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Background & Aims Pancreatic adenocarcinoma, among the most lethal human malignancies, is resistant to current chemotherapies. We have previously shown that triptolide inhibits the growth of pancreatic cancer cells in vitro and prevents tumor growth in vivo. This study investigates the mechanism by which triptolide kills pancreatic cancer cells, which has not been previously studied. Methods Cells were treated with triptolide and viability and caspase-3 activity were measured using colorimetric assays. Annexin V, propidium iodide and acridine orange staining were measured by flow cytometry. Immunofluorescence was used to monitor the localization of cytochrome c and LC3 proteins. Caspase-3, Atg5 and Beclin1 levels were downregulated by exposing cells to their respective siRNA. Results We show that triptolide induces apoptosis in MiaPaCa-2, Capan-1 and BxPC-3 cells and autophagy in S2-013, S2-VP10 and Hs766T cells. Triptolide-induced autophagy has a pro-death effect, requires autophagy-specific genes, atg5 or beclin1, and is associated with the inactivation of the Akt/mTOR/p70S6K pathway and the upregulation of the ERK1/2 pathway. Inhibition of autophagy in S2-013 and S2-VP10 cells results in cell death via the apoptotic pathway whereas inhibition of both autophagy and apoptosis rescues cell death. Conclusions This study shows, for the first time, that triptolide kills pancreatic cancer cells by two different pathways. It induces caspase-dependent apoptotic death in MiaPaCa-2, Capan-1 and BxPC-3 and caspase-independent autophagic death in metastatic cell lines, S2-013, S2-VP10 and Hs766T, thereby making it an attractive chemotherapeutic agent against a broad spectrum of pancreatic cancers.

ERAS was associated with improved postoperative outcomes, including decreased length of stay and pulmonary and cardiac morbidity after thoracotomy, but not after minimally invasive operations. ERAS safety was demonstrated by low rates of adverse events without effect on hospital readmission or perioperative deaths.

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There has been a dramatic increase in the detection of lung nodules, many of which are preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22), AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal pulmonary nodules from the same patients reveal evidence of convergent evolution.