25471253
15.  Oxygen Pathway Modeling Estimates High Reactive Oxygen Species Production above the Highest Permanent Human Habitation 
PLoS ONE  2014;9(11):e111068.
The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po2 (). Because depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the “death zone” in mountaineering.
doi:10.1371/journal.pone.0111068
PMCID: PMC4222897  PMID: 25375931
16.  13C metabolic flux analysis shows that resistin impairs the metabolic response to insulin in L6E9 myotubes 
BMC Systems Biology  2014;8:109.
Background
It has been suggested that the adipokine resistin links obesity and insulin resistance, although how resistin acts on muscle metabolism is controversial. We aimed to quantitatively analyse the effects of resistin on the glucose metabolic flux profile and on insulin response in L6E9 myotubes at the metabolic level using a tracer-based metabolomic approach and our in-house developed software, Isodyn.
Results
Resistin significantly increased glucose uptake and glycolysis, altering pyruvate utilisation by the cell. In the presence of resistin, insulin only slightly increased glucose uptake and glycolysis, and did not alter the flux profile around pyruvate induced by resistin. Resistin prevented the increase in gene expression in pyruvate dehydrogenase-E1 and the sharp decrease in gene expression in cytosolic phosphoenolpyruvate carboxykinase-1 induced by insulin.
Conclusions
These data suggest that resistin impairs the metabolic activation of insulin. This impairment cannot be explained by the activity of a single enzyme, but instead due to reorganisation of the whole metabolic flux distribution.
doi:10.1186/s12918-014-0109-z
PMCID: PMC4363945  PMID: 25217974
Resistin; Insulin resistance; Glucose metabolism; Fluxomics; Bioinformatics; Tracer-based metabolomics
17.  Cardiovascular Disease-Related Parameters and Oxidative Stress in SHROB Rats, a Model for Metabolic Syndrome 
PLoS ONE  2014;9(8):e104637.
SHROB rats have been suggested as a model for metabolic syndrome (MetS) as a situation prior to the onset of CVD or type-2 diabetes, but information on descriptive biochemical parameters for this model is limited. Here, we extensively evaluate parameters related to CVD and oxidative stress (OS) in SHROB rats. SHROB rats were monitored for 15 weeks and compared to a control group of Wistar rats. Body weight was recorded weekly. At the end of the study, parameters related to CVD and OS were evaluated in plasma, urine and different organs. SHROB rats presented statistically significant differences from Wistar rats in CVD risk factors: total cholesterol, LDL-cholesterol, triglycerides, apoA1, apoB100, abdominal fat, insulin, blood pressure, C-reactive protein, ICAM-1 and PAI-1. In adipose tissue, liver and brain, the endogenous antioxidant systems were activated, yet there was no significant oxidative damage to lipids (MDA) or proteins (carbonylation). We conclude that SHROB rats present significant alterations in parameters related to inflammation, endothelial dysfunction, thrombotic activity, insulin resistance and OS measured in plasma as well as enhanced redox defence systems in vital organs that will be useful as markers of MetS and CVD for nutrition interventions.
doi:10.1371/journal.pone.0104637
PMCID: PMC4130542  PMID: 25115868
18.  Effects of Cadmium and Mercury on the Upper Part of Skeletal Muscle Glycolysis in Mice 
PLoS ONE  2014;9(1):e80018.
The effects of pre-incubation with mercury (Hg2+) and cadmium (Cd2+) on the activities of individual glycolytic enzymes, on the flux and on internal metabolite concentrations of the upper part of glycolysis were investigated in mouse muscle extracts. In the range of metal concentrations analysed we found that only hexokinase and phosphofructokinase, the enzymes that shared the control of the flux, were inhibited by Hg2+ and Cd2+. The concentrations of the internal metabolites glucose-6-phosphate and fructose-6-phosphate did not change significantly when Hg2+ and Cd2+ were added. A mathematical model was constructed to explore the mechanisms of inhibition of Hg2+ and Cd2+ on hexokinase and phosphofructokinase. Equations derived from detailed mechanistic models for each inhibition were fitted to the experimental data. In a concentration-dependent manner these equations describe the observed inhibition of enzyme activity. Under the conditions analysed, the integral model showed that the simultaneous inhibition of hexokinase and phosphofructokinase explains the observation that the concentrations of glucose-6-phosphate and fructose-6-phosphate did not change as the heavy metals decreased the glycolytic flux.
doi:10.1371/journal.pone.0080018
PMCID: PMC3904826  PMID: 24489641
19.  Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle 
Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hallmark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM (the calcein acetoxymethyl-ester) is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phosphate pathway was significantly altered. To elucidate whether these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.
doi:10.1007/s11306-011-0328-x
PMCID: PMC3361763  PMID: 22661920
Cyclin-dependent kinases; CDK-inhibitor; Tracer-based metabolomics; Pentose phosphate pathway; Phase-plane analysis
20.  Maslinic Acid-Enriched Diet Decreases Intestinal Tumorigenesis in ApcMin/+ Mice through Transcriptomic and Metabolomic Reprogramming 
PLoS ONE  2013;8(3):e59392.
Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in ApcMin/+ mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid–supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in ApcMin/+ mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the ApcMin/+ mice model, suggesting its chemopreventive potential against colorectal cancer.
doi:10.1371/journal.pone.0059392
PMCID: PMC3601079  PMID: 23527181
21.  Multistationary and Oscillatory Modes of Free Radicals Generation by the Mitochondrial Respiratory Chain Revealed by a Bifurcation Analysis 
PLoS Computational Biology  2012;8(9):e1002700.
The mitochondrial electron transport chain transforms energy satisfying cellular demand and generates reactive oxygen species (ROS) that act as metabolic signals or destructive factors. Therefore, knowledge of the possible modes and bifurcations of electron transport that affect ROS signaling provides insight into the interrelationship of mitochondrial respiration with cellular metabolism. Here, a bifurcation analysis of a sequence of the electron transport chain models of increasing complexity was used to analyze the contribution of individual components to the modes of respiratory chain behavior. Our algorithm constructed models as large systems of ordinary differential equations describing the time evolution of the distribution of redox states of the respiratory complexes. The most complete model of the respiratory chain and linked metabolic reactions predicted that condensed mitochondria produce more ROS at low succinate concentration and less ROS at high succinate levels than swelled mitochondria. This prediction was validated by measuring ROS production under various swelling conditions. A numerical bifurcation analysis revealed qualitatively different types of multistationary behavior and sustained oscillations in the parameter space near a region that was previously found to describe the behavior of isolated mitochondria. The oscillations in transmembrane potential and ROS generation, observed in living cells were reproduced in the model that includes interaction of respiratory complexes with the reactions of TCA cycle. Whereas multistationarity is an internal characteristic of the respiratory chain, the functional link of respiration with central metabolism creates oscillations, which can be understood as a means of auto-regulation of cell metabolism.
Author Summary
The mitochondrial respiratory chain shows a variety of modes of behavior. In living cells, flashes of ROS production and oscillations accompanied by a decrease of transmembrane potential can be registered. The mechanisms of such complex behavior are difficult to rationalize without a mathematical formalization of mitochondrial respiration. Our most complete model of mitochondrial respiration accounts for the details of electron transport, reproducing the observed types of behavior, which includes the existence of multiple steady states and periodic oscillations. This most detailed model contains hundreds of differential equations, and such complexity makes it difficult to grasp the main determinants of its behavior. Therefore the full model was reduced to a simplified description of complex III only, and numerical bifurcation analysis was used to study its behavior. Then the evolution of its behavior was traced in a sequence of models with increasing complexity leading back to the full model. This analysis revealed the mechanism of switching between the modes of behavior and the conditions for persistence in a given state, which defines ATP production, ROS signaling and destructive effects. This is important for understanding the biochemical basics of many systemic diseases.
doi:10.1371/journal.pcbi.1002700
PMCID: PMC3447950  PMID: 23028295
22.  Diphenyl Urea Derivatives as Inhibitors of Transketolase: A Structure-Based Virtual Screening 
PLoS ONE  2012;7(3):e32276.
Transketolase is an enzyme involved in a critical step of the non-oxidative branch of the pentose phosphate pathway whose inhibition could lead to new anticancer drugs. Here, we report new human transketolase inhibitors, based on the phenyl urea scaffold, found by applying structure-based virtual screening. These inhibitors are designed to cover a hot spot in the dimerization interface of the homodimer of the enzyme, providing for the first time compounds with a suggested novel binding mode not based on mimicking the thiamine pyrophosphate cofactor.
doi:10.1371/journal.pone.0032276
PMCID: PMC3293897  PMID: 22403640
23.  Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions 
BMC Systems Biology  2011;5:175.
Background
Stable isotope tracers are used to assess metabolic flux profiles in living cells. The existing methods of measurement average out the isotopic isomer distribution in metabolites throughout the cell, whereas the knowledge of compartmental organization of analyzed pathways is crucial for the evaluation of true fluxes. That is why we accepted a challenge to create a software tool that allows deciphering the compartmentation of metabolites based on the analysis of average isotopic isomer distribution.
Results
The software Isodyn, which simulates the dynamics of isotopic isomer distribution in central metabolic pathways, was supplemented by algorithms facilitating the transition between various analyzed metabolic schemes, and by the tools for model discrimination. It simulated 13C isotope distributions in glucose, lactate, glutamate and glycogen, measured by mass spectrometry after incubation of hepatocytes in the presence of only labeled glucose or glucose and lactate together (with label either in glucose or lactate). The simulations assumed either a single intracellular hexose phosphate pool, or also channeling of hexose phosphates resulting in a different isotopic composition of glycogen. Model discrimination test was applied to check the consistency of both models with experimental data. Metabolic flux profiles, evaluated with the accepted model that assumes channeling, revealed the range of changes in metabolic fluxes in liver cells.
Conclusions
The analysis of compartmentation of metabolic networks based on the measured 13C distribution was included in Isodyn as a routine procedure. The advantage of this implementation is that, being a part of evaluation of metabolic fluxes, it does not require additional experiments to study metabolic compartmentation. The analysis of experimental data revealed that the distribution of measured 13C-labeled glucose metabolites is inconsistent with the idea of perfect mixing of hexose phosphates in cytosol. In contrast, the observed distribution indicates the presence of a separate pool of hexose phosphates that is channeled towards glycogen synthesis.
doi:10.1186/1752-0509-5-175
PMCID: PMC3292525  PMID: 22034837
24.  Transketolase-Like 1 Expression Is Modulated during Colorectal Cancer Progression and Metastasis Formation 
PLoS ONE  2011;6(9):e25323.
Background
Transketolase-like 1 (TKTL1) induces glucose degradation through anaerobic pathways, even in presence of oxygen, favoring the malignant aerobic glycolytic phenotype characteristic of tumor cells. As TKTL1 appears to be a valid biomarker for cancer prognosis, the aim of the current study was to correlate its expression with tumor stage, probability of tumor recurrence and survival, in a series of colorectal cancer patients.
Methodolody/Principal Findings
Tumor tissues from 63 patients diagnosed with colorectal cancer at different stages of progression were analyzed for TKTL1 by immunohistochemistry. Staining was quantified by computational image analysis, and correlations between enzyme expression, local growth, lymph-node involvement and metastasis were assessed. The highest values for TKTL1 expression were detected in the group of stage III tumors, which showed significant differences from the other groups (Kruskal-Wallis test, P = 0.000008). Deeper analyses of T, N and M classifications revealed a weak correlation between local tumor growth and enzyme expression (Mann-Whitney test, P = 0.029), a significant association of the enzyme expression with lymph-node involvement (Mann-Whitney test, P = 0.0014) and a significant decrease in TKTL1 expression associated with metastasis (Mann-Whitney test, P = 0.0004).
Conclusions/Significance
To our knowledge, few studies have explored the association between variations in TKTL1 expression in the primary tumor and metastasis formation. Here we report downregulation of enzyme expression when metastasis appears, and a correlation between enzyme expression and regional lymph-node involvement in colon cancer. This finding may improve our understanding of metastasis and lead to new and more efficient therapies against cancer.
doi:10.1371/journal.pone.0025323
PMCID: PMC3181277  PMID: 21980427
25.  A Systems Biology Approach Identifies Molecular Networks Defining Skeletal Muscle Abnormalities in Chronic Obstructive Pulmonary Disease 
PLoS Computational Biology  2011;7(9):e1002129.
Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.
Author Summary
Chronic Obstructive Pulmonary Disease (COPD) is a major life threatening disease of the lungs, characterized by airflow limitation and chronic inflammation. Progressive reduction of the body muscle mass is a condition linked to COPD that significantly decreases quality of life and survival. Physical exercise has been proposed as a therapeutic option but its utility is still a matter of debate. The mechanisms underlying muscle wasting are also still largely unknown. The results presented in this paper show that diseased muscles are largely unable to coordinate the expression of muscle remodelling and bioenergetics pathways and that the cause of this phenomena may be tissue hypoxia. These findings contrast with current hypotheses based on the role of chronic inflammation and show that a mechanism based on an oxygen driven, epigenetic control of these two important functions may be an important disease mechanism.
doi:10.1371/journal.pcbi.1002129
PMCID: PMC3164707  PMID: 21909251

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