USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2.

Gemcitabine (Gem) is the first-line chemotherapy drug for pancreatic cancer, but the acquired chemoresistance also hinders its application. Therefore, research about Gem resistance plays a crucial role in enhancing the therapeutic effect of Gem. As a deubiquitinating enzyme, ubiquitin-specific protease 8 (USP8) was shown to play vital roles in the tumorigenesis processes of several cancers; however, the effect of USP8 on Gem resistance of pancreatic cancer still remains largely unknown. In the current study, we observed that the expression of USP8 was increased in pancreatic cancer patients, it is related to the recurrence of Gem chemotherapy, and USP8 expression could be induced by Gem application. Furthermore, USP8 was found to promote Gem resistance both in vivo and in vitro via regulating cell viability and apoptosis. Moreover, USP8 enhanced the activation of Nrf2 signaling which is dependent on its deubiquitinase ability. At last, we illustrated that USP8 interacted with Nrf2 directly and deubiquitinated K48-linked polyubiquitin chains from Nrf2, stabilizing the expression of Nrf2. In summary, the manuscript revealed the role of USP8 in Gem chemoresistance and suggested USP8 as a potential therapeutic target for pancreatic cancer.

miR-222-3p-containing macrophage-derived extracellular vesicles confer gemcitabine resistance via TSC1-mediated mTOR/AKT/PI3K pathway in pancreatic cancer.

Gemcitabine resistance limits the efficacy of chemotherapy and maintains a challenge for treatment outcomes. Therefore, we aimed to clarify the downstream mechanisms underlying the role of miR-222-3p delivered by M2 macrophage-derived extracellular vesicles (M2 MDEs) in the chemoresistance of pancreatic cancer (PCa). We separated the mouse macrophages and polarized them to M2 phenotypes, from which the EVs were derived. miR-222-3p was highly expressed in M2 MDEs. M2 MDEs were internalized by PCa cells. miR-222-3p overexpressing M2 MDEs were treated with gemcitabine and co-cultured with PCa cells for in vitro experiments. Co-culture with M2 MDEs enriched with miR-222-3p suppressed the sensitivity to gemcitabine, accompanied by diminished apoptosis and promoted proliferation. Furthermore, the M2 MDEs and PCa cells were injected to mice with gemcitabine exposure for in vivo substantiation. The delivery of miR-222-3p inhibitor by M2 MDEs suppressed tumor growth and elevated sensitivity of cancer cells to gemcitabine. Moreover, miR-222-3p was indicated to target and suppress TSC1 expression, while miR-222-3p activated the PI3K/AKT/mTOR pathway. Together, miR-222-3p-containing M2 MDEs enhance chemoresistance in PCa through TSC1 inhibition and activation of the PI3K/AKT/mTOR pathway.

Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression.

Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.

Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression.

Background: It has been reported that signaling from the nerve growth factor (NGF) pathway associated with peripheral nerves is able to contribute to perineural invasion (PNI) of pancreatic cancer (PC). Nevertheless, the underlying mechanism by which NGF leads to PNI remained poorly understood. Methods: Western blotting was employed to determine NGF level in PC and paracarcinoma tissues and in PC cell lines as well as pancreatic ductal epithelial cells. MiaPaCa-2 and CFPAC-1 cells were treated with 100 ng/ml of NGF or the NGF inhibitor Tanezumab for 24 h, CCK-8 and Transwell assays were employed to test cell proliferation, invasion, and migration, respectively. TrkA expression was knocked down in MiaPaCa-2 and dorsal root ganglion (DRG) cells treated with NGF to determine its effect on the Warburg effect. To reveal that the NGF-TrkA signaling pathway was closely associated with PC PNI, in vitro neuroinvasion model was established by using MiaPaCa-2 cells via coculturing DRG cells in Matrigel. Further, exosomes were extracted from PC cells and identified by examining the levels of specific markers for exosomes. Then RT-qPCR was applied to test miR-21-5p level in tumor derived exosomal (TDE-miR-21-5p). RIP assay was performed to validate NGF and miR-21 binding ability in MiaPaCa-2 cells. Rescue experiments were performed by using coprocessing of Tanezumab and miR-21-5p mimic on MiaPaCa-2 cells, followed by coculture with DRG cells. Subsequently, we used a model of neuroinvasion in nude mice to assess the effect of NGF in vivo on tumor nerve invasion as well as on nociceptive transmission. Results: NGF level was preeminently higher in PC tissues and cell lines than in paracarcinoma tissues and normal pancreatic epithelial cell lines. NGF promoted MiaPaCa-2 and CFPAC-1 cell invasion and migration, while Tanezumab treatment showed the opposite results. Besides, NGF binding to TrkA receptors encouraged the intracellular Warburg effect in PC and DRG cells. TrkA blocking-up could restrain NGF induced PC cell migration and neural invasion. Mechanistically, NGF could upregulate TDE-miR-21-5p levels, and DRG cells took up TDE to activate the Warburg effect and stimulate nociceptor gene expression. miR-21-5p inhibitor could abolish the facilitative effect of NGF on PNI in MiaPaCa-2 cells. In vivo tumorigenesis experiments, Tanezumab markedly alleviated nerve invasion of PC cells as well as relieved nociceptive conduction in animal models. Conclusions: These findings displayed that NGF/TrkA encouraged the neuroinvasive potential of PC cells by activating the Warburg effect in DRG cells through upregulation of TDE-miR-21-5p expression.

Long Non-coding RNA DLEU2L Targets miR-210-3p to Suppress Gemcitabine Resistance in Pancreatic Cancer Cells via BRCA2 Regulation.

Gemcitabine (GEM) resistance remains a challenging clinical issue to overcome in chemotherapy against pancreatic cancer. We previously demonstrated that miR-210 derived from pancreatic cancer stem cells enhanced the GEM-resistant properties of pancreatic cancer cells, thus identifying miR-210 as an oncogenic miRNA. Herein, we report the existence of an upstream effector that acts as a competing endogenous RNA (ceRNA) to miR-210. Bioinformatic screening was performed to identify lncRNAs with a binding relationship to miR-210. Overexpression and interference vectors were constructed to demonstrate the effect of ceRNA activity in pancreatic cell behavior, both in vitro and in vivo. DLEU2L (deleted in lymphocytic leukemia 2-like), which is expressed at low levels in pancreatic cancer tissues, was shown to exhibit a binding relationship with miR-210-3p. Overexpression of DLEU2L and silencing of miR-210-3p suppressed the proliferation, migration, and invasion of pancreatic cancer cells while promoting apoptosis. These effects occurred via the inhibition of the Warburg effect (aerobic glycolysis) and AKT/mTOR signaling. In addition, we showed that BRCA2 is a target gene of miR-210-3p, and the downregulation of miR-210-3p by DLEU2L effectively induced an upregulation of BRCA2 via the ceRNA mechanism. In vivo, DLEU2L overexpression and miR-210-3p interference suppressed pancreatic tumor progression, consistent with the results of in vitro studies. The findings of our study establish DLEU2L as a ceRNA to miR-210-3p and reveal the critical role of the DLEU2L/miR-210-3p crosstalk in targeting GEM resistance.

Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a malignant tumor and ranks the sixth in incidence among cancers. Circular RNA (circRNA) has been reported to regulate the progression of pancreatic cancer. However, the effects of circ-membrane bound O-acyltransferase domain containing 2 (circ-MBOAT2) on regulating pancreatic cancer process were unclear. METHODS: The expression levels of circ-MBOAT2, microRNA-433-3p (miR-433-3p) and glutamic-oxaloacetic transaminase 1 (GOT1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). GOT1 protein expression was determined by western blot analysis. Cell proliferation was illustrated by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and cell colony formation assay. Cell apoptosis was demonstrated by flow cytometry analysis. Cell invasion and migration were investigated by transwell invasion and wound-healing assays. Glutamine catabolism was explained by detecting glutamine consumption, alpha ketoglutarate (α-KG) production and glutamate production. In vivo assay was performed to illustrate the impacts of circ-MBOAT2 silencing on tumor formation in vivo. The binding relationship between miR-433-3p and circ-MBOAT2 or GOT1 was predicted by circinteractome or starbase online databases, and identified by dual-luciferase reporter assay. RESULTS: Circ-MBOAT2 and GOT1 expression were significantly upregulated, while miR-433-3p expression was downregulated in pancreatic cancer tissues and cells compared with normal pancreatic tissues or cells. Circ-MBOAT2 silencing repressed cell proliferation, migration, invasion and glutamine catabolism, whereas promoted cell apoptosis in pancreatic cancer. Additionally, circ-MBOAT2 acted as a sponge of miR-433-3p, which was found to be associate with GOT1. MiR-433-3p inhibitors hindered circ-MBOAT2 silencing-mediated impacts on pancreatic cancer progression and glutamine catabolism. Furthermore, circ-MBOAT2 silencing repressed tumor formation in vivo. CONCLUSION: Circ-MBOAT2 modulated tumor development and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. This finding suggests that circ-MBOAT2 may be a therapeutic target for pancreatic cancer.

Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling.

BACKGROUND: Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. METHODS: The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. RESULTS: We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. CONCLUSIONS: Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

Long non-coding RNA MVIH promotes cell proliferation, migration, invasion through regulating multiple cancer-related pathways, and correlates with worse prognosis in pancreatic ductal adenocarcinomas.

We aimed to explore the effect of long non-coding RNA MVIH (lnc-MVIH) on cell proliferation, migration as well as invasion, and investigate the landscape of its molecular mechanism in pancreatic ductal adenocarcinomas (PDAC). Control overexpression (OE-NC group) and lnc-MVIH overexpression (OE-MVIH group) plasmids were transfected in BxPC-3 cells; control knock-down (KD-NC group) and lnc-MVIH knock-down (KD-MVIH group) plasmids were transfected in PANC-1 cells. Cellular functions were measured and mRNA sequencing was conducted. In 70 PDAC patients, lnc-MVIH expression in tumor and adjacent tissues was detected. Lnc-MVIH expression was higher in human PDAC cell lines than human normal pancreatic ductal epithelial cell line. Cell proliferation, migration and invasion were increased in OE-MVIH group compared to OE-NC group, but decreased in KD-MVIH group compared to KD-NC group. mRNA sequencing showed 145 differentially expressing genes (DEGs) upregulated in OE-MVIH group vs. OE-NC group and downregulated in KD-MVIH group vs. KD-NC group, and 51 DEGs downregulated in OE-MVIH group vs. OE-NC group and upregulated in KD-MVIH group vs. KD-NC group. These DEGs were enriched in several cancer-related pathways (including Hippo signaling pathway, cell cycle, Forkhead box O signaling pathway, apoptosis and advanced glycation end products-RAGE signaling pathway), and the effect of lnc-MVIH on regulating these DEGs was further validated by RT-qPCR. In PDAC patients, lnc-MVIH expression was increased in tumor tissue and correlated with advanced tumor size, lymph node metastasis, TNM stage and poor OS. In conclusion, lnc-MVIH might be a potential therapeutic target which regulated multiple cancer-related pathways in PDAC.

Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210.

PURPOSE: Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance. METHODS: GEM-sensitive BxPC-3-derived BxS and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived BxR cells (BxR-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in BxS and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo. RESULTS: BxR-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in BxS and PANC-1 cells. Elevated miR-210 expression levels were detected in BxR-CSCs and BxR-CSC-derived exosomes compared to those in BxS-CSCs and BxS-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in BxS and PANC-1 cells cultured with BxR-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in BxS cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by BxR-CSC-derived exosomes. CONCLUSIONS: Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.

Risk Factors and Management of Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy: Single-center Experience.

Pancreatic fistula (PF) remains the most frequent complication after pancreaticoduodenectomy (PD). This study was undertaken to explore the risk factors of postoperative PF following PD and discuss the management of PF in our center. A single-center respective study, involving 241 patients who underwent PD between September 2015 and June 2018, was conducted. Differences in the demographic data, preoperative, intraoperative and postoperative variables between the group with PF [International Study Group on Pancreatic Surgery (ISGPS) grade B/C] and the group without PF (no PF and ISGPS grade BL) were evaluated. The diagnosis and grading of PF were in strict accordance with ISGPS. Risk factors were analyzed by univariate analysis and multivariate logistic regression analysis. The results showed that postoperative PF occurred in 50 (20.7%) of the patients; 25 (10.4%) patients had a PF type BL, 46 (19.1%) patients developed a PF type B and 4 (1.6%) had a PF type C. Univariate analysis showed that fasting blood glucose (P=0.02), pancreatic texture (P< 0.001) and pancreatic duct diameter (P=0.01) were correlated with PF. Multivariate logistic regression analysis identified one independent risk factor for postoperative PF: soft pancreatic texture (OR=3.251, P=0.002). Among the cases, there were three postoperative deaths, giving a 60-day hospital mortality rate of 1.2% (3/241), and the mortality related to PF was 4.0% (2/50). One of the patients died from multiple organ failure caused by postoperative abdominal hemorrhage. In conclusion, soft pancreatic texture is an independent risk factor for PF. Surgeons should be well aware of this risk factor when performing a PD.

Natural history and therapeutic strategies of post-pancreatoduodenectomy abdominal fluid collections: Ten-year experience in a single institution.

TRIAL DESIGN: The aim of this study was to identify independent risk factors for post-pancreatoduodenectomy (post-PD) abdominal fluid collections (AFCs) and evaluate our management protocol on it. METHODS: A retrospective analysis of consecutive 2064 cases who underwent PD over the past decade in 1 single center was conducted. The patients were divided into AFCs and non-AFCs group. Univariable and multivariate logistic regression analysis was performed to identify independent risk factors of AFCs. The AFCs group was compared with the non-AFCs group with respect to the incidence of postoperative outcomes. The characteristics of AFCs were further analyzed in terms of clinical manifestations. RESULTS: Two thousand sixty-four cases with pancreaticoduodenectomy were recruited and 15% of them were found AFCs. Diameter of main pancreatic duct ≤3 mm was found to be an independent predictor of AFCs (P < .001), along with soft pancreatic texture (P = .002), mesenterico-portal vein resection (P < .001), and estimated intraoperative blood loss >800 mL (P < .001). The incidence of mild complications was significantly higher in AFCs group than in non-AFCs group (34% vs 20%, P < .001), whereas no significant differences were noted in the rate of severe complications between these 2 groups (15% vs 15%, P = .939). CONCLUSION: Enhanced drainage is recommended as an effective measure to decrease the incidence of severe complications caused by post-PD AFCs.

Risk factors for postoperative pancreatic fistula: Analysis of 170 consecutive cases of pancreaticoduodenectomy based on the updated ISGPS classification and grading system.

This study was designed to analyze the risk factors for postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD).Between September 2015 and August 2017, 170 successive patients underwent a radical PD in the Department of Pancreatic Surgery, Union Hospital, Wuhan. We carried out a retrospective study of these cases and the prospective conditions, which might be related to POPF, were examined with univariate and multivariate analysis. POPF was defined as a drain output of any measurable volume of fluid with an amylase level more than 3 times the upper limit of serum amylase activity on postoperative day 3, accompanied by a clinically relevant condition according to the 2016 update of the International Study Group for Pancreatic Surgery (ISGPS) definition. In our study, the POPF was just referred to as grade B and grade C pancreatic fistula in accordance with the ISGPS consensus, because the former grade A pancreatic fistula is now redefined as a biochemical leak, namely no-POPF, which has no clinical impact and needs no other special therapy.Pancreatic fistula occurred in 44 (25.9%) patients after PD, with a mean length of hospital stay of 24.98 ±â€Š14.30 days. Thirty-six patients (21.2%) developed grade B pancreatic fistula, and 8 patients (4.7%) had grade C pancreatic fistula. Among patients with grade C pancreatic fistula, 4 patients died, 3 patients were operated on again, and 3 patients developed multiple organ failure.Univariate analysis showed a significantly important association between POPF and the following factors: pancreas texture (soft vs hard: 39.1% vs 10.3%, P < .0001) and fasting blood glucose level (<108.0 mg/dL vs ≥108.0 mg/dL: 32.5% vs 12.5%, P = .005). Multivariate logistic regression analysis identified 2 independent factors related to POPF: soft pancreas texture and fasting blood glucose level <108.0 mg/dL.A soft pancreas and a fasting blood glucose level of <108.0 mg/dL are risk factors for the development of a POPF.

Serum lactate dehydrogenase is predictive of persistent organ failure in acute pancreatitis.

PURPOSE: Elevated serum lactate dehydrogenase (LDH) has been reported in a serious of clinical diseases. However, the relationship between LDH and the incidence of persistent organ failure (POF) in acute pancreatitis (AP) has not been characterized. MATERIALS AND METHODS: A total of 105 patients with AP who presented within 72h from symptom onset between 2014 and 2015 were included in this retrospective study. Demographic parameters and laboratory data on admission were compared between patients with and without POF. Multivariable logistic regression analyses were utilized to evaluate the prognostic value of LDH for predicting POF. RESULTS: 21 patients were diagnosed with POF. Compared to non-POF, patients with POF showed a significantly higher value of serum LDH on admission (741.57±331.72 vs. 296.08±135.73U/L, P<0.001). After multivariate logistic analysis, LDH remained an independent risk factor for POF (Hazard ratio 4.38, 95%CI: 1.42-13.47; P=0.010). A LDH value of 647U/L predicted POF with an area under the curve (AUC) of 0.876, a sensitivity with 76.2% and specificity with 98.8%, respectively. CONCLUSIONS: Our results indicate that serum LDH on admission is independently associated with POF in AP and may serve as a potential prognostic factor.

High risk factors of pancreatic carcinoma.

Over the past decades, cancer has become one of the toughest challenges for health professionals. The epidemiologists are increasingly directing their research efforts on various malignant tumor worldwide. Of note, incidence of cancers is on the rise more quickly in developed countries. Indeed, great endeavors have to be made in the control of the life-threatening disease. As we know it, pancreatic cancer (PC) is a malignant disease with the worst prognosis. While little is known about the etiology of the PC and measures to prevent the condition, so far, a number of risk factors have been identified. Genetic factors, pre-malignant lesions, predisposing diseases and exogenous factors have been found to be linked to PC. Genetic susceptibility was observed in 10% of PC cases, including inherited PC syndromes and familial PC. However, in the remaining 90%, their PC might be caused by genetic factors in combination with environmental factors. Nonetheless, the exact mechanism of the two kinds of factors, endogenous and exogenous, working together to cause PC remains poorly understood. The fact that most pancreatic neoplasms are diagnosed at an incurable stage of the disease highlights the need to identify risk factors and to understand their contribution to carcinogenesis. This article reviews the high risk factors contributing to the development of PC, to provide information for clinicians and epidemiologists.

Minimally invasive percutaneous catheter drainage versus open laparotomy with temporary closure for treatment of abdominal compartment syndrome in patients with early-stage severe acute pancreatitis.

This study aimed to examine the clinical efficacy of minimally invasive percutaneous catheter drainage (PCD) versus open laparotomy with temporary closure in the treatment of abdominal compartment syndrome (ACS) in patients with early-stage severe acute pancreatitis (SAP). Clinical data of 212 patients who underwent PCD and 61 patients who were given open laparotomy with temporary closure in our hospital over the last 10-year period were retrospectively analyzed, and outcomes were compared, including total and post-decompression intensive care unit (ICU) and hospital stays, physiological data, organ dysfunction, complications, and mortality. The results showed that the organ dysfunction scores were similar between the PCD and open laparotomy groups 72 h after decompression. In the PCD group, 134 of 212 (63.2%) patients required postoperative ICU support versus 60 of 61 (98.4%) in the open laparotomy group (P<0.001). Additionally, 87 (41.0%) PCD patients experienced complications as compared to 49 of 61 (80.3%) in the open laparotomy group (P<0.001). There were 40 (18.9%) and 32 (52.5%) deaths, respectively, in the PCD and open laparotomy groups (P<0.001). In conclusion, minimally invasive PCD is superior to open laparotomy with temporary closure, with fewer complications and deaths occurring in PCD group.

[Surgical treatment of necrotizing pancreatitis: 10-year experience at a single center].

OBJECTIVE: To investigate the indication, timing and methods of surgery for acute necrotizing pancreatitis. METHODS: There were 5 538 patients with acute pancreatitis (AP) were treated in the Union Hospital, Tongji Medical College from January 2005 to December 2014. Of all AP cases, 2 415 patients with acute necrotizing pancreatitis proved by computed tomography, and 732 patients underwent surgical treatment. Among 732 patients with surgical treatment, 439 (60.0%) were males and two hundreds and ninety-three (40.0%) were females. The median age was 45 years, ranging 20-76 years. Two hundreds and eighty-nine cases were treated with minimally invasive debridement and drainage and 684 cases were treated with open debridement. RESULTS: The cure rate of minimally invasive operation was 16.6% (48/289). The rest of the 241 patients were treated furtherly with open necrosectomy. Among 684 patients with open surgery, 523 patients (76.5%) were infected, and the median time from the onset of symptom to first open operation was 46 d (range 19-205 d). There were 115 patients need to surgery again because of necrotic tissue residual and the reoperation rate was 16.81% (115/684), 684 patients were performed open surgery on average 1.26 times per person. The main postoperative complications were intra-abdominal hemorrhage (37 cases), upper digestive tract fistula (34 cases), colonic fistula (12 cases), gastrointestinal obstruction (29 cases) and pancreatic fistula (83 cases). The overall incidence of complications were 28.5% (195/684). Forty-nine cases died after surgery and the mortality rate was 6.7% (49/732). CONCLUSION: Rational surgical indications and timing of surgical intervention are the key to improve the efficacy of necrotizing pancreatitis, open debridement is still an effective method for necrotizing pancreatitis.

Prediction of Severe Acute Pancreatitis Using a Decision Tree Model Based on the Revised Atlanta Classification of Acute Pancreatitis.

OBJECTIVE: To develop a model for the early prediction of severe acute pancreatitis based on the revised Atlanta classification of acute pancreatitis. METHODS: Clinical data of 1308 patients with acute pancreatitis (AP) were included in the retrospective study. A total of 603 patients who were admitted to the hospital within 36 hours of the onset of the disease were included at last according to the inclusion criteria. The clinical data were collected within 12 hours after admission. All the patients were classified as having mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) based on the revised Atlanta classification of acute pancreatitis. All the 603 patients were randomly divided into training group (402 cases) and test group (201 cases). Univariate and multiple regression analyses were used to identify the independent risk factors for the development of SAP in the training group. Then the prediction model was constructed using the decision tree method, and this model was applied to the test group to evaluate its validity. RESULTS: The decision tree model was developed using creatinine, lactate dehydrogenase, and oxygenation index to predict SAP. The diagnostic sensitivity and specificity of SAP in the training group were 80.9% and 90.0%, respectively, and the sensitivity and specificity in the test group were 88.6% and 90.4%, respectively. CONCLUSIONS: The decision tree model based on creatinine, lactate dehydrogenase, and oxygenation index is more likely to predict the occurrence of SAP.

MiR-652 inhibits acidic microenvironment-induced epithelial-mesenchymal transition of pancreatic cancer cells by targeting ZEB1.

Recent evidences suggest that the acidic microenvironment might facilitate epithelial mesenchymal transition (EMT) of tumor cells, while the effects of acidity on EMT of pancreatic cancer (PC) remain undefined. The present study demonstrated that acidity suppressed miR-652 expression, which further promoted EMT process by absenting inhibition on the transcriptional factor ZEB1 expression. At first, we found that acidity remarkably enhanced invasion ability of PC cells accompanying with increased mesenchymal and decreased epithelial markers. Meanwhile, miRNAs-microarray showed that miR-652, the potential regulator of ZEB1, was distinctly decreased in acidity-treated PC cells. Furthermore, restoration of miR-652 reversed acidity-induced EMT by inhibiting ZEB1 expression, while miR-652 inhibitor induced EMT in normal PC cells through promoting ZEB1 expression. Nevertheless, knockdown of ZEB1 significantly suppressed acidity-induced EMT in PC cells, but ZEB1 overexpression rescued the EMT which was inhibited by miR-652 overexpression. The in vivo results showed that the tumor growth and liver metastasis were remarkably retarded by both miR-652 overexpression and ZEB1 knockdown. The clinical samples further revealed that miR-652 was decreased in PC tissues and antagonistically correlated with ZEB1 expression, associating with late tumor stage, lymphatic invasion and metastasis. In conclusion, our study indicated a novel acidity/miR-652/ZEB1/EMT axis in the tumorigenesis of PC.

MiR-744 increases tumorigenicity of pancreatic cancer by activating Wnt/ß-catenin pathway.

The Wnt/ß-catenin signaling pathway, commonly hyperactivated in pancreatic cancer, has been reported to play an important role in the maintenance of stemness of cancer stem cells (CSCs), which is closely related to the progression of pancreatic cancer. Therefore, exploring the regulatory mechanism in Wnt/ß-catenin signaling may provide valuable clinical targets for cancer therapy. In the current study, we demonstrated that upregulation of miR-744 in pancreatic cancer promoted Wnt/ß-catenin signaling by directly targeting secreted frizzled-related protein 1 (SFRP1), glycogen synthase kinase 3ß (GSK3ß), and transducin-like enhancer of split 3 (TLE3), important negative modulators of Wnt/ß-catenin signaling. Expression of miR-744 was markedly upregulated in pancreatic cancer and positively correlated with poor patient survival. Furthermore, we found that overexpressing miR-744 enhanced, while inhibiting miR-744 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. Importantly, in vivo model of human-derived pancreatic xenografts showed that miR-744 upregulation enhanced the tumorigenicity of pancreatic cancer cells. These findings suggest that miR-744 plays a vital role in promoting the stem cell-like phenotype of pancreatic cancer cells, and may represent a novel prognostic biomarker and therapeutic target.