TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited.</p> <p>Methods</p> <p>Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed.</p> <p>Results</p> <p>High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival.</p> <p>Conclusion</p> <p>Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.</p

The Third GABLS Intercomparison Case for Evaluation Studies of Boundary-Layer Models. Part B: Results and Process Understanding

We describe and analyze the results of the third global energy and water cycle experiment atmospheric boundary layer Study intercomparison and evaluation study for single-column models. Each of the nineteen participating models was operated with its own physics package, including land-surface, radiation and turbulent mixing schemes, for a full diurnal cycle selected from the Cabauw observatory archive. By carefully prescribing the temporal evolution of the forcings on the vertical column, the models could be evaluated against observations. We focus on the gross features of the stable boundary layer (SBL), such as the onset of evening momentum decoupling, the 2-m minimum temperature, the evolution of the inertial oscillation and the morning transition. New process diagrams are introduced to interpret the variety of model results and the relative importance of processes in the SBL; the diagrams include the results of a number of sensitivity runs performed with one of the models. The models are characterized in terms of thermal coupling to the soil, longwave radiation and turbulent mixing. It is shown that differences in longwave radiation schemes among the models have only a small effect on the simulations; however, there are significant variations in downward radiation due to different boundary-layer profiles of temperature and humidity. The differences in modelled thermal coupling to the land surface are large and explain most of the variations in 2-m air temperature and longwave incoming radiation among models. Models with strong turbulent mixing overestimate the boundary-layer height, underestimate the wind speed at 200 m, and give a relatively large downward sensible heat flux. The result is that 2-m air temperature is relatively insensitive to turbulent mixing intensity. Evening transition times spread 1.5 h around the observed time of transition, with later transitions for models with coarse resolution. Time of onset in the morning transition spreads 2 h around the observed transition time. With this case, the morning transition appeared to be difficult to study, no relation could be found between the studied processes, and the variation in the time of the morning transition among the model