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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.

Background: Pancreatic cancer was prone to metastasis, which leaded to the poor survival and low quality of life. Here, we found that FAM83H-AS1 was highly correlated with metastasis of pancreatic cancer and further explored the functions and mechanisms involving in the malignant progression of pancreatic cancer. Method: We profiled and analyzed the aberrant expression of lncRNA (long non-coding RNA) in TCGA database and screened FAM83H-AS1 most effective in promoting the migration of pancreatic cancer cells. Firstly, the expression level of FAM83H-AS1 in serum, tissues and cells were detected by RT-qPCR, and the distribution of it in pancreatic cancer cells was tested by FISH and nuclear/cytosol fractionation RT-qPCR. Next, a series of functional assays were conducted to elucidate the relationship between FAM83H-AS1 and pancreatic cancer in vivo and vitro. The regulation relationship between FAM83H-AS1 and FAM83H was verified by protein and RNA degradation assays respectively. A series of Co-immunoprecipitation assays was utilized to explore the potential mechanism of FAM83H and β-catenin. Rescue assays were used to illustrate the regulation axis of FAM83H-AS1/FAM83H/ Wnt/β-catenin in pancreatic cancer.Results: FAM83H-AS1 was highly expressed in cancer tissues and serum of PDAC patients, and was correlated with poorer survival. FAM83H-AS1, as an oncogene, promoted the proliferation, invasion and metastasis of PDAC cells by functional assays and bioinformatics analysis. FAM83H, the homologous gene of FAM83H-AS1, also manifested the same biological behaviour as FAM83H-AS1 in PDAC. Also, FAM83H-AS1 protected FAM83H mRNA from degradation and FAM83H directly bound β-catenin. Mechanically, FAM83H-AS1 facilitated the expression of FAM83H by stabilizing its mRNA and promoted FAM83H to decrease the ubiquitylation of β-catenin, which activated the effect genes of Wnt/β-catenin signalling.Conclusions: This study revealed the function of FAM83H-AS1 involving in the progression of PDAC, and might provide a new prognostic indicator and therapy target for PDAC.

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.

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.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.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.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.

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.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.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.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.

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. 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). 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

Background: Due to the significant heterogeneity in previous studies, concerns persist regarding the safety and effectiveness of laparoscopic pancreatoduodenectomy (LPD). Therefore, with the publication of new researches, a comprehensive systematic review is needed to evaluate the potential benefits of laparoscopic pancreatoduodenectomy. We aimed to compare safety and effectiveness of laparoscopic and open pancreatoduodenectomy (OPD) from the published studies, and investigate the source of heterogeneity from the surgeons’ and patients’ perspectives. Methods: We searched PubMed, Cochrane, Embase, and Web of Science databases for relevant studies published before February 1, 2021 comparing laparoscopic and open pancreatoduodenectomy. The database search yielded a total of 6,578 articles, and 81 articles were full-text reviewed. Studies of laparoscopic-assisted surgery were not included. 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. Meta-analyses were conducted in random-effect and fixed-effect models. Different meta-analyses were conducted according to the different designs of the studies. The sensitivity analyses and meta-regression were conducted to explore the source of heterogeneity. This study was registered with PROSPERO, ID CRD42021234579. Findings: We analyzed 34 studies involving 46,729 patients (4,705 LPD and 42,024 OPD). LPD was associated with lower mortality in overall studies (odds ratio [OR] 0·800, 95% confidence interval [CI] 0·659–0·973, P=0·025, I2=0·0%) and unmatched studies (OR 0·774, 95%CI 0·628–0·954, P=0·017, I2=0·0%). However, no differences in mortality were seen in RCTs (randomized controlled trial) (risk ratio 1·080, 95%CI 0·473–2·466, P=0·854, I2=13·4%) and matched studies (OR 0·904, 95%CI 0·515–1·587, P=0·726, I2=0·0%). Sensitivity analysis found that mortality was also similar between the two groups in elderly patients, patients with pancreatic ductal adenocarcinoma (PDAC), high-volume hospitals, and low-volume hospitals (all P >0·05). However, LPD showed non-inferiority in length of stay (LOS), severe complications, clinical relevant-postoperative pancreatic fistula, clinical relevant-biliary leak, intra-abdominal infection, readmission, overall survival, and 2-year relapse. Elderly patients benefited marginally from LPD, while patients with PDAC and patients in high-volume hospitals benefit significantly. Meta-regression confirmed that baseline differences including the proportion of males, age, proportion of biliary drainage, diagnosis of PDAC, and lesion size between LPD and OPD groups had a significant impact on LOS, severe complications, ICU stay, estimated intraoperative blood loss, and lymph node harvest (all P

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.

Novel biomarkers for pancreatic adenocarcinoma are urgently needed because of its poor prognosis. Here, by using The Cancer Genome Atlas (TCGA) RNA-seq data, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a five-miRNA signature that could effectively predict patient overall survival (OS). The Kaplan-Meier overall survival curves of two groups based on the five miRNAs were notably different, showing overall survival in 10.2% and 47.8% at five years for patients in high-risk and low-risk groups, respectively. The ROC curve analysis achieved AUC of 0.775, showing good sensitivity and specificity of the five-miRNA signature model in predicting pancreatic adenocarcinoma patient survival risk. The functional enrichment analysis suggested that the target genes of the miRNA signature may be involved in various pathways related to cancer, including PI3K-Akt, TGF-β, and pluripotent stem cell signaling pathways. Finally, we analyzed expression of the five specific miRNAs in the miRNA signature, and validated the reliability of the results in 20 newly diagnosed pancreatic adenocarcinoma patients using qRT-PCR. The expression results of qRT-PCR were consistent with the TCGA results. Taken together, these findings suggested that the five-miRNA signature (hsa-miR-203, hsa-miR-424, hsa-miR-1266 hsa-miR-1293, and hsa-miR-4772) could be used as a prognostic marker for pancreatic adenocarcinoma.

// Xiuhui Shi 1 , Yan Zhao 1 , Ruizhi He 1 , Min Zhou 1 , Shutao Pan 1 , Shuo Yu 1 , Yu Xie 1 , Xu Li 1 , Min Wang 1 , Xingjun Guo 1 and Renyi Qin 1 1 Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Correspondence to: Renyi Qin, email: ryqin@tjh.tjmu.edu.cn Xingjun Guo, email: xjguo@tjh.tjmu.edu.cn Keywords: long noncoding RNA; pancreatic adenocarcinoma; TCGA; ceRNA; prognosis Received: August 23, 2017 Accepted: February 01, 2018 Epub: February 08, 2018 Published: May 11, 2018 ABSTRACT Pancreatic adenocarcinoma (PAAD) is a highly aggressive and metastatic cancer characterized by poor survival rates. Long non-coding RNAs (lncRNAs) play important roles in various biological processes, including cancer and PAAD. To identify the specific lncRNAs associated with PAAD and analyze their function, we constructed a global triple network based on the competitive endogenous RNA (ceRNA) theory and RNA-seq data from The Cancer Genome Atlas. Using 182 PAAD cases, we established a lncRNA–miRNA–mRNA co-expression network, which was composed of 43 lncRNA nodes, 253 mRNA nodes, 11 miRNA nodes, and 475 edges. Six lncRNAs in the ceRNA network were closely related to overall survival, and a three-lncRNA signature predicted survival of PAAD patients. Protein–protein interaction network data revealed that five genes were associated with overall survival. These results provide novel insight into the function of a lncRNA-associated ceRNA network in the pathogenesis of PAAD, and indicate that the identified three-lncRNA signature may serve as an independent prognostic marker in PAAD.