Comparison of prognosis and postoperative morbidities between standard pancreaticoduodenectomy and the TRIANGLE technique for resectable pancreatic ductal adenocarcinoma.

BACKGROUND: Radical surgery combined with systemic chemotherapy offers the possibility of long-term survival or even cure for patients with pancreatic ductal adenocarcinoma (PDAC), although tumor recurrence, especially locally, still inhibits the treatment efficacy. The TRIANGLE technique was introduced as an extended dissection procedure to improve the R0 resection rate of borderline resectable or locally advanced PDAC. However, there was a lack of studies concerning postoperative complications and long-term outcomes of this procedure on patients with resectable PDAC. AIM: To compare the prognosis and postoperative morbidities between standard pancreaticoduodenectomy (PD) and the TRIANGLE technique for resectable PDAC. METHODS: Patients with resectable PDAC eligible for PD from our hospital between June 2018 and December 2021 were enrolled in this retrospective cohort study. All the patients were divided into PDstandard and PDTRIANGLE groups according to the surgical procedure. Baseline characteristics, surgical data, and postoperative morbidities were recorded. All of the patients were followed up, and the date and location of tumor recurrence, and death were recorded. The Kaplan-Meier method and log-rank test were used for the survival analysis. RESULTS: There were 93 patients included in the study and 37 underwent the TRIANGLE technique. Duration of operation was longer in the PDTRIANGLE group compared with the PDstandard group [440 (410-480) min vs 320 (265-427) min] (P = 0.001). Intraoperative blood loss [700 (500-1200) mL vs 500 (300-800) mL] (P = 0.009) and blood transfusion [975 (0-1250) mL vs 400 (0-800) mL] (P = 0.009) were higher in the PDTRIANGLE group. There was a higher incidence of surgical site infection (43.2% vs 12.5%) (P = 0.001) and postoperative diarrhea (54.1% vs 12.5%) (P = 0.001) in the PDTRIANGLE group. The rates of R0 resection and local recurrence, overall survival, and disease-free survival did not differ significantly between the two groups. CONCLUSION: The TRIANGLE technique is safe, with acceptable postoperative morbidities compared with standardized PD, but it does not improve prognosis for patients with resectable PDAC.

Loss of Claudin-1 incurred by DNMT aberration promotes pancreatic cancer progression.

Pancreatic cancer (PC) is one of the most malignant and deadly tumors of digestive system with complex etiology and pathogenesis. Dysregulations of oncogenes and tumor suppressors due to epigenetic modifications causally affect tumorogenesis; however the key tumor suppressors and their regulations in PC are only partially defined. In this study, we found that Claudin-1 (encoded by CLDN1 gene) was significantly suppressed in PC that correlated with a poor clinical prognosis. Claudin-1 knockdown enhanced PC cell proliferation, migration, and stemness. Pancreatic specific Cldn1 knockout in KPC (LSLKrasG12D/Pdx1-Cre/Trp53R172H+) and KC (LSLKrasG12D/Pdx1-Cre) mice reduced mouse survival, promoted acinar-to-ductal metaplasia (ADM) process, and accelerated the development of pancreatic intraepithelial neoplasia (PanIN) and PC. Further investigation revealed that Claudin-1 suppression was mainly caused by aberrant DNA methylatransferase 1 (DNMT1) and DNMT3A elevations and the resultant CLDN1 promoter hypermethylation, as a DNMT specific inhibitor SGI-1027 effectively reversed the Claudin-1 suppression and inhibited PC progression both in vitro and in vivo in a Claudin-1 preservation-dependent manner. Together, our data suggest that Claudin-1 functions as a tumor suppressor in PC and its epigenetic suppression due to DNMT aberrations is a crucial event that promotes PC development and progression.

Low expression of PEBP1P2 promotes metastasis of clear cell renal cell carcinoma by post-transcriptional regulation of PEBP1 and KLF13 mRNA.

BACKGROUND: Pseudogenes play an essential role in tumor occurrence and progression. However, the functions and mechanisms of pseudogenes in clear cell renal cell carcinoma (ccRCC) remain largely elusive. METHODS: We quantified PEBP1P2 expression in ccRCC tissues and cells using fluorescence in situ hybridization and real-time PCR. Besides, we evaluated the role of PEBP1P2 in ccRCC using a lung metastasis model and a transwell assay. Finally, we documented the interactions between PEBP1P2, PEBP1, and KLF13 by performing luciferase, RNA immunoprecipitation, RNA pulldown, and targeted RNA demethylation assays. RESULTS: Low PEBP1P2 expression correlates significantly with advanced stages and poor prognosis in ccRCC patients. Besides, PEBP1P2 overexpression inhibits ccRCC metastasis formation in vivo and in vitro. Interestingly, PEBP1P2 directly interacted with 5-methylcytosine (m5C)-containing PEBP1 mRNA and recruited the YBX1/ELAVL1 complex, stabilizing PEBP1 mRNA. In addition, PEBP1P2 increased KLF13 mRNA levels by acting as a sponge for miR-296, miR-616, and miR-3194. CONCLUSIONS: PEBP1P2 inhibits ccRCC metastasis formation and regulates both PEBP1 and KLF13. Therefore, molecular therapies targeting PEBP1P2 might be an effective treatment strategy against ccRCC and other cancers with low PEBP1P2 levels.

Movement Disorder and Neurotoxicity Induced by Chronic Exposure to Microcystin-LR in Mice.

Microcystins are produced by some species of cyanobacteria, which are hazardous materials to the environment and human beings. It has been demonstrated that microcystin-LR (MC-LR) could disrupt the blood-brain barrier and cause learning and memory deficits, but the neurotoxicity of MC-LR on motor function remains unclear. In this study, the mice were exposed to MC-LR dissolved in drinking water at doses of 1, 7.5, or 15 µg/L for 15 months. We observed that 15 µg/L MC-LR could enter mouse brain tissues such as the cortex, hippocampus, and substantia nigra (SN). And 15 µg/L MC-LR also caused hypokinesia in mice and induced the loss and apoptosis of SN dopaminergic neurons (DA neurons). Meanwhile, MC-LR induced the accumulation of alpha synuclein (α-syn) in DA neurons and decreased the proteins of tyrosine hydroxylase (TH), dopa decarboxylase (DDC) and dopamine transporter (DAT), resulting in a reduction in dopamine (DA) content, which are pathological features of Parkinson's disease (PD). These results suggested that chronic MC-LR might induce PD-like lesions in mice. Moreover, chronic MC-LR exposure caused the inflammatory response in the SN, manifested by the increased numbers of glial cells and the release of inflammatory factors (TNF-α, MCP-1, and IL-6). In vitro, it was proved that MC-LR mediated SH-SY5Y cell apoptosis by activating oxidative stress and damaging mitochondria. Collectively, this study revealed a novel molecular mechanism for MC-LR neurotoxicity with significant implications for human health and the public environment.