Mathematical modelling unravels regulatory mechanisms of interferon-γ-induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells.

Interferon-γ (IFNγ)-mediated signal transduction via upregulation of signal transducer and activator of transcription (STAT) 1 leads to the expression of the mucin (MUC) 4 gene in pancreatic cancer cells. Upregulation of STAT1 may also implicate STAT1 tyrosine- or serine-phosphorylation. Experimental data indicate that reaction steps involved in IFN-γ induced serine-phosphorylation of STAT1 vary between cell types in contrast to conserved IFN-γ induced tyrosine-phosphorylation of STAT1. The above observations raise the following two questions: (i) How does IFNγ stimulation regulates serine-phosphorylation of STAT1 in the pancreatic cancer cell line CD18/HPAF? (ii) Which type of STAT1 acts as a transcription factor of MUC4? Our objective is to address these two questions by data-driven mathematical modelling. Simulation results of the parameterised ordinary differential equation models show that serine-phosphorylation of unphosphorylated STAT1 occurs in the cytoplasm. In contrast, serine-phosphorylation of tyrosine-phosphorylated STAT1 can take place in the cytoplasm or in the nucleus. In addition, our results propose that unphosphorylated or serine-phosphorylated STAT1 can act as transcription factors of MUC4, either alone by progressive binding to different sites in the promoter or both together.

Preoperative risk analysis--a reliable predictor of postoperative outcome after transthoracic esophagectomy?

BACKGROUND AND AIMS: In patients with esophageal carcinoma, transthoracic esophagectomy is associated with high postoperative morbidity and mortality rates. The question of this study was whether an individualized preoperative risk analysis is able to predict postoperative outcome. MATERIALS AND METHODS: Based on prospectively accumulated data of 126 patients with a malignant esophageal tumor, a preoperative composite risk score using objective parameters was evaluated. All patients underwent a transthoracic en bloc esophagectomy with two-field lymphadenectomy. The risk score was correlated to the postoperative course which was classified according to the days of intensive care unit (ICU) treatment, hours of mechanical ventilation, and reoperation and readmission to the ICU. A multivariate analysis was performed to identify single risk factors. RESULTS: The overall morbidity rate was 55%, while the mortality rate was 5.6%. According to the composite risk score, 22.8% of the patients had a "low" risk, 53.2% had a "moderate" risk, and in 19% the preoperative risk was classified as "high". There was a significant correlation of the preoperative risk and the postoperative course (p<0.001). Multivariate analysis identified age, general status, and preoperative pulmonary function as independent risk factors of the postoperative outcome. CONCLUSION: Preoperative risk analysis in particular pulmonary function and general status helps to select patients for transthoracic esophagectomy to reduce postoperative morbidity.