Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway.

BACKGROUND: Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques. RESULTS: Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales. CONCLUSION: The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling), nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the approach itself

Long Non Coding RNA in Triple Negative Breast Cancer: A Promising Biomarker in Tumorigenesis

Globally, Triple-negative breast cancer (TNBC) is an unsurpassed variant of breast cancer (BC) with a very high fatality rate, and disease burden. Nevertheless, the deficit of diagnostic markers and focused treatment are major hurdles for potent therapeutics. They are also the reason for bad outcomes and causes of a worse prognosis and a high rate of flare up in patients with TNBC diagnosis. Long non-coding RNAs (lncRNA) are a new class of molecules that have recently gained interest in healthcare management due to their potential as biomarkers for human diseases especially cancers. The growing interest in lncRNA in clinical practice has created an unmet need for developing assays to test lncRNA quickly and accurately for early diagnostics. These lncRNA modulate multiple stages of tumor development, including growth, proliferation, invasion, angiogenesis, and metastases, by controlling several genes and changing metabolic networks. Highly invasive phenotype and chemo resistance are prominent characteristics of TNBC subtypes that require accurate diagnostic and prognostic instruments involving lncRNA. This review focusses on the evolving purpose and coalition of lncRNAs in TNBC and accentuates their capable effects in diagnosis and treatment of cancer. Moreover, the extensive literature analysis of our review creates an opportunity in the translational application concerning the TNBC lncRNAs described until now. The depiction of lncRNAs enrolled in TNBC is comprehensive, and sufficient substantiation studies are the need of the hour to authenticate the current outcomes and create imminent upcoming of elemental research setting into clinical practice

Linking migraine to gut dysbiosis and chronic non-communicable diseases

In the world, migraine is one of the most common causes of disability in adults. To date, there is no a single cause for this disorder, but rather a set of physio-pathogenic triggers in combination with a genetic predisposition. Among the factors related to migraine onset, a crucial role seems to be played by gut dysbiosis. In fact, it has been demonstrated how the intestine is able to modulate the central nervous system activities, through the gut-brain axis, and how gut dysbiosis can influence neurological pathologies, including migraine attacks. In this context, in addition to conventional pharmacological treatments for migraine, attention has been paid to an adjuvant therapeutic strategy based on different nutritional approaches and lifestyle changes able to positively modulate the gut microbiota composition. In fact, the restoration of the balance between the different gut bacterial species, the reconstruction of the gut barrier integrity, and the control of the release of gut-derived inflammatory neuropeptides, obtained through specific nutritional patterns and lifestyle changes, represent a possible beneficial additive therapy for many migraine subtypes. Herein, this review explores the bi-directional correlation between migraine and the main chronic non-communicable diseases, such as diabetes mellitus, arterial hypertension, obesity, cancer, and chronic kidney diseases, whose link is represented by gut dysbiosis

Climate Change and Reproductive Biocomplexity in Fishes: Innovative Management Approaches towards Sustainability of Fisheries and Aquaculture

The ongoing rapid climate change, combined with the disturbance of fish breeding grounds, may impact reproduction by endangering successful breeding and survival, and thus affect the viable sustainability in aquaculture systems as well as in the sea. In this study we focus on the biocomplexity of fish reproduction in response to climate change. Further, we propose adaptive strategies, including technological advancements, using a noninvasive and non-lethal approach, and we outline an assisted reproduction and nutrigenomics approach to mitigating fish reproductive risks posed by climate change. This was done in an effort to monitor fish aquaculture and ensure that, as a livelihood, it may provide a useful source of nutrition for our society

Cost-Effectiveness Analysis of Administering Tranexamic Acid to Bleeding Trauma Patients Using Evidence from the CRASH-2 Trial

OBJECTIVE: To assess the cost effectiveness of giving tranexamic acid (TXA) to bleeding trauma patients in low, middle and high income settings. METHODS: The CRASH-2 trial showed that TXA administration reduces the risk of death in bleeding trauma patients with a small but statistically significant increase in non-intensive care stay. A Markov model was used to assess the cost effectiveness of TXA in Tanzania, India and the United Kingdom (UK). The health outcome was the number of life years gained (LYs). Two costs were considered: the cost of administering TXA and the cost of additional days in hospital. Cost data were obtained from hospitals, World Health Organization (WHO) database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Both deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions. FINDINGS: Administering TXA to bleeding trauma patients within three hours of injury saved an estimated 372, 315 and 755 LYs per 1,000 trauma patients in Tanzania, India and the UK respectively. The cost of giving TXA to 1,000 patients was$17,483 in Tanzania, $19,550 in India and$30,830 in the UK. The incremental cost of giving TXA versus not giving TXA was $18,025 in Tanzania,$20,670 in India and $48,002 in the UK. The estimated incremental cost per LY gained of administering TXA is$48, $66 and$64 in Tanzania, India and the UK respectively. CONCLUSION: Early administration of TXA to bleeding trauma patients is likely to be highly cost effective in low, middle and high income settings. TRIAL REGISTRATION: This paper uses data collected by the CRASH 2 trial: Controlled-Trials.com ISRCTN86750102, Clinicaltrials.govNCT00375258 and South African Clinical Trial Register DOH-27-0607-1919

Therapeutic Impact and Management of Persistent Head and Neck Atopic Dermatitis in Dupilumab-Treated Patients

Background: Localization of atopic dermatitis (AD) in exposed areas such as the hands, head, and neck has been considered as a negative factor impacting on dupilumab response, although a comparison of exposed versus unexposed areas is not currently available. Objectives: The aim of this study is to evaluate the clinical response to dupilumab depending on the presence or persistency of AD skin manifestations in specific body areas. Methods: The study retrospectively collected clinical and demographic data of adult patients affected by moderate to severe AD. Based on the anatomical sites involved, 5 subcohorts of patients were identified. Results: A total of 41 patients were included in the study. Disease amelioration was detected during the study period, although baseline head/neck and hand localization was associated with a significantly lower likelihood of achieving an Eczema Area Severity Index (EASI) ≤1. In addition, patients with head/neck persistency showed a significantly lower response when compared to patients without persistency of head/neck AD in terms of both mean EASI and Dermatology Life Quality Index (DLQI) reduction. Conclusion: AD localization in exposed areas at the baseline and AD persistency at the head/neck may have a negative impact on certain treatment response parameters to dupilumab therapy

Emotions and policy information predicting water-quality policy support

The public acknowledges the importance of water quality, and threats to water quality can provoke strong emotional responses. Despite this, the public often resists policies protecting water quality. Research with 349 US residents demonstrated that (1) emotions about specific water policies were more predictive of policy support than emotions about water quality and (2) hope about water policies was a particularly strong predictor of water policy support. In both between-person and within-person analyses, water-policy hope was a stronger predictor of water-policy support than water-policy anxiety, anger, and neutral affect–although these other emotions were related to water-policy support. These findings among water-policy emotions replicated results from a Pilot study with 148 US undergraduate students. The main study also demonstrated that water-policy support increased when policy descriptions explained how policies would improve water quality via hydro systems, and it did so by increasing feelings of water-policy hope. This research suggests that a full range of affective reactions to water policy and water quality should be considered when motivating support for policies protecting water quality

Computational Modeling for the Activation Cycle of G-proteins by G-protein-coupled Receptors

In this paper, we survey five different computational modeling methods. For comparison, we use the activation cycle of G-proteins that regulate cellular signaling events downstream of G-protein-coupled receptors (GPCRs) as a driving example. Starting from an existing Ordinary Differential Equations (ODEs) model, we implement the G-protein cycle in the stochastic Pi-calculus using SPiM, as Petri-nets using Cell Illustrator, in the Kappa Language using Cellucidate, and in Bio-PEPA using the Bio-PEPA eclipse plug in. We also provide a high-level notation to abstract away from communication primitives that may be unfamiliar to the average biologist, and we show how to translate high-level programs into stochastic Pi-calculus processes and chemical reactions.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer.

Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8+ T cell infiltration and activation in vivo, and that CD8+ T cell depletion severely compromises anti-tumor efficacy. Olaparib-induced T cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-deficient compared to HR-proficient TNBC cells and in vivo models. CRISPR-knockout of STING in cancer cells prevents proinflammatory signaling and is sufficient to abolish olaparib-induced T cell infiltration in vivo. These findings elucidate an additional mechanism of action of PARP inhibitors and provide rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC