Postoperative biliary fistula and need for reoperation are risk factors for PLA following PD. Antibiotics and selective percutaneous drainage was effective in 86% of patients with no adverse effects on long-term hepatic function or survival.
Dimethylamino-parthenolide and celecoxib have the potential to be novel chemotherapeutic agents for pancreatic cancer; however, further optimization or the use of other modalities may be required for chemoprevention.
Rationale
Transmembrane TNF-α (tmTNF-α) is the prime ligand for TNFR2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy more than 30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs.
Objective
The goal of this study was to determine the role of transmembrane TNF-α in the proliferation of ECFCs.
Methods and Results
Here we show that tmTNF-α expression on ECFCs selects for higher proliferative potential and when removed from the cell surface promotes ECFC senescence. Moreover, the induction of premature senescence by chronic inflammatory conditions is blocked by inhibition of tmTNF-α cleavage. Indeed, the mechanism of chronic inflammation-induced premature senescence involves an abrogation of tmTNF/TNFR2 signaling. This process is mediated by activation of the tmTNF cleavage metalloprotease TACE via p38 MAP kinase activation and its concurrent export to the cell surface by means of increased iRhom2 expression.
Conclusion
Thus we conclude that tmTNF-α on the surface of highly proliferative ECFCs plays an important role in the regulation of their proliferative capacity.
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