Curriculum vitae of the LOTOS-EUROS (v2.0) chemistry transport model

The development and application of chemistry transport models has a long tradition. Within the Netherlands the LOTOS–EUROS model has been developed by a consortium of institutes, after combining its independently developed predecessors in 2005. Recently, version 2.0 of the model was released as an open-source version. This paper presents the curriculum vitae of the model system, describing the model's history, model philosophy, basic features and a validation with EMEP stations for the new benchmark year 2012, and presents cases with the model's most recent and key developments. By setting the model developments in context and providing an outlook for directions for further development, the paper goes beyond the common model description. With an origin in ozone and sulfur modelling for the models LOTOS and EUROS, the application areas were gradually extended with persistent organic pollutants, reactive nitrogen, and primary and secondary particulate matter. After the combination of the models to LOTOS–EUROS in 2005, the model was further developed to include new source parametrizations (e.g. road resuspension, desert dust, wildfires), applied for operational smog forecasts in the Netherlands and Europe, and has been used for emission scenarios, source apportionment, and long-term hindcast and climate change scenarios. LOTOS–EUROS has been a front-runner in data assimilation of ground-based and satellite observations and has participated in many model intercomparison studies. The model is no longer confined to applications over Europe but is also applied to other regions of the world, e.g. China. The increasing interaction with emission experts has also contributed to the improvement of the model's performance. The philosophy for model development has always been to use knowledge that is state of the art and proven, to keep a good balance in the level of detail of process description and accuracy of input and output, and to keep a good record on the effect of model changes using benchmarking and validation. The performance of v2.0 with respect to EMEP observations is good, with spatial correlations around 0.8 or higher for concentrations and wet deposition. Temporal correlations are around 0.5 or higher. Recent innovative applications include source apportionment and data assimilation, particle number modelling, and energy transition scenarios including corresponding land use changes as well as Saharan dust forecasting. Future developments would enable more flexibility with respect to model horizontal and vertical resolution and further detailing of model input data. This includes the use of different sources of land use characterization (roughness length and vegetation), detailing of emissions in space and time, and efficient coupling to meteorology from different meteorological models

E-cadherin breast tumor expression, risk factors and survival : Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium

E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, > 2 cm, and HER2-negative. Loss of E-cadherin expression (score <100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.Peer reviewe

Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signaling

BACKGROUND: HER2 overexpression leads to aggressive mammary tumor growth. Although the prognosis of HER2+ tumors in humans is greatly improved using biologicals, therapy resistance, which may be caused by increased PI3K, cSRC or Wnt activity, is a major concern. A recent analysis of 12 canine mammary cell lines showed an association between HER2/3 overexpression and PTEN deletion with elevated Wnt-signaling. Wnt-activity appeared to be insensitive to PI3K inhibitors but sensitive to Src-I1. We hypothesized that Wnt activation, was caused by HER2/3-activated cSRC activation. METHODS: The role of HER2/3 on Wnt signaling was investigated by silencing HER2/3 expression using specific siRNAs. Next, the effect of an EGFR/HER2 tyrosine kinase inhibitor on Wnt activity and migration was investigated and compared to other TKIs of related signaling pathways. Finally, two TKIs, a cSRC and a PI3K inhibitor, were investigated in a zebrafish xenograft model. RESULTS: Silencing of HER1-3 did not inhibit the intrinsic high Wnt activity, whereas the HER kinase inhibitor afatinib showed enhanced Wnt activity. The strongest inhibition of Wnt activity and cell viability and migration was shown by cSRC inhibitors, which also showed strong inhibition of cell viability and metastasis in a zebrafish xenograft model. CONCLUSION: HER2/3 overexpression or HER2/3-induced cSRC activation is not the cause of enhanced Wnt activity. However, inhibition of cSRC resulted in a strong inhibition of Wnt activity and cell migration and metastasis. Further studies are needed to unravel the mechanism of cSRC activation and cSRC inhibition to restore sensitivity to HER-inhibitors in HER2/3-positive breast cancer. This article is protected by copyright. All rights reserved

Dasatinib inhibition of cSRC prevents the migration and metastasis of canine mammary cancer cells with enhanced Wnt and HER signaling

BACKGROUND: HER2 overexpression leads to aggressive mammary tumor growth. Although the prognosis of HER2+ tumors in humans is greatly improved using biologicals, therapy resistance, which may be caused by increased PI3K, cSRC or Wnt activity, is a major concern. A recent analysis of 12 canine mammary cell lines showed an association between HER2/3 overexpression and PTEN deletion with elevated Wnt-signaling. Wnt-activity appeared to be insensitive to PI3K inhibitors but sensitive to Src-I1. We hypothesized that Wnt activation, was caused by HER2/3-activated cSRC activation. METHODS: The role of HER2/3 on Wnt signaling was investigated by silencing HER2/3 expression using specific siRNAs. Next, the effect of an EGFR/HER2 tyrosine kinase inhibitor on Wnt activity and migration was investigated and compared to other TKIs of related signaling pathways. Finally, two TKIs, a cSRC and a PI3K inhibitor, were investigated in a zebrafish xenograft model. RESULTS: Silencing of HER1-3 did not inhibit the intrinsic high Wnt activity, whereas the HER kinase inhibitor afatinib showed enhanced Wnt activity. The strongest inhibition of Wnt activity and cell viability and migration was shown by cSRC inhibitors, which also showed strong inhibition of cell viability and metastasis in a zebrafish xenograft model. CONCLUSION: HER2/3 overexpression or HER2/3-induced cSRC activation is not the cause of enhanced Wnt activity. However, inhibition of cSRC resulted in a strong inhibition of Wnt activity and cell migration and metastasis. Further studies are needed to unravel the mechanism of cSRC activation and cSRC inhibition to restore sensitivity to HER-inhibitors in HER2/3-positive breast cancer. This article is protected by copyright. All rights reserved

Curriculum vitae of the LOTOS–EUROS (v2.0) chemistry transport model

The development and application of chemistry transport models has a long tradition. Within the Netherlands the LOTOS–EUROS model has been developed by a consortium of institutes, after combining its independently developed predecessors in 2005. Recently, version 2.0 of the model was released as an open-source version. This paper presents the curriculum vitae of the model system, describing the model's history, model philosophy, basic features and a validation with EMEP stations for the new benchmark year 2012, and presents cases with the model's most recent and key developments. By setting the model developments in context and providing an outlook for directions for further development, the paper goes beyond the common model description. With an origin in ozone and sulfur modelling for the models LOTOS and EUROS, the application areas were gradually extended with persistent organic pollutants, reactive nitrogen, and primary and secondary particulate matter. After the combination of the models to LOTOS–EUROS in 2005, the model was further developed to include new source parametrizations (e.g. road resuspension, desert dust, wildfires), applied for operational smog forecasts in the Netherlands and Europe, and has been used for emission scenarios, source apportionment, and long-term hindcast and climate change scenarios. LOTOS–EUROS has been a front-runner in data assimilation of ground-based and satellite observations and has participated in many model intercomparison studies. The model is no longer confined to applications over Europe but is also applied to other regions of the world, e.g. China. The increasing interaction with emission experts has also contributed to the improvement of the model's performance. The philosophy for model development has always been to use knowledge that is state of the art and proven, to keep a good balance in the level of detail of process description and accuracy of input and output, and to keep a good record on the effect of model changes using benchmarking and validation. The performance of v2.0 with respect to EMEP observations is good, with spatial correlations around 0.8 or higher for concentrations and wet deposition. Temporal correlations are around 0.5 or higher. Recent innovative applications include source apportionment and data assimilation, particle number modelling, and energy transition scenarios including corresponding land use changes as well as Saharan dust forecasting. Future developments would enable more flexibility with respect to model horizontal and vertical resolution and further detailing of model input data. This includes the use of different sources of land use characterization (roughness length and vegetation), detailing of emissions in space and time, and efficient coupling to meteorology from different meteorological models