Over-expression of cFos by the Transcription Factors NFATc2 and Sp1 in Pancreatic Cancer Cells.

BACKGROUND/AIM: The transcription factors NFATc2 and Sp1 play a key role in the progression of pancreatic cancer because they interact inside the cells and exert their carcinogenic effect through transcriptional modification. Drugs can also induce a variety of oncogenic signalling cascades. The risk of tumour progression and metastasis seems to be significantly increased in the perioperative period. Our research group has previously demonstrated the function of the interaction between NFATc2 and Sp1 in pancreatic cancer and has identified the proto-oncogene cFos as a target gene. We also found that the anaesthetic drug propofol has anti-tumour properties. The aim of the present study was to investigate the effect of propofol on the expression of the transcription factors NFATc2, Sp1 and cFos in the pancreatic cancer cell lines PaTu 8988t and PANC-1 and to analyse the relevance of this effect for the cells. MATERIALS AND METHODS: Stimulation with propofol and its effects on the expression of NFATc2, Sp1 and cFos were assessed by immunoblot. Cell cycle distribution was analysed by flow cytometry, and cell proliferation was measured with the ELISA BrdU assay. Propofol and siRNA against cFos were used for stimulation. RESULTS: Propofol regulated the expression of NFATc2, Sp1 and cFos. Stimulation with 250 µM or 500 µM propofol decreased NFATc2, Sp1 and cFos signalling in the Western blot analysis. At the same time, propofol significantly inhibited proliferation and activated cell cycle. The same proliferation behaviour was observed after transient cFos inhibition. These effects were potentiated by simultaneous stimulation with propofol and transient inhibition of cFos, further inhibiting cell proliferation. Interestingly, the cell cycle activation observed after stimulation with propofol alone was reversed in both cell lines. CONCLUSION: Anaesthetists only see oncological patients in a short time window. However, the perioperative period is increasingly recognised as a very vulnerable time with a major impact on tumour progression. Further studies are needed to identify the underlying mechanisms and to verify their clinical relevance, especially in anaesthesia.

Effect of NFATc2- and Sp1-mediated TNFalpha Regulation on the Proliferation and Migration Behavior of Pancreatic Cancer Cells.

BACKGROUND/AIM: One in two people will develop a tumor during their lifetime. Adenocarcinoma of the pancreas is one of the most aggressive types of cancer in humans with very poor long-term survival. A central role in the carcinogenesis of pancreatic cancer has been attributed to NFAT transcription factors. Previous studies have identified the transcription factor Sp1 as a binding partner of NFATc2 in pancreatic cancer. Using expression profile analysis, our group was able to identify the tumor necrosis factor TNFalpha as a target gene of the interaction between NFATc2 and Sp1. The present study investigated the effect of TNFalpha over-expression via the transcription factors NFATc2 and Sp1 on the pancreatic cancer cell lines PaTu 8988t and PANC-1. MATERIALS AND METHODS: Transient transfection of NFATc2, Sp1, and TNFalpha siRNAs and their effects on the expression were investigated with immunoblot. Cell proliferation was measured with the ELISA BrdU assay. Cell migration was assayed with a Cell Migration Assay Kit using a Boyden chamber. RESULTS: Inhibition of the transfection factors NFATc2, Sp1, or TNFalpha by siRNA significantly inhibited proliferation, which was exacerbated when using the combination of NFATc2 and Sp1. TNFalpha was able to counterbalance this effect. In contrast to proliferation, migration of pancreatic cancer cells was increased by inhibiting these transfection factors. CONCLUSION: Tumor progression is strongly influenced by transcriptional changes in signaling cascades and oncogene mutations as well as by changes in tumor suppressor genes. Further studies are needed to understand the underlying mechanisms of these processes.

Continuous intra-arterial nimodipine infusion as rescue treatment of severe refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

Severe refractory cerebral vasospasm (CV) is a major cause of disability and death in patients with aneurysmal subarachnoid hemorrhage (SAH). One rescue therapy in selected patients is intra-arterial nimodipine, either given as a single shot or as continuous infusion. To evaluate treatment efficacy, we analyzed outcome factors such as the incidence of craniectomy, ventriculo-peritonial (VP) shunting, and tracheotomy after intra-arterial nimodipine infusion. We retrospectively analyzed the rates of cerebral infarction, decompressive craniectomy, VP shunting, and tracheotomy in patients with severe CV after SAH. Three different patient groups were compared: group 1 had only been treated with oral nimodipine and hypervolemic hypertensive therapy (HHT) (2006-2010), group 2 with a single shot of intra-arterial nimodipine (SSN) in addition to oral conservative treatment (2006-2010), and group 3 with continuous intra-arterial nimodipine (CIAN) (2011-2017). The incidence of cerebral infarction was significantly lower in CIAN group (p = 0.005) than in conservative and SSN group. The indication for consecutive decompressive craniectomy was significantly lower in CIAN group in comparison with the conservative group (p = 0.018). The rates of VP shunting and tracheotomy were significantly higher in the CIAN group than in the conservative group (p = 0.028 for VP, and p = 0.003 for tracheotomy). The significantly lower rate of craniectomy in the CIAN group was most probably attributable to the significantly lower rate of CV-induced infarction. The higher rate of tracheotomy reflects more extensive sedation and the need of longer stays on the intensive care unit. Thus, the effect on long-term neurological outcome and quality of life has to be evaluated separately.

III. Ventricle diameter increase during ventricular drainage challenge - A predictor of shunt dependency after subarachnoid hemorrhage.

Hydrocephalus with the need for shunt placement is a common sequela after aneurysmal subarachnoid hemorrhage (aSAH). In 2009 Chan et al. published a formula to predict shunt dependency in SAH patients, the failure risk index (FRI). We reevaluated the FRI within the aSAH population in our hospital and wanted to identify easier measurements forecast shunt dependency. We retrospectively analyzed data from patients with aSAH treated in our neuro-intensive care unit and calculated the FRI according to the paper by Chan et al. 2013 and data were compared to the results of Chan et al. 38 patients were included in this study, 24 female and 14 male. 38% suffered a SAH WFNS I, 19% WFNS II, 24% WFNS III, 5% WFNS IV and 14% WFNS V. 17 patients underwent a shunt implantation (group 1), 21 patients did not (group 2). The calculated FRI Index did not correlate with the expectancy of shunt implantation in 22% of the cases (group 1). In group 2 the FRI index and the prediction of shunt dependency did not match in 33% of the cases. Furthermore, we found the increase of the third ventricle diameter to be predictive in 67% for failed EVD challenge and the decrease of the third ventricle diameter predictive in 67% for successful EVD challenge. In this study, we were not able to confirm the results of the FRI designed by Chan et al within our patient population. Furthermore, we consider the increase of the third ventricle diameter to be a simpler and more reliable predictor of shunt dependency.

Restoration of Functional Integrity After Evacuation of Chronic Subdural Hematoma-An Age-Adjusted Analysis of 697 Patients.

OBJECTIVE: Although chronic subdural hematoma (CSH) can be treated by surgery, little is known about age-dependent symptoms and age-adjusted rates of restoring functional integrity. To evaluate the clinical symptoms and the course of CSH in patients of different age groups (AGs), we reviewed patients with CSH treated at our department over the past 22 years. METHODS: This retrospective analysis included 697 patients with CSH (461 men, 236 women; mean age 70.1 years). Subgroup analysis was done according to AG 1) <65 years, 2) 66-75 years, 3) 76-85 years, 4) 86-95 years, and 5) >95 years. RESULTS: Most patients had been treated with burr-hole trephination and implantation of a subdural drain (96.5%; n = 673). No significant difference concerning surgical morbidity and mortality was found between the AGs, but patients >75 years more frequently required reoperation (P = 0.001). Preoperatively, the most common symptoms were headache in AGs 1 and 2 (56.3% and 48.5%) and mnestic deficits in AGs 3-5 (54.9%, 51.9%, and 50.0%). After surgery, the clinical symptoms of CSH had significantly abated in all age groups. The most common clinical residuals were motor deficits in AG 1 (10.4%), mnestic deficits in AG 2 (10.7%), AG 4 (24.1%), and AG 5 (50.0%), and organic brain syndrome in AG 3 (15.0%). CONCLUSION: CSH predominantly caused unspecific symptoms such as headache and cognitive decline. CSH surgery immediately relieved symptoms in patients of all AGs. However, improvement rates significantly depended on patient age. This should be taken into consideration when advising on surgical treatment of CSH.