Hypoxia-induced epigenetic regulation of miR-485-3p promotes stemness and chemoresistance in pancreatic ductal adenocarcinoma via SLC7A11-mediated ferroptosis.

The mechanism of hypoxia in chemoresistance of pancreatic ductal adenocarcinoma (PDAC) remains elusive. In this study, we revealed the essential role of miR-485-3p in PDAC, particularly its impact on cancer stemness and gemcitabine resistance under hypoxic conditions. We found substantial downregulation of miR-485-3p in PDAC tissues, with lower expression correlating to poor patient outcomes. Mechanistically, miR-485-3p influenced stemness characteristics, as evidenced by reduced tumor-sphere formation and increased sensitivity to gemcitabine upon overexpression. Moreover, we identified SOX9 and SLC7A11 as two targets of miR-485-3p, which play a vital role in stemness and ferroptosis. Under the hypoxic condition, DNMT3B expression was upregulated, leading to hypermethylation of the miR-485-3p promoter region. The reduced miR-485-3p expression promoted stemness and chemoresistance of PDAC. In conclusion, our findings elucidate the intricate interplay of hypoxia, epigenetic modifications, and ferroptosis in PDAC and shed light on potential avenues for targeted interventions that modulate cancer stemness and chemosensitivity, offering prospects for improved therapeutic strategies for PDAC.

Cancer associated fibroblasts and metabolic reprogramming: unraveling the intricate crosstalk in tumor evolution.

Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Prophylactic Intra-Peritoneal Drainage After Pancreatic Resection: An Updated Meta-Analysis.

INTRODUCTION: Prophylactic intra-peritoneal drainage has been considered to be an effective measure to reduce postoperative complications after pancreatectomy. However, routinely placed drainage during abdominal surgery may be unnecessary or even harmful to some patients, due to the possibility of increasing complications. And there is still controversy about the prophylactic intra-peritoneal drainage after pancreatectomy. This meta-analysis aimed to analyze the incidence of complications after either pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) in the drain group and no-drain group. METHODS: Data were retrieved from four electronic databases PubMed, EMBASE, the Cochrane Library and Web of Science up to December 2020, including the outcomes of individual treatment after PD and DP, mortality, morbidity, clinically relevant postoperative pancreatic fistula (CR-POPF), bile leak, wound infection, postoperative hemorrhage, delayed gastric emptying (DGE), intra-abdominal abscess, reoperation, intervened radiology (IR), and readmission. Cochrane Collaboration Handbook and the criteria of the Newcastle-Ottawa scale were used to assess the quality of studies included. RESULTS: We included 15 studies after strict screening. 13 studies with 16,648 patients were analyzed to assess the effect of drain placement on patients with different surgery procedures, and 4 studies with 6,990 patients were analyzed to assess the effect of drain placement on patients with different fistula risk. For patients undergoing PD, the drain group had lower mortality but higher rate of CR-POPF than the no-drain group. For patients undergoing DP, the drain group had higher rates of CR-POPF, wound infection and readmission. There were no significant differences in bile leak, hemorrhage, DGE, intra-abdominal abscess, and IR in either overall or each subgroup. For Low-risk subgroup, the rates of hemorrhage, DGE and morbidity were higher after drainage. For High-risk subgroup, the rate of hemorrhage was higher while the rates of reoperation and morbidity were lower in the drain group. CONCLUSIONS: Intraperitoneal drainage may benefit some patients undergoing PD, especially those with high pancreatic fistula risk. For DP, current evidences suggest that routine drainage might not benefit patients, but no clear conclusions can be drawn because of the study limitations.

Effects of parecoxib after pancreaticoduodenectomy: A single center randomized controlled trial.

BACKGROUND: Parecoxib, a selective cyclooxygenase-2 inhibitor, is a potential alternative analgesic to reduce opioid consumption after Pancreaticoduodenectomy (PD). Further, the safety and efficacy of long-term use of parecoxib for patients after PD remain a major concern. MATERIALS AND METHODS: In this single-center, randomized clinical trial, 134 patients undergoing open PD were randomized into the parecoxib group (group P) and control group (group C) at a 1:1 ratio. Besides a routine patient-controlled epidural analgesia (PCEA) until 3 days postoperatively for both groups, patients in group P (n = 68) received parecoxib (40 mg, intravenously, Q 12 h) for the first 5 postoperative days and were encouraged to receive opioid analgesics to control severe pain as needed. Patients in group C (n = 66) received on-demand opioid analgesics (pethidine or morphine) postoperatively. The primary outcomes included the effectiveness of parecoxib in controlling pain (measured using the visual analog scale (VAS)) and reduction of opioid use (measured as accumulated doses). Secondary outcomes included the postoperative recovery process, rate of postoperative complications, and the anti-inflammatory effect of parecoxib. RESULTS: The VAS scores were not significantly different between the two groups. The number of doses of opioids for patients in group P (3.2 ± 0.3 doses) was significantly lower than in group C (8.5 ± 0.4 doses) (p = 0.0007). The incidence of opioid-related side effects was significantly lower in group P than in group C (p = 0.001). There were no significant differences in postoperative complications or readmission rates between the two groups. The postoperative time to first pass flatus, time to first mobilization out of bed, and time of removal of nasogastric tube in group P were significantly shorter than those in group C (P < 0.05). The postoperative serum IL-6 levels of patients in group P were significantly lower than those in group C at each time point (P < 0.05). CONCLUSIONS: Parecoxib effectively controls pain after PD. Prophylactic analgesia using parecoxib for up to 5 days after PD is safe, feasible, and can provide the same optimal pain control as opioids without adverse effects.