How integrative modelling can break down disciplinary silos

This paper has been published in a peer-reviewed journal as: Kragt, M.E., Robson, B.J. & Macleod, C.J.A. (2013) Modellers’ roles in structuring integrative research projects. Environmental Modelling & Software, 39(1): 322-330. DOI: 10.1016/j.envsoft.2012.06.015Environmental modelling, Interdisciplinary research, Transdisciplinarity, Integration, Research Methods/ Statistical Methods, Q57, Y80, Z19,

Hypoxia-induced nitric oxide production and tumour perfusion is inhibited by pegylated arginine deiminase (ADI-PEG20).

The hypoxic tumour microenvironment represents an aggressive, therapy-resistant compartment. As arginine is required for specific hypoxia-induced processes, we hypothesised that arginine-deprivation therapy may be useful in targeting hypoxic cancer cells. We explored the effects of the arginine-degrading agent ADI-PEG20 on hypoxia-inducible factor (HIF) activation, the hypoxia-induced nitric oxide (NO) pathway and proliferation using HCT116 and UMUC3 cells and xenografts. The latter lack argininosuccinate synthetase (ASS1) making them auxotrophic for arginine. In HCT116 cells, ADI-PEG20 inhibited hypoxic-activation of HIF-1α and HIF-2α, leading to decreased inducible-nitric oxide synthase (iNOS), NO-production, and VEGF. Interestingly, combining hypoxia and ADI-PEG20 synergistically inhibited ASS1. ADI-PEG20 inhibited mTORC1 and activated the unfolded protein response providing a mechanism for inhibition of HIF and ASS1. ADI-PEG20 inhibited tumour growth, impaired hypoxia-associated NO-production, and decreased vascular perfusion. Expression of HIF-1α/HIF-2α/iNOS and VEGF were reduced, despite an increased hypoxic tumour fraction. Similar effects were observed in UMUC3 xenografts. In summary, ADI-PEG20 inhibits HIF-activated processes in two tumour models with widely different arginine biology. Thus, ADI-PEG20 may be useful in the clinic to target therapy-resistant hypoxic cells in ASS1-proficient tumours and ASS1-deficient tumours.Thanks to Dr John Bomalaski, (Polaris Pharmaceuticals, Inc) for supplying the ADI-PEG20, to Dr Simon S Hoer for useful discussions and to members of Histopathology/ISH (CRUK Cambridge Institute, UK) for IHC and imaging assistance. This work was supported by the Wellcome Trust and the NIHR Cambridge Biomedical Research Centre Senior Investigator Awards (to P.H.M., supporting N.B.), EU FP7 Metoxia Grant agreement no. 222741 (to P.H.M., supporting G.C.), UCL Cancer Research UK Centre (to M.R.), King’s College London and UCL Comprehensive Cancer Imaging Centre, Cancer Research UK and EPSRC in association with the Medical Research Council (MRC), the DoH (England: to R.B.P.), MRC Cancer Unit Core Funding (to C.F., supporting E.G.).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep2295

Incorporating a generalised additive model of river nutrient concentrations into a mechanistic receiving water model

eReefs is a large, collaborative project that is building catchment and marine models for Australia's Great Barrier Reef Lagoon (GBRL), a world-heritage environmental asset. The eReefs package includes three-dimensional mechanistic biogeochemical, sediment and hydrodynamic models for the entire GBRL on 4 km and 1 km grid scales, along with a relocatable coastal and estuary model (RECOM) that can be nested within the larger-scale models. Source Catchment models developed by the Government of Queensland for each GBRL catchment will be used to run scenarios to predict the effects of management and land use changes on nitrogen, phosphorus and sediment loads reaching each river. For day-to-day near-real-time and forecast-mode running of the marine models, however, another approach is needed to provide the river loads of sediments, dissolved and particulate loads required as boundary conditions. Generalised Additive Models (GAMs) have been shown (e. g. Kuhnert et al., 2012) to be powerful tools for the prediction of suspended sediment and particulate nutrient loads in tropical rivers. Here, we extend previous work to build GAMs that are able to predict concentrations of suspended sediments, dissolved and particulate nutrients in the Fitzroy River (Queensland) on a daily time-step. In developing the GAMs, we tested a number of routinely and frequently measured meteorological and hydrological variables for potential predictive power. The new terms considered included water temperature (which may alter biogeochemical processing rates), air temperature (a more reliably measured proxy for water temperature), electrical conductivity (which may reflect the influence of particular subcatchment sources), barometric pressure (an indicator of local storm activity), wind stress (which may affect resuspension and mixing in the river and its weirs) and flow from river tributaries (a direct measure of the influence of particular subcatchments). The models generated were tested with regard to the validity of key statistical assumptions, and were then validated against a subset of observational data that had been held back from the original calibration. The strongest models included flow in the Fitzroy River, flow in one or more tributaries, and a discounted flow term that reflected flow in the preceding days and weeks. Models that did not include tributary flow were able to predict concentrations of particulate, but not dissolved materials. Neither meteorological terms nor electrical conductivity proved to be useful predictors, while water temperature was of marginal value. The final GAM provide more accurate predictions on a daily time-step than previously available methods, for both dissolved and particulate materials, and is being used to provide time-series input (e. g. Figure 1) to mechanistic marine models

A Dynamic Model of Primary Production and Plant Coverage in an Oligotrophic Tropical River

Many of Australia\u27s tropical rivers are amongst the most ecologically intact inthe world, but have been relatively little studied. Now, however, there is pressure forfurther development of these tropical land and water resources. To avoid repeatingmanagement mistakes that have been made elsewhere, it is essential to improve ourunderstanding of how these rivers function. As part of the Tropical Rivers and CoastalKnowledge Research hub, we studied flow, nutrients, and primary production in the DalyRiver (N.T.), a perennial tropical river maintained in the dry season by ground-water anddeveloped a dynamic simulation model to predict the coverage and biomass of each of fivekey plant and algae groups in the river. Flow is the key driver in this model, controllingboth loss and growth terms for plants. When flow (and hence shear stress) is high,sloughing and bed-scouring contribute to loss of biomass, while shear stresses (and hencehigher boundary layer thickness) limit the rate of transfer of nutrients to benthic plants.This paper will describe work to understand and model these dynamics, and will discusswhat this might mean for the river\u27s future

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Peer reviewedPublisher PD

eReefs modelling suggests Trichodesmium may be a major nitrogen source in the Great Barrier Reef

Trichodesmium can fix nitrogen that is later released into the water column. This process may be a major source of ‘new’ nitrogen in the Great Barrier Reef (GBR), but to date this contribution is poorly resolved. We have estimated the seasonal, spatial and annual contributions of Trichodesmium to the annual nitrogen budget of the GBR using the eReefs marine models. Models were run for the interval December 2010 to November 2012. During this period La Niña conditions produced record rainfalls and widespread flooding of GBR catchments. Model outputs suggest nitrogen fixation by Trichodesmium in the GBR (which covers about 348,000 km2) contributes approximately 0.5 MT/yr, exceeding the total average annual riverine nitrogen loads (0.05–0.08 MT/yr). Nitrogen fixation loads are exceeded by riverine loads only if the comparison is restricted to inshore waters and during the wet season. The river pollution is likely to have impacts in freshwater wetlands, mangroves, seagrasses and in-shore coral reefs; while Trichodesmium blooms are likely to be less intense but more widespread and affect offshore coral reefs and other oceanic ecosystems. Phosphorus and iron are suggested to be potential drivers of Trichodesmium growth and nitrogen fixation. This result is provisional but reinforces the need for more detailed assessment and reliable quantification of the annual nitrogen contribution from nitrogen fixation in the GBR and other coastal waters. Such advances will improve understandings of the role of terrestrial nitrogen loads in the GBR and of terrestrial phosphorus and iron loads which can modulate Trichodesmium abundance. These findings will help to broaden the focus of water quality management programmes and support management to improve GBR water quality

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations