The clinical outcomes of extended resections in patients with IV stage gallbladder cancers: A retrospective study from a large tertiary center.

Background and aim: The role of extended resections in patients with clinical stage IV gallbladder cancer (GBC) remains unclear. This study retrospectively analyzed the clinical outcomes of patients who underwent extended resections for IV GBC. Methods: Patients who were diagnosed with IV stage GBCs and underwent extended resections in Eastern Hepatobiliary Surgery Hospital, Shanghai, China, were retrospectively included in our study. Extended resection was defined as a major hepatectomy (resection of ≥3 liver segments), a pancreatoduodenectomy, or both. The clinical outcomes (baseline characteristics, preoperative variables, intraoperative variables, pathological outcomes, and follow-up data) were obtained and analyzed. The factors associated with major postoperative complications and long-term survival were analyzed by logistic regression analyses. Results: From January 2011 to June 2017, 74 patients were included in our study. There were 33 (44.6%) males and the median age was 62.5 years (interquartile range [IQR], 56.0-67.0 years). According to pathological specimens, the median tumor size was 7cm (IQR, 6-8cm), 73(98.6%) of them received R0 resection and 72 (97.2%) of them were IV A stage GBC. Three perioperative deaths (5.4%) occurred, and major postoperative complications occurred for 15 patients (20.3%). Among them, 61 patients (82.4%) experienced recurrence and 17 patients (23.0%) were still alive after a median follow-up period of 52 months. The disease free survival time was 9 months (95% confidence interval [CI], 7.8-10.2 months) and the overall survival was 18.0 months (95% CI, 15.2-20.8 months). Longer hospital stay days [odds ratio, (OR)=1.979, 95%CI:1.038-1.193, P=0.003), initial symptoms with abdominal pain (OR=21.489, 95%CI=1.22-37.57, P=0.036), more blood transfusion volume during hospitalization (OR=1.036, 95%CI:1.021-1.058, P=0.005), and intraoperative hemorrhage (OR=18.56, 95%C:3.54-47.65, P=0.001) were independently associated with postoperative complications. Moreover, locally recurrence (OR=1.65, 95%CI:1.17-1.96, P=0.015), and more adjuvant chemotherapy cycles (OR=1.46, 95%CI:1.13-1.76, P=0.026) were independently associated with long-term survival. Conclusion: Our retrospective study identified that extended resections can be safely and efficaciously performed on stage IV GBC patients in selected cases and performed by experienced surgeons.

A phenylalanine ammonia lyase from Fritillaria unibracteata promotes drought tolerance by regulating lignin biosynthesis and SA signaling pathway.

Drought is one of the key threatening environmental factors for plant and agriculture. Phenylalanine ammonia lyase (PAL) is a key enzyme involved in plant defense against abiotic stress, however, the role of PAL in drought tolerance remains elusive. Here, a PAL member (FuPAL1) containing noncanonical Ala-Ser-Gly triad was isolated from Fritillaria unibracteata, one important alpine pharmaceutical plant. FuPAL1, mainly distributed in cytosol, was more conserved than FuCOMT and FuCHI at both nucleotide and amino acid levels. FuPAL1 was overexpressed in Escherichia coli and the purified recombinant FuPAL1 protein showed catalytic preference on L-Phe than L-Tyr. Homology modeling and site-mutation of FuPAL1 exhibited FuPAL1 took part in the ammonization process by forming MIO-like group, and Phe141, Ser208, Ileu218 and Glu490 played key roles in substrate binding and (or) catalysis. HPLC analysis showed that lignin and salicylic acid levels increased but total flavonoid levels decreased in FuPAL1 transgenic Arabidopsis compared to wild-type plants. Moreover, FuPAL1 transgenic Arabidopsis significantly enhanced its drought tolerance, which suggested that FuPAL1 mediated tolerance to drought by inducing the biosynthesis and accumulation of salicylic acid and lignin. Taken together, our results confirmed that the FuPAL1 played an important role in drought tolerance, and FuPAL1 might be a valuable target for genetic improvement of drought resistance in future.

miR-4461 inhibits the progression of Gallbladder carcinoma via regulating EGFR/AKT signaling.

Increasing evidence has demonstrated that microRNAs (miRNAs) participated in the tumorigenesis, progression and recurrence of various malignancies including Gallbladder carcinoma (GBC). miR-4461 was reported to work as a tumor suppressor gene in renal cell carcinoma. However, the role of miR-4461 in GBC remains unknown. Herein, we show that miR-4461 is downregulated in gallbladder cancer stem cells (CSCs). Forced miR-4461 expression attenuates the self-renewal, tumorigenicity of gallbladder CSCs, and inhibits proliferation and metastasis of GBC cells. Conversely, miR-4461 knockdown promotes the self-renewal of gallbladder CSCs, and facilities proliferation and metastasis of GBC cells. Mechanistically, miR-4461 inhibits GBC progression via downregulating EGFR/AKT pathway. Special EGFR siRNA or AKT overexpression virus abolishes the discrepancy of self-renewal, tumorigenesis, growth, and metastasis between miR-4461 overexpression GBC cells and their control cells. In conclusion, miR-4461 suppresses GBC cells self-renewal, tumorigenicity, proliferation, and metastasis by inactivating EGFR/AKT signaling, and may therefore prove to be a potential therapeutic target for GBC patients.

Gemcitabine-induced pancreatic cancer cell death is associated with MST1/cyclophilin D mitochondrial complexation.

The pancreatic adenocarcinoma remains the most aggressive human malignancy with an extremely low 5-year overall survival. Postoperative gemcitabine could significantly delay recurrence after complete resection of pancreatic cancer. However, the underlying mechanisms are not fully understood. The chemo-resistance factors against gemcitabine still need further characterizations. Here we studied the mechanism of gemcitabine-induced pancreatic cancer cell death by focusing on mammalian sterile 20-like kinase 1 (MST1) and cyclophilin D (Cyp-D). We found that MST1 and Cyp-D expressions were significantly lower in gemcitabine-resistant pancreatic cancer tissues and cell lines. In vitro, gemcitabine activated MST1 through reactive oxygen species (ROS) production, which was prevented by antioxidant n-acetyl-cysteine (NAC). We found that gemcitabine-activated MST1 translocated to mitochondria and formed a complex with the local protein Cyp-D. Gemcitabine-induced cell death was alleviated by MST1 or Cyp-D shRNA silencing, but was aggravated by MST1 or Cyp-D over-expression. Further, cyclosporin A (CsA), the Cyp-D inhibitor, prevented gemcitabine-induced MST1/Cyp-D mitochondrial complexation and cancer cell death. We suggest that gemcitabine-induced death of pancreatic cancer cells requires MST1/Cyp-D mitochondrial complexation.