Banxia Xiexin decoction promotes gastric lymphatic pumping by regulating lymphatic smooth muscle cell contraction and energy metabolism in a stress-induced gastric ulceration rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) formula Banxia Xiexin decoction (BXD) has definite therapeutic effect in treating stress-induced gastric ulceration (SIGU) and many other gastrointestinal diseases, but its effect on gastric lymphatic pumping (GLP) remains unclear. AIM OF THE STUDY: Elucidating the role of GLP in SIGU and BXD treatment, and exploring the molecular mechanisms of GLP regulation. MATERIALS AND METHODS: In vivo GLP imaging were performed on SIGU rat model, and the lymphatic dynamic parameters were evaluated. Gastric antrum tissues and serum were collected for macroscopic, histopathological and ulcerative parameters analysis. Gastric lymphatic vessel (GLV) tissues were collected for RNA-Seq assays. Differentially expressed genes (DEGs) were screened from RNA-Seq result and submitted for transcriptomic analysis. Key DEGs and their derivative proteins were measured by qRT-PCR and WB. RESULTS: GLP was significantly suppressed in SIGU rats. BXD could recover GLP, ameliorate stomach lymphostasis, and alleviate the ulcerative damage. Transcriptome analysis of GLV showed the top up-DEGs were concentrated in smooth muscle contraction signaling pathway, while the top the down-DEGs were concentrated in energy metabolism pathways especially fatty acid degradation pathway, which indicated BXD can promote lymphatic smooth muscle contraction, regulate energy metabolism, and reduce fatty acid degradation. The most possible target of these mechanisms was the lymphatic smooth muscle cells (LSMCs) which drove the GLP. This speculation was further validated by the qRT-PCR and WB assessments for the level of key genes and proteins. CONCLUSIONS: By activating the smooth muscle contraction signaling pathway, restoring energy supply, modulating energy metabolism program and reducing fatty acid degradation, BXD effectively recovered GLP, mitigated the accumulation of inflammatory cytokines and metabolic wastes in the stomach, which importantly contributes to its efficacy in treating SIGU.

Effect of Laparoscopic and Open Pancreaticoduodenectomy for Pancreatic or Periampullary Tumors: Three-year Follow-up of a Randomized Clinical Trial.

OBJECTIVE: This study aimed to estimate whether the potential short-term advantages of laparoscopic pancreaticoduodenectomy (LPD) could allow patients to recover in a more timely manner and achieve better long-term survival than with open pancreaticoduodenectomy (OPD) in patients with pancreatic or periampullary tumors. BACKGROUND: LPD has been demonstrated to be feasible and may have several potential advantages over OPD in terms of shorter hospital stay and accelerated recovery than OPD. METHODS: This noninferiority, open-label, randomized clinical trial was conducted in 14 centers in China. The initial trial included 656 eligible patients with pancreatic or periampullary tumors enrolled from May 18, 2018, to December 19, 2019. The participants were randomized preoperatively in a 1:1 ratio to undergo either LPD (n=328) or OPD (n=328). The 3-year overall survival (OS), quality of life, which was assessed using the 3-level version of the European Quality of Life-5 Dimensions, depression, and other outcomes were evaluated. RESULTS: Data from 656 patients [328 men (69.9%); mean (SD) age: 56.2 (10.7) years] who underwent pancreaticoduodenectomy were analyzed. For malignancies, the 3-year OS rates were 59.1% and 54.3% in the LPD and OPD groups, respectively ( P =0.33, hazard ratio: 1.16, 95% CI: 0.86-1.56). The 3-year OS rates for others were 81.3% and 85.6% in the LPD and OPD groups, respectively ( P =0.40, hazard ratio: 0.70, 95% CI: 0.30-1.63). No significant differences were observed in quality of life, depression and other outcomes between the 2 groups. CONCLUSION: In patients with pancreatic or periampullary tumors, LPD performed by experienced surgeons resulted in a similar 3-year OS compared with OPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03138213.

Long-term quality of life between duodenum-preserving pancreatic head resection and pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: The authors aimed to compare the differences in quality of life (QOL) and overall survival (OS) between duodenum-preserving pancreatic head resection (DPPHR) and pancreatoduodenectomy (PD) during long-term follow-up. DPPHR and PD have been shown to be effective in alleviating symptoms and controlling malignancies, but there is ongoing debate over whether DPPHR has an advantage over PD in terms of long-term benefits. METHOD: The authors searched the PubMed, Cochrane, Embase, and Web of Science databases for relevant studies comparing DPPHR and PD published before 1 May 2023. This study was registered with PROSPERO. Randomised controlled trials and non-randomised studies were included. The Mantel-Haenszel model and inverse variance method were used as statistical approaches for data synthesis. Subgroup analyses were conducted to evaluate the heterogeneity of the results. The primary outcome was the global QOL score, measured using the QLQ-C30 system. RESULTS: The authors analysed ten studies involving 976 patients (456 DPPHR and 520 PD). The global QOL score did not differ significantly between the DPPHR and PD groups [standard mean difference (SMD) 0.21, 95% CI (-0.05, 0.46), P =0.109, I2 =70%]; however, the OS time of patients with DPPHR was significantly improved [hazard ratio 0.59, 95% CI (0.44, 0.77), P <0.001, I2 =0%]. The follow-up length may be an important source of heterogeneity. Studies with follow-up length between two to seven years showed better global QOL for DPPHR than for PD [SMD 0.43, 95% CI (0.23, 0.64), P <0.001, I2 =0%]. There were no significant differences between the two groups in any of the functional scales of the QLQ-C30 system (all P >0.05). On the symptom scale, patients in the DPPHR group had lower scores for fatigue, nausea and vomiting, loss of appetite, insomnia, and diarrhoea than those in the PD group (all P <0.05). CONCLUSIONS: There were no significant differences in global QOL scores between the two surgeries; however, DPPHR had advantages over PD in terms of safer perioperative outcomes, lower long-term symptom scores, and longer OS times. Therefore, DPPHR should be recommended over PD for the treatment of benign pancreatic diseases and low-grade malignant tumours.

Short-Term Outcomes Following Laparoscopic vs Open Pancreaticoduodenectomy in Patients With Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial.

Importance: The safety and efficacy of laparoscopic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma remain controversial. Objective: To compare laparoscopic and open pancreaticoduodenectomy performed by experienced surgeons in patients with pancreatic ductal adenocarcinoma. Design, Setting, and Participants: This was a noninferiority, open-label randomized clinical trial between September 20, 2019 and March 20, 2022, at 10 hospitals in China. A total of 412 adult patients were assessed for eligibility; 200 patients with histologically confirmed or clinically diagnosed pancreatic ductal adenocarcinoma who were eligible to undergo pancreaticoduodenectomy were enrolled. Study recruitment is complete, and follow-up is ongoing. This article reports prespecified early safety results from the trial. Interventions: Participants were randomized in a 1:1 ratio to undergo either laparoscopic or open pancreaticoduodenectomy, to be performed by experienced surgeons who had already performed at least 104 laparoscopic pancreaticoduodenectomy operations. Main Outcomes and Measures: The primary end point is 5-year overall survival, but the data for this end point are not yet mature; thus, secondary short-term outcomes, including operative findings, complications, mortality, and oncological results are reported here. The outcomes were analyzed according to a modified intention-to-treat and per-protocol principle. Results: Among 412 patients for eligibility, 200 patients were enrolled and randomly assigned 1:1 to have laparoscopic pancreaticoduodenectomy or open pancreaticoduodenectomy. The mean (SD) age was 61.3 (9.3) years, and 78 participants (39%) were female. Laparoscopic procedures had longer operative times (median [IQR], 330.0 [287.5-405.0] minutes vs 297.0 [245.0-340.0] minutes; P < .001). Patients in the laparoscopic group lost less blood than those in the open group (median [IQR], 145.0 [100.0-200.0] mL vs 200.0 [100.0-425.0] mL; P = .02). Ninety-day mortality occurred in 2 of 100 patients in the laparoscopic group and 0 of 100 patients in the open group. There was no difference in the rates of complications of the Clavien-Dindo grades III-IV (n = 17 [17.0%] vs n = 23 [23.0%]; P = .29), comprehensive complication index (median [IQR], 0.0 [0.0-22.6] vs 8.7 [0.0-26.2]; P = .79) or median (IQR) postoperative length of stay (14.0 [11.0-17.0] days vs 14.0 [12.0-18.5] days; P = .37) between the 2 groups. Conclusions and Relevance: Laparoscopic pancreaticoduodenectomy performed by experienced surgeons in high-volume specialized institutions resulted in similar short-term outcomes compared with open pancreaticoduodenectomy among patients with pancreatic ductal adenocarcinoma. Trial Registration: ClinicalTrials.gov Identifier: NCT03785743.

A comparative study of the "superior mesenteric artery first" approach versus the conventional approach in short-term and long-term outcomes in patients with pancreatic ductal adenocarcinoma undergoing laparoscopic pancreaticoduodenectomy.

BACKGROUND: The use of laparoscopic pancreaticoduodenectomy (LPD) in pancreatic head cancer remains controversial, and an appropriate surgical approach can help improve perioperative safety and oncological outcomes. This study aimed to assess the short-term outcomes and long-term survival of the superior mesenteric artery first (SMA-first) approach in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing LPD. METHODS: The data of 91 consecutive PDAC patients who underwent LPD from June 2014 to June 2021 were retrospectively analyzed. Patients were divided into two groups, the modified SMA-first approach group, using a combined posterior and anterior approach, and the conventional approach group. Perioperative outcomes, pathologic results, and overall survival (OS) were compared between groups, and propensity score-matched (PSM) analysis was performed. RESULTS: The number of lymph nodes harvested was greater in the SMA-first approach group (19 vs. 15, P = 0.021), as did the results in the matched cohort (21 vs. 15, P = 0.046). No significant difference was observed in the R0 resection rate (93.3% vs. 82.6%, P = 0.197), but the involvement of the SMA margin was indeed lower in the SMA-first approach group (0 vs. 13%). There were no obvious variances between the two groups in terms of intraoperative bleeding, operative time, overall and major postoperative complication rates, and mortality in either the original cohort or matched cohort. The median OS was 21.8 months in the SMA-first group, whereas it was 19.8 months in the conventional group (P = 0.900). Survival also did not differ in the matched cohort (P = 0.558). TNM stage, resection margin, overall complications, and adjuvant therapy were independent risk factors affecting OS. CONCLUSION: The modified SMA-first approach is safe and feasible for PDAC patients undergoing LPD. It had a slight advantage in specimen quality, but OS was not significantly prolonged.

A self-amplifying USP14-TAZ loop drives the progression and liver metastasis of pancreatic ductal adenocarcinoma.

With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC.

An E3 ubiquitin-proteasome gene signature for predicting prognosis in patients with pancreatic cancer.

Pancreatic cancer is the seventh leading cause of cancer death worldwide, which is demonstrated with remarkable resistance to radiotherapy and chemotherapy. The identification of prognosis signature and novel prognostic markers will facilitate patient stratification and an individualized precision therapy strategy. In this study, TCGA-PAAD was used to screen prognostic E3 ubiquitin ligases and establish prognostic signatures, and GEO database was used to verify the accuracy of prognostic signatures. Functional analysis, in vitro experiments and clinical cohort studies were used to analyze the function and prognostic efficacy of the target gene. An E3 ligase-based signature of 9 genes and the nomogram were developed, and the signature was proved to accurately predict the prognosis of patients with pancreatic cancer. WDR37 might be the most prognostic E3 ubiquitin ligase in pancreatic cancer, and the clinical cohort analyses suggested a tumor-suppressive role. The results of functional analysis and in vitro experiments indicated that WDR37 may promote the degradation of TCP1 complex to inhibit tumor and improve immune cell infiltration. The E3 ligase-based signature accurately predicted the prognosis of patients with pancreatic cancer, so it can be used as a decision-making tool to guide the treatment of patients with pancreatic cancer. At the same time, WDR37, the main gene in E3PMP signature, can be used as the most prognostic E3 ubiquitin ligase in the treatment of pancreatic cancer.

Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition.

BACKGROUND: Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). METHODS: The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. FINDINGS: We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. INTERPRETATION: Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. FUNDING: This study was supported by The National Natural Science Foundation of China.

LncRNA FAM83H-AS1 promotes the malignant progression of pancreatic ductal adenocarcinoma by stabilizing FAM83H mRNA to protect ß-catenin from degradation.

BACKGROUND: Pancreatic ductal adenocarcinoma is prone to metastasis, resulting in short survival and low quality of life. LncRNAs are pivotal orchestrators that participate in various tumor progress. The underlying role and mechanism of lncRNA FAM83H-AS1 is still unknown in PDAC progression. METHODS: To address this issue, firstly, we profiled and analyzed the aberrant lncRNA expression in TCGA database and identified FAM83H-AS1 as the most effective one in promoting the migration of pancreatic cancer cells. Then, the expression levels of FAM83H-AS1 in patient's serum, tumor tissues and PDAC cells were detected using RT-qPCR, and FAM83H-AS1 distribution in PDAC cells was determined by performing FISH and RT-qPCR. Next, a series of in vivo and in vitro functional assays were conducted to elucidate the role of FAM83H-AS1 in cell growth and metastasis in PDAC. The regulatory relationship between FAM83H-AS1 and FAM83H (the homologous gene of FAM83H-AS1) was verified by performing protein and RNA degradation assays respectively. Co-IP assays were performed to explore the potential regulatory mechanism of FAM83H to ß-catenin. Rescue assays were performed to validate the regulation of the FAM83H-AS1/FAM83H/ß-catenin axis in PDAC progression. RESULTS: FAM83H-AS1 was highly expressed in the tumor tissues and serum of patients with PDAC, and was correlated with shorter survival. FAM83H-AS1 significantly promoted the proliferation, invasion and metastasis of PDAC cells, by protecting FAM83H mRNA from degradation. Importantly, FAM83H protein manifested the similar malignant functions as that of FAM83H-AS1 in PDAC cells, and could bind to ß-catenin. Specifically, FAM83H could decrease the ubiquitylation of ß-catenin, and accordingly activated the effector genes of Wnt/ß-catenin signaling. CONCLUSIONS: Collectively, FAM83H-AS1 could promote FAM83H expression by stabilizing its mRNA, allowing FAM83H to decrease the ubiquitylation of ß-catenin, thus resulted in an amplified FAM83H-AS1/FAM83H/ß-catenin signal axis to promote PDAC progression. FAM83H-AS1 might be a novel prognostic and therapeutic target for combating PDAC.

Comparison of safety and effectiveness between laparoscopic and open pancreatoduodenectomy: A systematic review and meta-analysis.

BACKGROUND: Validity of the laparoscopic approach in pancreatic head lesion remains debatable. This study aims to compare the safety and effectiveness of laparoscopic pancreatoduodenectomy (LPD) and open pancreatoduodenectomy (OPD) and investigate the source of heterogeneity from surgeons' and patients' perspectives. METHOD: We searched PubMed, Cochrane, Embase, and Web of Science for studies published before February 1, 2021. Of 6578 articles, 81 were full-text reviewed. The primary outcome was mortality. Three independent reviewers screened and extracted the data and resolved disagreements by consensus. Studies were evaluated for quality using ROB2.0 and ROBINS-I. According to different study designs, sensitivity and meta-regression analyses were conducted to explore the heterogeneity source. This meta-analyses was also conducted to explore the learning curve's heterogeneity. This study was registered with PROSPERO, CRD42021234579. RESULTS: We analyzed 34 studies involving 46,729 patients (4705 LPD and 42,024 OPD). LPD was associated with lower (P = 0.025) in unmatched studies (P = 0.017). No differences in mortality existed in randomized controlled trials (P = 0.854) and matched studies (P = 0.726). Sensitivity analysis found no significant difference in mortality in elderly patients, patients with pancreatic cancer, and in high- and low-volume hospitals (all P > 0.05). In studies at the early period of LPD (<40 cases), higher mortality (P < 0.001) was found (all P < 0.05).LPD showed non-inferiority in length of stay, complications, and survival outcomes in all analyses. CONCLUSION: In high-volume centers with adequate surgical experience, LPD in selected patients appears to be a valid alternative to LPD with comparable mortality, LOS, complications, and survival outcomes.

One hundred most cited article related to pancreaticoduodenectomy surgery: A bibliometric analysis.

BACKGROUND: In light of the challenges associated with pancreaticoduodenectomy (PD) and recent key improvements, this bibliometric analysis aimed to analyze the 100 top-cited (T100) articles related to PD surgery to widen the awareness of relevant research on this procedure. METHODS: The term "pancreaticoduodenectomy" was used to retrieve articles from the Web of Science Core Collection database. The 100 most cited manuscripts in the English language were identified and further analyzed by their countries of origin, publication journals, authors, and themes. RESULTS: A thorough literature search was performed on the Web of Science until April 2020. The total number of citations for the T100 articles ranged from 227 to 3029. The T100 articles came from 18 different countries, with the USA accounting for the plurality (n = 72). Professor J.L. Cameron from Johns Hopkins Medicine USA published the most articles (n = 22), including one as the first author and two as a co-author. Furthermore, Johns Hopkins Medicine, USA, published the most articles on PD surgery (n = 24), with a total citation count of 14,151. The journal Annals of Surgery published 40 of the T100 articles, with 15,847 citations and an average citation count of 396. Among the T100 articles, the citation frequency following the year of publication showed a parabolic trend, with citations peaking in the 9th year following publication. CONCLUSION: Our study identified and analyzed the T100 articles in PD surgery. The USA was the dominant country regarding articles, researchers, and institutions. The citations of the articles peaked in the 9th year after publication.

Laparoscopic versus open pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Pancreatic cancer is one of the deadliest cancers and pancreaticoduodenectomy (PD) is recommended as the optimal operation for resectable pancreatic head cancer. Minimally invasive surgery, which initially emerged as hybrid-laparoscopy and recently developed into total laparoscopy surgery, has been widely used for various abdominal surgeries. However, controversy persists regarding whether laparoscopic PD (LPD) is inferior to open PD (OPD) for resectable pancreatic ductal adenocarcinoma (PDAC) treatment. Further studies, especially randomised clinical trials, are warranted to compare these two surgical techniques. METHODS AND ANALYSIS: The TJDBPS07 study is designed as a prospective, randomised controlled, parallel-group, open-label, multicentre noninferiority study. All participating pancreatic surgical centres comprise specialists who have performed no less than 104 LPDs and OPDs, respectively. A total of 200 strictly selected PD candidates diagnosed with PDAC will be randomised to receive LPD or OPD. The primary outcome is the 5-year overall survival rate, whereas the secondary outcomes include overall survival, disease-free survival, 90-day mortality, complication rate, comprehensive complication index, length of stay and intraoperative indicators. We hypothesise that LPD is not inferior to OPD for the treatment of resectable PDAC. The enrolment schedule is estimated to be 2 years and follow-up for each patient will be 5 years. ETHICS AND DISSEMINATION: This study received approval from the Tongji Hospital Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology, and monitor from an independent third-party organisation. Results of this trial will be presented in international meetings and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03785743.

Comparison of laparoscopic versus open pancreaticoduodenectomy in patients with resectable pancreatic ductal adenocarcinoma: A propensity score-matching analysis of long-term survival.

BACKGROUND: Many studies have shown the short-term feasibility and effectiveness of laparoscopic pancreaticoduodenectomy (LPD) are comparable to open pancreaticoduodenectomy (OPD). However, the long-term oncological safety of LPD in patients with pancreatic ductal adenocarcinoma (PDAC) remains to be elucidated. METHODS: Patients who underwent LPD or OPD between July 2014 and July 2018 at our institution were identified, and those with resectable, pathologically diagnosed PDAC were analyzed. The primary outcome was overall survival (OS). Propensity score-matching (PSM) analysis was performed to balance the baseline characteristics between groups. Cox proportional hazards model was constructed to determine independent predictors of OS. RESULTS: The original cohort consisted of 64 LPD and 80 OPD cases, in which, the laparoscopic group had a significantly longer median OS (25 vs. 17 months; P = 0.034). A higher proportion of laparoscopic patients received adjuvant therapy (51.6 vs. 32.5%; P = 0.021). PSM analysis identified 47 patient pairs. No significant differences in OS (21 vs. 17 months; P = 0.220) or adjuvant therapy utilization (53.2 vs. 38.3%; P = 0.248) were observed between the matched groups. Multivariate Cox analyses showed that receiving adjuvant therapy (HR = 0.44; 95% CI, 0.28-0.68), histopathological differentiation (poor vs. moderate-to-well differentiation; HR = 1.93; 95% CI, 1.26-2.95), and sex (female vs. male, HR = 0.47, 95% CI, 0.30-0.75) were independent predictors of OS. CONCLUSIONS: LPD can be comparable to OPD in terms of long-term safety for patients with resectable pancreatic ductal adenocarcinoma when performed in a high-volume center.

Long Noncoding Competing Endogenous RNA Networks in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly malignant disease characterized by insidious onset, rapid progress, and poor therapeutic effects. The molecular mechanisms associated with PC initiation and progression are largely insufficient, hampering the exploitation of novel diagnostic biomarkers and development of efficient therapeutic strategies. Emerging evidence recently reveals that noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), extensively participate in PC pathogenesis. Specifically, lncRNAs can function as competing endogenous RNAs (ceRNAs), competitively sequestering miRNAs, therefore modulating the expression levels of their downstream target genes. Such complex lncRNA/miRNA/mRNA networks, namely, ceRNA networks, play crucial roles in the biological processes of PC by regulating cell growth and survival, epithelial-mesenchymal transition and metastasis, cancer stem cell maintenance, metabolism, autophagy, chemoresistance, and angiogenesis. In this review, the emerging knowledge on the lncRNA-associated ceRNA networks involved in PC initiation and progression will be summarized, and the potentials of the competitive crosstalk as diagnostic, prognostic, and therapeutic targets will be comprehensively discussed.

Clinical Efficacy of the Preservation of the Hepatic Branch of the Vagus Nerve on Delayed Gastric Emptying After Laparoscopic Pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is a common complication following laparoscopic pancreaticoduodenectomy (LPD), although it remains incompletely understood, and only few studies have investigated the clinical benefits of hepatic branch of the vagus nerve (HBVN) preservation on DGE after LPD until now. We intended to evaluate the effect of preservation of the HBVN during LPD on the incidence of DGE. METHODS: A total of 274 consecutive LPDs performed at a single center between July 2014 and December 2019 with available videos were retrospectively reviewed. DGE was defined according to the International Study Group of Pancreatic Surgery (ISGPS) criteria, and HBVN condition during the LPD procedure was evaluated through a video review. Risk factors associated with DGE were assessed by performing univariate and multivariate logistic regression analyses. Postoperative outcomes between the HBVN-preserved and HBVN-injury groups were compared before and after propensity score matching (PSM). RESULTS: One hundred fifty-six (56.93%) patients underwent LPD with HBVN-preserved and 118 (43.07%) with HBVN injury. DGE occurred in 33.2% of patients (n = 91) with grades B and C occurring at 13.9% (n = 38) and 7.7% (n = 21), respectively. Longer operative time, more EIBL, HBVN injury, POPF (grades B and C), postoperative hemorrhage, intra-abdominal infection, and Clavien-Dindo ≥III were identified as risk factors for DGE in the univariate analysis. Then, in the multivariate analysis, HBVN injury and intra-abdominal infection were found to be independent risk factors affecting the incidence of DGE (any grade) or clinically relevant DGE (grades B and C). Furthermore, the prevalence of DGE was significantly higher in the HBVN-injury group than in the HBVN-preserved group before and after PSM analysis (46.61% vs. 23.08%, P<0.001; 42.59% vs. 23.15%, P=0.013). CONCLUSIONS: HBVN preservation during LPD might be associated with a reduced incidence of DGE as a framework for prospective quality improvement.

Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells.

Several natural products have been demonstrated to both enhance the anti-tumor efficacy and alleviate the side effects of conventional chemotherapy drugs. Rhein, a main constituent of the Chinese herb rhubarb, has been shown to induce apoptosis in various cancer types. However, the exact pharmacological mechanisms controlling the influence of Rhein on chemotherapy drug effects in pancreatic cancer (PC) remain largely undefined. In this study, we found that Rhein inhibited the growth and proliferation of PC cells through G1 phase cell cycle arrest. Moreover, Rhein induced caspase-dependent mitochondrial apoptosis of PC cells through inactivation of the PI3K/AKT pathway. Combination treatment of Rhein and oxaliplatin synergistically enhanced apoptosis of PC cells through increased generation of intracellular reactive oxygen species (ROS) and inactivation of the PI3K/AKT pathway. Pre-treatment with the ROS scavenger N-acetyl-L-cysteine attenuated the combined treatment-induced apoptosis and restored the level of phosphorylated AKT, indicating that ROS is an upstream regulator of the PI3K/AKT pathway. The combination therapy also exhibited stronger anti-tumor effects compared with single drug treatments in vivo. Taken together, these data demonstrate that Rhein can induce apoptosis and enhance the oxaliplatin sensitivity of PC cells, suggesting that Rhein may be an effective strategy to overcome drug resistance in the chemotherapeutic treatment of PC.

MicroRNA­137 suppresses the proliferation, migration and invasion of cholangiocarcinoma cells by targeting WNT2B.

It is widely known that abnormal regulation of microRNAs (miRNAs/miRs) may contribute to the occurrence or development of tumors. The objective of the present study was to elucidate the function and underlying mechanism of miR­137 in the progression of cholangiocarcinoma (CCA). The expression levels of miR­137 in CCA tissues and cell lines were measured using reverse transcription­quantitative PCR. The role of miR­137 in the proliferation of CCA cells was assessed using the Cell Counting Kit­8 assay, colony formation assay and cell cycle distribution analysis, while its effects on the migration and invasion of CCA cells were evaluated using Transwell assays. The function of miR­137 on CCA growth in vivo was also investigated using a xenograft mouse model. Furthermore, the association between miR­137 and Wnt family member 2B (WNT2B) was analyzed using bioinformatics, double luciferase assay and western blotting. It was verified that the expression of miR­137 was low in CCA tissues and cell lines, whereas increased expression of miR­137 significantly suppressed cell proliferation, decreased colony formation ability and induced G1 phase arrest. miR­137 overexpression suppressed the migration and invasion ability of TFK­1 and HuCCT1 cells. Furthermore, the results of the xenograft mouse model assays revealed that miR­137 overexpression decreased tumor growth in vivo. The results of bioinformatics analysis and dual luciferase reporter assays demonstrated that WNT2B is directly regulated by miR­137. The expression of WNT2B and Wnt­pathway­related proteins was decreased when miR­137 was overexpressed. Restoring the expression of WNT2B notably reversed the inhibitory effect of miR­137 on CCA cells. Therefore, the findings of the present study demonstrated that miR­137 acts as a suppressor in CCA and inhibits CCA cell proliferation, migration and invasion through suppressing the expression of WNT2B.

Long noncoding RNA LINC01111 suppresses pancreatic cancer aggressiveness by regulating DUSP1 expression via microRNA-3924.

Dysfunction in long noncoding RNAs (lncRNAs) is reported to participate in the initiation and progression of human cancer; however, the biological functions and molecular mechanisms through which lncRNAs affect pancreatic cancer (PC) are largely unknown. Here, we report a novel lncRNA, LINC01111, that is clearly downregulated in PC tissues and plasma of PC patients and acts as a tumor suppressor. We found that the LINC01111 level was negatively correlated with the TNM stage but positively correlated with the survival of PC patients. The overexpression of LINC01111 significantly inhibited cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, the knockdown of LINC01111 enhanced cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Furthermore, we found that high expression levels of LINC01111 upregulated DUSP1 levels by sequestering miR-3924, resulting in the blockage of SAPK phosphorylation and the inactivation of the SAPK/JNK signaling pathway in PC cells and thus inhibiting PC aggressiveness. Overall, these data reveal that LINC01111 is a potential diagnostic biomarker for PC patients, and the newly identified LINC01111/miR-3924/DUSP1 axis can modulate PC initiation and development.

TFEB-driven autophagy potentiates TGF-ß induced migration in pancreatic cancer cells.

BACKGROUND: Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of less than 8%. The complicated tumor microenvironment, particularly TGF-ß, provides possible convenience for the progression of PC cells. TGF-ß regulates critical cellular processes, including autophagy. However, the mechanism and effects of TGF-ß-mediated autophagy are still poorly understood. METHODS: Bioinformatics analysis, western blot, transmission electron microscopy and confocal microscopy were used to identify that TFEB is the key factors in TGF-ß-induced autophagy. The biological effects of TFEB-driven autophagy were investigated in vitro using transwell and wound healing assays and in vivo using liver metastasis and LSL-KrasG12D/Pdx1-Cre mice models. Luciferase assays and motif analysis were used to assess regulation of RAB5A gene promoter activity by TGF-ß-induced TFEB. TFEB levels were measured by real-time PCR, western blot and immunohistochemical staining in clinical pancreatic ductal adenocarcinoma tissues. RESULTS: We demonstrated that TGF-ß induces TFEB expression via the canonical smad pathway in Smad4-positive PC cells and facilitates TFEB-mediated autophagic activation. TFEB-driven autophagy caused by TGF-ß regulates RAB5A-dependent endocytosis of Itgα5 and promotes progression of PC cells. We further showed that enhanced TFEB expression and its direct target RAB5A both predict poor prognosis in PC patients. CONCLUSIONS: Our findings reveal TFEB-driven autophagy is required for TGF-ß induced migration and metastasis of PC cells by promoting endocytosis of Itgα5ß1 and focal adhesion disassembly through the TGF-ß-TFEB-RAB5A axis. Our results highlight the potential utility of suppressing TFEB-driven autophagy to block PC metastasis.

Alantolactone induces apoptosis and improves chemosensitivity of pancreatic cancer cells by impairment of autophagy-lysosome pathway via targeting TFEB.

The lysosome is emerging as a central regulator of the autophagic process, which plays a critical role in tumor growth and chemoresistance. Alantolactone, which is a natural compound produced by Inula helenium, has been shown to induce apoptosis in numerous cancer types. However, the mechanism by which alantolactone regulates apoptosis is still poorly understood. In this work, we observed that alantolactone caused the accumulation of autophagosomes due to impaired autophagic degradation and substantially inhibited the activity and expression of CTSB/CTSD proteins that when depleted caused lysosomal dysfunction. Furthermore, we found that alantolactone inhibited the proliferation of pancreatic cancer cells in vitro and in vivo and enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin. In addition, a reduction in TFEB levels was a critical event in the apoptosis and cell death caused by alantolactone. Our data demonstrated that alantolactone, which impaired autophagic degradation, was a pharmacological inhibitor of autophagy in pancreatic cancer cells and markedly enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.