Semantics based approach for analyzing disease-target associations.

J Biomed Inform. 2016 Jun 24;

Authors: Kaalia R, Ghosh I

Abstract
BACKGROUND: A complex disease is caused by heterogeneous biological interactions between genes and their products along with the influence of environmental factors. There have been many attempts for understanding the cause of these diseases using experimental, statistical and computational methods. In the present work the objective is to address the challenge of representation and integration of information from heterogeneous biomedical aspects of a complex disease using semantics based approach.
METHODS: Semantic web technology is used to design Disease Association Ontology (DAO-db) for representation and integration of disease associated information with diabetes as the case study. The functional associations of disease genes are integrated using RDF graphs of DAO-db. Three semantic web based scoring algorithms (PageRank, HITS (Hyperlink Induced Topic Search) and HITS with semantic weights) are used to score the gene nodes on the basis of their functional interactions in the graph.
RESULTS: Disease Association Ontology for Diabetes (DAO-db) provides a standard ontology-driven platform for describing genes, proteins, pathways involved in diabetes and for integrating functional associations from various interaction levels (gene-disease, gene-pathway, gene-function, gene-cellular component and protein-protein interactions). An automatic instance loader module is also developed in present work that helps in adding instances to DAO-db on a large scale.
CONCLUSIONS: Our ontology provides a framework for querying and analyzing the disease associated information in the form of RDF graphs. The above developed methodology is used to predict novel potential targets involved in diabetes disease from the long list of loose (statistically associated) gene-disease associations.

PMID: 27349858 [PubMed - as supplied by publisher]

Where to now in cardiovascular disease prevention.

Atherosclerosis. 2016 Jun 18;

Authors: Najam O, Ray KK

Abstract
Clinical trials have been instrumental in reducing the morbidity and mortality associated with cardiovascular disease, especially in the developed world. Recently however this improvement has plateaued, highlighting the importance of optimising current strategies and considering alternative practises. Inequalities in global healthcare, the changing patient profile as a result of an obesity and diabetes epidemic, and inadequate utilisation of evidence-based treatments are partly responsible. Despite pharmacotherapies such as statins having substantial evidence for cardiovascular benefit, patient response may be variable with genetic factors thought to be partly responsible. Although randomised controlled trials remain the backbone of clinical research, they have limitations including time taken to complete a trial and the financial costs associated with it. In this opinion-based paper, we discuss some of the key considerations for the future of cardiovascular disease prevention.

PMID: 27350327 [PubMed - as supplied by publisher]

Impact of Long-Term Tiotropium Bromide Therapy on Annual Lung Function Decline in Adult Patients with Cystic Fibrosis.

PLoS One. 2016;11(6):e0158193

Authors: Brandt C, Thronicke A, Roehmel JF, Krannich A, Staab D, Schwarz C

Abstract
BACKGROUND: Chronic lung disease is the leading cause of death in patients with Cystic Fibrosis (CF) and is often treated with bronchodilators. It is not known whether long-term tiotropium bromide treatment may have a positive impact on lung function.
METHODS: This retrospective cohort study estimated annual lung function decline utilizing longitudinal data for forced expiratory volume in 1 s (FEV1).
RESULTS: A total of 160 adult patients with CF were analyzed. The subjects treated for 24 months with tiotropium bromide had a significantly slower decline of mean annual change of FEV1 (treated: -0.3±4.0%; control: -2.3±5.0%; p = 0.0130). In patients with FEV1 ≥70% predicted, long-term tiotropium bromide treatment was associated with greater improvements in annual lung function decline (FEV1 ≥70% predicted: treated: +0.5±4.7%; control: -4.0±6.3%; p = 0.0132; FEV1 50-69% predicted: treated: -0.5±4.4%; control: -0.8±3.8%; p = 0.7142; FEV1 ≤49% predicted: treated: -0.6±3.4%; control: -2.4±4.8%; p = 0.0898).
CONCLUSION: This study suggests that long-term tiotropium bromide treatment may be associated with reduced annual decline of FEV1 in patients with CF, particularly in adults with a mild degree of severity.

PMID: 27351829 [PubMed - as supplied by publisher]

Bacterial evolution in PCD and CF patients follows the same mutational steps.

Sci Rep. 2016;6:28732

Authors: Sommer LM, Alanin MC, Marvig RL, Nielsen KG, Høiby N, von Buchwald C, Molin S, Johansen HK

Abstract
Infections with Pseudomonas aeruginosa increase morbidity in primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) patients. Both diseases are associated with a defect of the mucociliary clearance; in PCD caused by non-functional cilia, in CF by changed mucus. Whole genome sequencing of P. aeruginosa isolates from CF patients has shown that persistence of clonal lineages in the airways is facilitated by genetic adaptation. It is unknown whether this also applies to P. aeruginosa airway infections in PCD. We compared within-host evolution of P. aeruginosa in PCD and CF patients. P. aeruginosa isolates from 12 PCD patients were whole genome sequenced and phenotypically characterised. Ten out of 12 PCD patients were infected with persisting clone types. We identified convergent evolution in eight genes, which are also important for persistent infections in CF airways: genes related to antibiotic resistance, quorum sensing, motility, type III secretion and mucoidity. We document phenotypic and genotypic parallelism in the evolution of P. aeruginosa across infected patients with different genetic disorders. The parallel changes and convergent adaptation and evolution may be caused by similar selective forces such as the intensive antibiotic treatment and the inflammatory response, which drive the evolutionary processes.

PMID: 27349973 [PubMed - in process]

Treatment of pulmonary exacerbations in cystic fibrosis-could do better?

Paediatr Respir Rev. 2016 Jun 15;

Authors: Smyth A

Abstract
This article describes the nature and significance of pulmonary exacerbations in cystic fibrosis (CF). The effectiveness and safety of current exacerbation treatment are explored. The article concludes with a summary of clinical trials (completed and ongoing) which aim to improve the efficacy and safety of exacerbation treatment.

PMID: 27349725 [PubMed - as supplied by publisher]

Lifestyle treatments in CF-the NHS should not pay.

Paediatr Respir Rev. 2016 Jun 15;

Authors: Hull J

Abstract
Lifestyle treatments can be defined as those which may have in impact on quality of life but do not affect health outcomes. Particular treatment options may be preferred by patients because they are for example, easier to use, take up less time or taste better. The impact on adherence needs to be considered. Treatment options that promote greater adherence to therapy are likely to be more efficacious and so are not, by definition, lifestyle treatments. The NHS is facing unprecedented financial pressure and resources are limited. When lifestyle treatments are more expensive than standard therapy, they should not be funded by the NHS.

PMID: 27349724 [PubMed - as supplied by publisher]

Abnormal activation of calpain and protein kinase Cα promotes a constitutive release of matrix metalloproteinase 9 in peripheral blood mononuclear cells from cystic fibrosis patients.

Arch Biochem Biophys. 2016 Jun 24;

Authors: Averna M, Bavestrello M, Cresta F, Pedrazzi M, De Tullio R, Minicucci L, Sparatore B, Salamino F, Pontremoli S, Melloni E

Abstract
Matrix metalloproteinase 9 (MMP9) is physiologically involved in remodeling the extracellular matrix components but its abnormal release has been observed in several human pathologies. We here report that peripheral blood mononuclear cells (PBMCs), isolated from cystic fibrosis (CF) patients homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR), express constitutively and release at high rate MMP9 due to the alteration in their intracellular Ca(2+) homeostasis. This spontaneous and sustained MMP9 secretion may contribute to the accumulation of this protease in fluids of CF patients. Conversely, in PBMCs isolated from healthy donors, expression and secretion of MMP9 are undetectable but can be evoked, after 12 h of culture, by paracrine stimulation which also promotes an increase in [Ca(2+)]i. We also demonstrate that in both CF and control PBMCs the Ca(2+)-dependent MMP9 secretion is mediated by the concomitant activation of calpain and protein kinase Cα (PKCα), and that MMP9 expression involves extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation. Our results are supported by the fact that either the inhibition of Ca(2+) entry or chelation of [Ca(2+)]i as well as the inhibition of single components of the signaling pathway or the restoration of CFTR activity all promote the reduction of MMP9 secretion.

PMID: 27349634 [PubMed - as supplied by publisher]

The complexities and versatility of the RAS-to-ERK signalling system in normal and cancer cells.

Semin Cell Dev Biol. 2016 Jun 24;

Authors: Fey D, Matallanas D, Rauch J, Rukhlenko OS, Kholodenko BN

Abstract
The intricate dynamic control and plasticity of RAS to ERK mitogenic, survival and apoptotic signalling has mystified researches for more than 30 years. Therapeutics targeting the oncogenic aberrations within this pathway often yield unsatisfactory, even undesired results, as in the case of paradoxical ERK activation in response to RAF inhibition. A direct approach of inhibiting single oncogenic proteins misses the dynamic network context governing the network signal processing. In this review, we discuss the signalling behaviour of RAS and RAF proteins in normal and in cancer cells, and the emerging systems-level properties of the RAS-to-ERK signalling network. We argue that to understand the dynamic complexities of this control system, mathematical models including mechanistic detail are required. Looking into the future, these dynamic models will build the foundation upon which more effective, rational approaches to cancer therapy will be developed.

PMID: 27350026 [PubMed - as supplied by publisher]

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide.

Clin Exp Metastasis. 2016 Jun 27;

Authors: Jeanne A, Boulagnon-Rombi C, Devy J, Théret L, Fichel C, Bouland N, Diebold MD, Martiny L, Schneider C, Dedieu S

Abstract
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.

PMID: 27349907 [PubMed - as supplied by publisher]

Gene Network Rewiring to Study Melanoma Stage Progression and Elements Essential for Driving Melanoma.

PLoS One. 2015;10(11):e0142443

Authors: Kaushik A, Bhatia Y, Ali S, Gupta D

Abstract
Metastatic melanoma patients have a poor prognosis, mainly attributable to the underlying heterogeneity in melanoma driver genes and altered gene expression profiles. These characteristics of melanoma also make the development of drugs and identification of novel drug targets for metastatic melanoma a daunting task. Systems biology offers an alternative approach to re-explore the genes or gene sets that display dysregulated behaviour without being differentially expressed. In this study, we have performed systems biology studies to enhance our knowledge about the conserved property of disease genes or gene sets among mutually exclusive datasets representing melanoma progression. We meta-analysed 642 microarray samples to generate melanoma reconstructed networks representing four different stages of melanoma progression to extract genes with altered molecular circuitry wiring as compared to a normal cellular state. Intriguingly, a majority of the melanoma network-rewired genes are not differentially expressed and the disease genes involved in melanoma progression consistently modulate its activity by rewiring network connections. We found that the shortlisted disease genes in the study show strong and abnormal network connectivity, which enhances with the disease progression. Moreover, the deviated network properties of the disease gene sets allow ranking/prioritization of different enriched, dysregulated and conserved pathway terms in metastatic melanoma, in agreement with previous findings. Our analysis also reveals presence of distinct network hubs in different stages of metastasizing tumor for the same set of pathways in the statistically conserved gene sets. The study results are also presented as a freely available database at http://bioinfo.icgeb.res.in/m3db/. The web-based database resource consists of results from the analysis presented here, integrated with cytoscape web and user-friendly tools for visualization, retrieval and further analysis.

PMID: 26558755 [PubMed - indexed for MEDLINE]

Mapping nonlinear receptive field structure in primate retina at single cone resolution.

Elife. 2015;4

Authors: Freeman J, Field GD, Li PH, Greschner M, Gunning DE, Mathieson K, Sher A, Litke AM, Paninski L, Simoncelli EP, Chichilnisky EJ

Abstract
The function of a neural circuit is shaped by the computations performed by its interneurons, which in many cases are not easily accessible to experimental investigation. Here, we elucidate the transformation of visual signals flowing from the input to the output of the primate retina, using a combination of large-scale multi-electrode recordings from an identified ganglion cell type, visual stimulation targeted at individual cone photoreceptors, and a hierarchical computational model. The results reveal nonlinear subunits in the circuity of OFF midget ganglion cells, which subserve high-resolution vision. The model explains light responses to a variety of stimuli more accurately than a linear model, including stimuli targeted to cones within and across subunits. The recovered model components are consistent with known anatomical organization of midget bipolar interneurons. These results reveal the spatial structure of linear and nonlinear encoding, at the resolution of single cells and at the scale of complete circuits.

PMID: 26517879 [PubMed - indexed for MEDLINE]

Quantitative time-resolved analysis reveals intricate, differential regulation of standard- and immuno-proteasomes.

Elife. 2015;4:e07545

Authors: Liepe J, Holzhütter HG, Bellavista E, Kloetzel PM, Stumpf MP, Mishto M

Abstract
Proteasomal protein degradation is a key determinant of protein half-life and hence of cellular processes ranging from basic metabolism to a host of immunological processes. Despite its importance the mechanisms regulating proteasome activity are only incompletely understood. Here we use an iterative and tightly integrated experimental and modelling approach to develop, explore and validate mechanistic models of proteasomal peptide-hydrolysis dynamics. The 20S proteasome is a dynamic enzyme and its activity varies over time because of interactions between substrates and products and the proteolytic and regulatory sites; the locations of these sites and the interactions between them are predicted by the model, and experimentally supported. The analysis suggests that the rate-limiting step of hydrolysis is the transport of the substrates into the proteasome. The transport efficiency varies between human standard- and immuno-proteasomes thereby impinging upon total degradation rate and substrate cleavage-site usage.

PMID: 26393687 [PubMed - indexed for MEDLINE]

A balance of positive and negative regulators determines the pace of the segmentation clock.

Elife. 2015;4:e05842

Authors: Wiedermann G, Bone RA, Silva JC, Bjorklund M, Murray PJ, Dale JK

Abstract
Somitogenesis is regulated by a molecular oscillator that drives dynamic gene expression within the pre-somitic mesoderm. Previous mathematical models of the somitogenesis clock that invoke the mechanism of delayed negative feedback predict that its oscillation period depends on the sum of delays inherent to negative-feedback loops and inhibitor half-lives. We develop a mathematical model that explores the possibility that positive feedback also plays a role in determining the period of clock oscillations. The model predicts that increasing the half-life of the positive regulator, Notch intracellular domain (NICD), can lead to elevated NICD levels and an increase in the oscillation period. To test this hypothesis, we investigate a phenotype induced by various small molecule inhibitors in which the clock is slowed. We observe elevated levels and a prolonged half-life of NICD. Reducing NICD production rescues these effects. These data provide the first indication that tight control of the turnover of positive as well as negative regulators of the clock determines its periodicity.

PMID: 26357015 [PubMed - indexed for MEDLINE]

Hemostasis and thrombosis beyond biochemistry: roles of geometry, flow and diffusion.

Thromb Res. 2015 Oct;136(4):699-711

Authors: Panteleev MA, Dashkevich NM, Ataullakhanov FI

Abstract
An important trend in the modern concept of blood coagulation is the growing agreement that, in order to understand regulation of coagulation in vivo and disorders of its function, it is essential to take into account its spatial heterogeneity, diffusion, and flow. In a way, this suggests that the idea of the "coagulation cascade" itself becomes increasingly misleading because there is no such place in an organism where reactions of this cascade really co-exist: activation, propagation and termination of coagulation are regulated by different subsets of chemical reactions that have different spatial localization and depend on cofactors expressed by different cell types in different tissues, so that only diffusion and flow can link these distinct "compartments" together into the one functional system. Here we review the last two decades of evidence obtained from in vitro, in vivo and computational systems biology approaches. When combined, the data comprise into an adequately comprehensive picture of the spatial regulation and organization of blood coagulation. In addition to the basic insights into the regulatory mechanisms, these approaches provided interesting results in the fields of coagulation diagnostics and other applications. Finally, the remaining unresolved and conflicting issues in the spatiotemporal regulation of coagulation are discussed.

PMID: 26278966 [PubMed - indexed for MEDLINE]

Interplay of cell dynamics and epithelial tension during morphogenesis of the Drosophila pupal wing.

Elife. 2015;4:e07090

Authors: Etournay R, Popović M, Merkel M, Nandi A, Blasse C, Aigouy B, Brandl H, Myers G, Salbreux G, Jülicher F, Eaton S

Abstract
How tissue shape emerges from the collective mechanical properties and behavior of individual cells is not understood. We combine experiment and theory to study this problem in the developing wing epithelium of Drosophila. At pupal stages, the wing-hinge contraction contributes to anisotropic tissue flows that reshape the wing blade. Here, we quantitatively account for this wing-blade shape change on the basis of cell divisions, cell rearrangements and cell shape changes. We show that cells both generate and respond to epithelial stresses during this process, and that the nature of this interplay specifies the pattern of junctional network remodeling that changes wing shape. We show that patterned constraints exerted on the tissue by the extracellular matrix are key to force the tissue into the right shape. We present a continuum mechanical model that quantitatively describes the relationship between epithelial stresses and cell dynamics, and how their interplay reshapes the wing.

PMID: 26102528 [PubMed - indexed for MEDLINE]

Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage.

Ann Rheum Dis. 2016 Feb;75(2):449-58

Authors: Hui W, Young DA, Rowan AD, Xu X, Cawston TE, Proctor CJ

Abstract
OBJECTIVE: To use a computational approach to investigate the cellular and extracellular matrix changes that occur with age in the knee joints of mice.
METHODS: Knee joints from an inbred C57/BL1/6 (ICRFa) mouse colony were harvested at 3-30 months of age. Sections were stained with H&E, Safranin-O, Picro-sirius red and antibodies to matrix metalloproteinase-13 (MMP-13), nitrotyrosine, LC-3B, Bcl-2, and cleaved type II collagen used for immunohistochemistry. Based on this and other data from the literature, a computer simulation model was built using the Systems Biology Markup Language using an iterative approach of data analysis and modelling. Individual parameters were subsequently altered to assess their effect on the model.
RESULTS: A progressive loss of cartilage matrix occurred with age. Nitrotyrosine, MMP-13 and activin receptor-like kinase-1 (ALK1) staining in cartilage increased with age with a concomitant decrease in LC-3B and Bcl-2. Stochastic simulations from the computational model showed a good agreement with these data, once transforming growth factor-β signalling via ALK1/ALK5 receptors was included. Oxidative stress and the interleukin 1 pathway were identified as key factors in driving the cartilage breakdown associated with ageing.
CONCLUSIONS: A progressive loss of cartilage matrix and cellularity occurs with age. This is accompanied with increased levels of oxidative stress, apoptosis and MMP-13 and a decrease in chondrocyte autophagy. These changes explain the marked predisposition of joints to develop osteoarthritis with age. Computational modelling provides useful insights into the underlying mechanisms involved in age-related changes in musculoskeletal tissues.

PMID: 25475114 [PubMed - indexed for MEDLINE]

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("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

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These pubmed results were generated on 2016/06/28

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Inflammatory pathway network-based drug repositioning and molecular phenomics.

Mol Biosyst. 2016 Jun 27;

Authors: Gu J, Crosier PS, Hall CJ, Chen L, Xu X

Abstract
Inflammation is a protective biological response to body/tissue damage that involves immune cells, blood vessels and molecular mediators. In this work, we constructed the pathway network of inflammation, including 11 sub-pathways of inflammatory factors. Pathway-based network efficiency and network flux were adopted to evaluate drug efficacy. By using approved and experimentally validated anti-inflammatory drugs as training sets, a predictive model was built to screen potential anti-inflammatory drugs from approved drugs in DrugBank. This drug repositioning approach would bring a fast and cheap way to find new indications for approved drugs. Moreover, molecular phenomics profiles of the expression of inflammatory factors will provide new insight into the drug mechanism of action.

PMID: 27345454 [PubMed - as supplied by publisher]

Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).

Aging (Albany NY). 2016 Jun 22;

Authors: Fiorillo M, Lamb R, Tanowitz HB, Cappello AR, Martinez-Outschoorn UE, Sotgia F, Lisanti MP

Abstract
Bedaquiline (a.k.a., Sirturo) is an anti-microbial agent, which is approved by the FDA for the treatment of multi-drug resistant pulmonary tuberculosis (TB). Bedaquiline is a first-in-class diaryl-quinoline compound, that mechanistically inhibits the bacterial ATP-synthase, and shows potent activity against both drug-sensitive and drug-resistant TB. Interestingly, eukaryotic mitochondria originally evolved from engulfed aerobic bacteria. Thus, we hypothesized that, in mammalian cells, bedaquiline might also target the mitochondrial ATP-synthase, leading to mitochondrial dysfunction and ATP depletion. Here, we show that bedaquiline has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that bedaquiline treatment of MCF7 breast cancer cells inhibits mitochondrial oxygen-consumption, as well as glycolysis, but induces oxidative stress. Importantly, bedaquiline significantly blocks the propagation and expansion of MCF7-derived CSCs, with an IC-50 of approx. 1-μM, as determined using the mammosphere assay. Similarly, bedaquiline also reduces both the CD44+/CD24low/- CSC and ALDH+ CSC populations, under anchorage-independent growth conditions. In striking contrast, bedaquiline significantly increases oxygen consumption in normal human fibroblasts, consistent with the fact that it is well-tolerated in patients treated for TB infections. As such, future pre-clinical studies and human clinical trials in cancer patients may be warranted. Interestingly, we also highlight that bedaquiline shares certain structural similarities with trans-piceatannol and trans-resveratrol, which are known natural flavonoid inhibitors of the mitochondrial ATP-synthase (complex V) and show anti-aging properties.

PMID: 27344270 [PubMed - as supplied by publisher]