Stent placement for the prevention of clinically-relevant postoperative pancreatic fistula following pancreaticojejunostomy: A systematic review and meta-analysis.

OBJECTIVES: There remains a lack of consensus regarding the benefits of stent placement following pancreaticojejunostomy in terms of clinically relevant postoperative pancreatic fistulas (CR-POPFs). This study was aimed at analyzing the effects of stent placement, stent technique (internal and external), stent size, and dilation of the main pancreatic duct on CR-POPFs. METHODS: Our study comprised a systematic review and meta-analysis of randomized controlled trials involving patients undergoing pancreaticojejunostomy. The primary outcome was defined as the incidence of CR-POPFs. Additionally, subgroup analyses were conducted, and pooled analyses were performed to provide comparative references. RESULTS: Twelve randomized controlled trials, including a total of 1117 patients, were included. Compared with no stent placement, stenting did not exhibit a significant association with reduced CR-POPF incidence (odds ratio [OR] â€‹= â€‹0.60, 95% CI: 0.34-1.04, P â€‹= â€‹0.07). Subgroup analysis revealed that only external stents, and not internal stents, were significantly associated with a reduced CR-POPF incidence compared with no stent placement (OR â€‹= â€‹0.53, 95% CI: 0.28-0.99, P â€‹= â€‹0.05 vs. OR â€‹= â€‹0.92, 95% CI: 0.28-3.05, P â€‹= â€‹0.89). Furthermore, stent placement in patients with a main pancreatic duct diameter of ≤3 â€‹mm, and not in those with a main pancreatic duct diameter of >3 â€‹mm, was associated with a significantly reduced CR-POPF incidence compared with no stent placement (OR â€‹= â€‹0.24, 95% CI: 0.07-0.78, P â€‹= â€‹0.02 vs. OR â€‹= â€‹1.58, 95% CI: 0.41-6.06, P â€‹= â€‹0.50). CONCLUSIONS: The findings suggest a potential role for external stent placement in the prevention of CR-POPFs after pancreaticojejunostomy, particularly in patients with undilated pancreatic ducts. The reliability of our findings is constrained by the limited number of studies included. PROSPERO REGISTRATION NUMBER: CRD42022380103.

Laparoscopic necrosectomy for acute necrotizing pancreatitis: mesocolon-preserving approach and outcomes.

The surgical treatment of acute necrotizing pancreatitis has significantly evolved in recent years with the advent of enhanced imaging techniques and minimally invasive surgery. Various minimally invasive techniques, such as video-assisted retroperitoneal debridement (VARD) and endoscopic transmural necrosectomy (ETN), have been employed in the management of acute necrotizing pancreatitis and are often part of step-up approaches. However, almost all reported step-up approaches only employ a fixed minimally invasive technique prior to open surgery. In contrast, we implemented different minimally invasive techniques during the treatment of acute pancreatitis based on the extent of pancreatic necrosis. For acute necrotizing pancreatitis of the pancreatic bed with or without extension into the left retroperitoneum, we performed mesocolon-preserving laparoscopic necrosectomy for debridment. The quantitative indication for pancreatic debridment in our institute has been described previously. For acute necrotizing pancreatitis of the pancreatic bed with or without extension into the left retroperitoneum, mesocolon-preserving laparoscopic necrosectomy was performed for debridment. To safeguard the mesocolon, the pancreatic bed was entered via the gastrocolic ligament, and the left retroperitoneum was accessed via the lateral peritoneal attachments of the descending colon. Of the 77 patients requiring pancreatic debridment, 41 patients were deemed suitable for mesocolon-preserving laparoscopic necrosectomy by multiple disciplinary team and informed consent was acquired. Of these 41 patients, 27 underwent percutaneous drainage, 10 underwent transluminal drainage, and 2 underwent transluminal necrosectomy prior to laparoscopic necrosectomy. Two patients (4.88%) died of sepsis, three patients (7.32%) required further laparotomic necrosectomy, and five patients (12.20%) required additional percutaneous drainage for residual infection. Three patients (7.32%) experienced duodenal fistula, all of which were cured through non-surgical treatments. Nineteen patients (46.34%) developed pancreatic fistula that persisted for over 3 weeks, with 17 being successfully treated non-surgically. The remaining two patients had pancreatic fistulas that lasted over 3 months; an internal drainage procedure has been planned for them. No patient developed colonic fistula. Mesocolon-preserving laparoscopic necrosectomy proved to be safe and effective in selected patients. It can serve as a supplementary procedure for step-up approaches or as an alternative to other debridment procedures such as VARD, ETN, and laparotomic necrosectomy.

Mapping the evolution of inhaled drug delivery research: Trends, collaborations, and emerging frontiers.

Inhaled drug delivery is a unique administration route known for its ability to directly target pulmonary or brain regions, facilitating rapid onset and circumventing the hepatic first-pass effect. To characterize current global trends and provide a visual overview of the latest trends in inhaled drug delivery research, bibliometric analysis of data acquired from the Web of Science Core Collection database was performed via VOSviewer and CiteSpace. Inhaled drug delivery can not only be utilized in respiratory diseases but also has potential in other types of diseases for both fundamental and clinical applications. Overall, we provide an overview of present trends, collaborations, and newly discovered frontiers of inhaled drug delivery.

A New Assessment Method of Vitiligo by Combination of Dermoscopy and Reflectance Confocal Microscopy.

Purpose: The aim is to investigate the application value of dermoscopy combined with reflectance confocal microscopy (RCM) in assessing vitiligo disease activity and treatment response. Patients and Methods: We enrolled 279 patients with vitiligo and evaluated the disease activity by Vitiligo Disease Activity (VIDA) score, dermoscopy, RCM and dermoscopy combined with RCM respectively. The sensitivity and specificity of different assessment techniques were compared with VIDA score by the differences and consistency. The different characteristics of dermoscopy and RCM with different treatment responses were also analyzed. Results: The results showed that the sensitivity and specificity of dermoscopy combined RCM were higher than RCM or dermoscopy alone (P values less than 0.05). In the repigmentation process, leukotrichia, pigment network absent and perilesional hyperpigmentation under dermoscopy at the baseline suggested a poor treatment response, while the incompletely disappearing pigment rings under RCM and perifollicular hyperpigmentation under dermoscopy indicated a good treatment response. We also found the proportion of patients with telangiectasia, increased pigment at the lesions and around the hair follicles was significantly higher in the good treatment response group than that in the poor one by dermoscopy (χ2 = 4.423, 32.471, 4.348, P = 0.035 0.000, 0.037) and by RCM the proportion of patients with both increased pigment granules and dendritic melanocytes in the good treatment response group was higher than that in the poor one (χ2 = 38.215, 5.283, P = 0.000, 0.022, respectively). Conclusion: With the higher sensitivity and specificity than dermoscopy or RCM alone, a combination of dermoscopy and RCM may be a new more accurate measure to assess the vitiligo disease activity and the treatment response.

Fractional laser combined with 5-Aminolevulinic acid photodynamic therapy for the treatment of Cutaneous Rosai-Dorfman Disease: A case report.

Rosai-Dorfman disease(RDD) is a rare benign histiocytic proliferative disorder. Cutaneous Rosai-Dorfman disease(CRDD)is a rare variant of RDD with lesions localized to the skin. We report a case of patients with CRDD who was refractory to methotrexate, thalidomide, cyclosporine, glucocorticoid for local injection and external use, but resolved with fractional laser combined with 5-aminolevulinic acid photodynamic therapy (ALA-PDT). We believe that fractional laser technology combined with ALA-PDT for CRDD is a minimally invasive, effective and satisfactory treatment.

Clinical-radiomics nomogram using contrast-enhanced CT to predict histological grade and survival in pancreatic ductal adenocarcinoma.

Objectives: Tumor grading is important for prognosis of pancreatic ductal adenocarcinoma (PDAC). In this study, we developed preoperative clinical-radiomics nomograms using features from contrast-enhanced CT (CECT), to discriminate high-grade and low-grade PDAC and predict overall survival (OS). Methods: In this single-center, retrospective study conducted from February 2014 to April 2021, consecutive PDAC patients who underwent CECT and had pathologically identified grading were randomized to training (n=200) and test (n=84) cohorts for development of model to predict histological grade based on radiomics scores from CECT (HGrad). Another 42 patients were used as external validation cohort of HGrad. A nomogram (HGnom) was constructed using radiomics score, CA12-5 and smoking to predict histological grade. A second nomogram (Pnom) was constructed using radiomics score, CA12-5, TNM, adjuvant treatment, resection margin and microvascular invasion to predict OS in radical resection patients (217 of 284). Results: Among 326 patients, 122 were high-grade (120 poorly differentiated and 2 undifferentiated). The HGrad yielded AUCs of 0.75 (95% CI: 0.64, 0.85) and 0.76 (95% CI: 0.60, 0.91) in test and validation cohorts. The HGnom achieved AUCs of 0.77 (95% CI: 0.66, 0.87), and the predicted grades calibrated well with actual grades (P=.13). OS was different between the grades predicted by radiomics scores (P=.01). The integrated AUC of the Pnom for predicting OS was 0.80 (95% CI: 0.75, 0.88). Conclusion: Compared with the HGrad using features from CECT, the HGnom demonstrated higher performance for predicting histological grade. The Pnom helped identify patients with high survival outcome in pancreatic ductal adenocarcinoma.

Circular RNA circLOC101928570 suppresses systemic lupus erythematosus progression by targeting the miR-150-5p/c-myb axis.

BACKGROUND: Accumulating evidence supports the implication of circular RNAs (circRNAs) in systemic lupus erythematosus (SLE). However, little is known about the detailed mechanisms and roles of circRNAs in the pathogenesis of SLE. METHODS: Quantitative real-time PCR was used to determine the levels of circLOC101928570 and miR-150-5p in peripheral blood mononuclear cells of SLE. Overexpression and knockdown experiments were conducted to assess the effects of circLOC101928570. Fluorescence in situ hybridization, RNA immunoprecipitation, luciferase reporter assays, Western blot, flow cytometry analysis and enzyme-linked immunosorbent assay were used to investigate the molecular mechanisms underlying the function of circLOC101928570. RESULTS: The results showed that the level of circLOC101928570 was significantly downregulated in SLE and correlated with the systemic lupus erythematosus disease activity index. Functionally, circLOC101928570 acted as a miR-150-5p sponge to relieve the repressive effect on its target c-myb, which modulates the activation of immune inflammatory responses. CircLOC101928570 knockdown enhanced apoptosis. Moreover, circLOC101928570 promoted the transcriptional level of IL2RA by directly regulating the miR-150-5p/c-myb axis. CONCLUSION: Overall, our findings demonstrated that circLOC101928570 played a critical role in SLE. The downregulation of circLOC101928570 suppressed SLE progression through the miR-150-5p/c-myb/IL2RA axis. Our findings identified that circLOC101928570 serves as a potential biomarker for the diagnosis and therapy of SLE.

One-step laparoscopic pancreatic necrosectomy verse surgical step-up approach for infected pancreatic necrosis: a case-control study.

BACKGROUND: The surgical step-up approach often requires multiple debridements and might not be suitable for infected pancreatic necrosis (IPN) patients with various abscesses or no safe route for percutaneous catheter drainage (PCD). This case-control study aimed to investigate the safety and effectiveness of one-step laparoscopic pancreatic necrosectomy (LPN) in treating IPN. METHODS: This case-control study included IPN patients undergoing one-step LPN or surgical step-up in our center from January 2015 to December 2020. The short-term and long-term complications after surgery, length of hospital stay, and postoperative ICU stays in both groups were analyzed. Univariate and multivariate logistic regression analyses were performed to explore the risk factors of major complications or death. RESULTS: A total of 53 IPN patients underwent one-step LPN and 37 IPN patients underwent surgical step-up approach in this study. There was no significant difference in the incidence of death, major complications, new-onset diabetes, or new-onset pancreatic exocrine insufficiency between the two groups. However, the length of hospital stay in the one-step LPN group was significantly shorter than that in the surgical step-up group. Univariate regression analysis showed that the surgical approach (one-step/step-up) was not the risk factor for major complications or death. Multivariate logistic regression analysis indicated that computed tomography (CT) severity index, American Society of Anesthesiologists (ASA) class IV, and white blood cell (WBC) were the significant risk factors for major complications or death. CONCLUSION: One-step LPN is as safe and effective as the surgical step-up approach for treating IPN patients, and reduces total hospital stay.

LncRNA HIF1A-AS1 Promotes Gemcitabine Resistance of Pancreatic Cancer by Enhancing Glycolysis through Modulating the AKT/YB1/HIF1α Pathway.

Gemcitabine (GEM) resistance is a major challenge for chemotherapy of pancreatic cancer. Previous studies have reported on the role of long noncoding RNA (lncRNA) in tumorigenesis of pancreatic cancer, however, the involvement of lncRNA in the development of GEM resistance of pancreatic cancer remains unclear. In the present study, we demonstrated that the antisense RNA1 of HIF1α (HIF1A-AS1) was significantly elevated in the GEM-resistant pancreatic cancer cells. Gain- and lost-of-function experiments validated that HIF1A-AS1 promoted GEM resistance of pancreatic cancer cells both in vitro and vivo. We further revealed that HIF1A-AS1 upregulated HIF1α expression and thus promoted glycolysis to enhance GEM resistance of pancreatic cancer cells. Mechanistically, HIF1A-AS1 facilitated the interaction between serine/threonine kinase AKT and Y-box-binding protein 1 (YB1), which promoted phosphorylation of YB1 (pYB1). Meanwhile, HIF1A-AS1 recruited pYB1 to HIF1α mRNA that consequently promoted translation of HIF1α. Furthermore, HIF1α promoted HIF1A-AS1 transcription by directly binding to the HIF1α response element in the promoter area of HIF1A-AS1 to form a positive feedback. Consistently, both HIF1A-AS1 and HIF1α were upregulated in pancreatic cancer tissues and associated with poor overall survival. Together, our results underline a reciprocal loop of HIF1A-AS1 and HIF1α that contributes to GEM resistance of pancreatic cancer and indicate that HIF1A-AS1 might serve as a novel therapeutic target for GEM resistance of pancreatic cancer. SIGNIFICANCE: These findings show that a reciprocal feedback of HIF1A-AS1 and HIF1α promotes gemcitabine resistance of pancreatic cancer, which provides an applicable therapeutic target.

Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis.

Research has indicated that hypoxia profoundly contributes to chemoresistance of pancreatic cancer (PC), while the precise mechanism has not been fully elucidated. In this study, we report a hypoxic exosomal circular RNA (circRNA)-mediated mechanism of conferred chemoresistance in PC cells. Gemcitabine (GEM) resistance was enhanced in normoxic PC cells incubated with exosomes derived from hypoxic PC cells. CircRNA microarray displayed that circZNF91 was remarkably increased in hypoxic exosomes of PC cells compared with normoxic exosomes. Overexpression of circZNF91 obviously stimulated chemoresistance in PC cells, while knockdown of circZNF91 retarded the hypoxic exosome-transmitted chemoresistance. Mechanistically, the hypoxic-induced exosomal circZNF91 transmitted into normoxic PC cells could competitively bind to miR-23b-3p, which deprives the inhibition of miR-23b-3p on expression of deacetylase Sirtuin1 (SIRT1). Consequently, the upregulated SIRT1 enhanced deacetylation-dependent stability of HIF-1α protein, leading to glycolysis and GEM chemoresistance of recipient PC cells. In addition, we revealed that the increased circZNF91 in hypoxic exosome was attributed to the transcriptional regulation by HIF-1α. Coincidently, transmission of hypoxic exosomes into subcutaneous xenografts in nude mice obviously facilitated the chemoresistance of transplanted PC tumor, which could be reversed by depletion of circZNF91 or upregulation of miR-23b-3p. Furthermore, clinical data showed that circZNF91 was significantly upregulated in PC tissues and correlated with overexpression of glycolytic enzymes and short overall survival time. Collectively, exosomal circZNF91 can function as a cargo mediating the signal transmission between hypoxic and normoxic tumor cells to promote GEM chemoresistance of PC and may potentially serve as a therapeutic target.

Pancreatic Ductal Adenocarcinoma at CT: A Combined Nomogram Model to Preoperatively Predict Cancer Stage and Survival Outcome.

OBJECTIVES: To construct a nomogram model that combines clinical characteristics and radiomics signatures to preoperatively discriminate pancreatic ductal adenocarcinoma (PDAC) in stage I-II and III-IV and predict overall survival. METHODS: A total of 135 patients with histopathologically confirmed PDAC who underwent contrast-enhanced CT were included. A total of 384 radiomics features were extracted from arterial phase (AP) or portal venous phase (PVP) images. Four steps were used for feature selection, and multivariable logistic regression analysis were used to build radiomics signatures and combined nomogram model. Performance of the proposed model was assessed by using receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA). Kaplan-Meier analysis was applied to analyze overall survival in the stage I-II and III-IV PDAC groups. RESULTS: The AP+PVP radiomics signature showed the best performance among the three radiomics signatures [training cohort: area under the curve (AUC) = 0.919; validation cohort: AUC = 0.831]. The combined nomogram model integrating AP+PVP radiomics signature with clinical characteristics (tumor location, carcinoembryonic antigen level, and tumor maximum diameter) demonstrated the best discrimination performance (training cohort: AUC = 0.940; validation cohort: AUC = 0.912). Calibration curves and DCA verified the clinical usefulness of the combined nomogram model. Kaplan-Meier analysis showed that overall survival of patients in the predicted stage I-II PDAC group was longer than patients in stage III-IV PDAC group (p<0.0001). CONCLUSIONS: We propose a combined model with excellent performance for the preoperative, individualized, noninvasive discrimination of stage I-II and III-IV PDAC and prediction of overall survival.

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer.

Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.

Long noncoding RNA ITGB2-AS1 promotes growth and metastasis through miR-4319/RAF1 axis in pancreatic ductal adenocarcinoma.

Long noncoding RNA (lncRNA) has been considered as potentially critical regulators in pancreatic ductal adenocarcinoma (PDAC). In this study, we prospectively investigate the effect and mechanism of lncRNA integrin subunit beta 2-anti-sense RNA 1 (ITGB2-AS1) on regulation of PDAC progression. The expression of ITGB2-AS1 and its target were analyzed by quantitative real-time polymerase chain reaction and in situ hybridization. 3-(4,5-Dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, wound healing, and transwell assays were used to investigate the influence of ITGB2-AS1 on cell proliferation, cell cycle, migration, and invasion, respectively. The interaction between ITGB2-AS1 and its target was determined via luciferase activity assay and RNA immunoprecipitation. The subcutaneous xenotransplanted tumor model was established and employed to detect the tumorigenic function of ITGB2-AS1, which was evaluated by western blot analysis, immunohistochemistry, and hematoxylin and eosin staining. The results showed that ITGB2-AS1 was elevated in both PDAC tumor tissues and cell lines, predicting a poor prognosis in PDAC patients. Knocking down of ITGB2-AS1 suppressed PDAC cell proliferation, invasion, and migration but induced cell apoptosis in vitro. Moreover, ITGB2-AS1 could target and inhibit the expression of miR-4319 and miR-4319-targeted and -suppressed serine/threonine kinase RAF1. ITGB2-AS1 promoted PDAC progression via inhibition of miR-4319. Interference of ITGB2-AS1 could suppress in vivo tumorigenic ability of PDAC via downregulation of RAF1. In conclusion, ITGB2-AS1 promoted PDAC progression via sponging miR-4319 to upregulate RAF1, suggesting the potential therapeutic target ability of ITGB2-AS1 in PDAC.

LncRNA differentiation antagonizing non-protein coding RNA promotes proliferation and invasion through regulating miR-135a/NLRP37 axis in pancreatic cancer.

Background It is well-known that long-chain non-coding RNA (LncRNA) plays an important role in the development of tumor. DANCR, which is one crucial part of the lncRNA family, has been shown to be involved in the invasion of various tumors. However, its molecular mechanism in pancreatic cancer remains unknown. Methods qRT-PCR was used to detect the expression of DANCR, miR-135a mRNA in pancreatic cancer tissues or cells. E-cadherin and NLRP3 protein levels were measured by Western Blot. CCK-8, cell scratch, and transwell assays were applied to detect the proliferation and invasion of pancreatic cancer cells. Bioinformatical analysis and luciferase assay were performed to explore the relationship among DANCR, miR-135a and NLRP3. Results In pancreatic cancer, DANCR was up-regulated while miR-135a was down-regulated. The over-expression of DANCR promoted the proliferation and invasion of pancreatic cancer cells. A negative relationship was found between DANCR and miR-135a expression. Moreover, we found that miR-135a reversed the effects of DANCR in the promoting of pancreatic cancer cells, which was achieved by regulating the downstream protein of NLRP3. The correlations among DANCR, miR-135a and NLRP3 were confirmed in animal experiments. Conclusion DANCR promoted proliferation and invasion through the regulating of miR-135a / NLRP3 axis in pancreatic cancer cell. Our results suggest that DANCR may be a potential target for the therapy of pancreatic cancer.

ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer.

Poor prognosis in pancreatic cancer (PanCa) is partially due to chemoresistance to gemcitabine (GEM). Glucose metabolism has been revealed to contribute to the therapeutic resistance and pluripotent state of PanCa cells. However, few studies have focused on the effects of GEM on cancer cell metabolism, stemness of tumor cells, and molecular mechanisms that critically influence PanCa treatment. We demonstrate that GEM treatment induces metabolic reprogramming, reducing mitochondrial oxidation and upregulating aerobic glycolysis, and promotes stem-like behaviors in cancer cells. Inhibiting aerobic glycolysis suppresses cancer cell stemness and strengthens GEM's cytotoxicity. GEM-induced metabolic reprogramming is KRAS dependent, as knockdown of KRAS reverses the metabolic shift. GEM-induced metabolic reprogramming also activates AMP-activated protein kinase (AMPK), which promotes glycolytic flux and cancer stemness. In addition, GEM-induced reactive oxygen species (ROS) activate the KRAS/AMPK pathway. This effect was validated by introducing exogenous hydrogen peroxide (H2O2). Taken together, these findings reveal a counterproductive GEM effect during PanCa treatment. Regulating cellular redox, targeting KRAS/AMPK signaling, or reversing metabolic reprogramming might be effective approaches to eliminate cancer stem cells (CSCs) and enhance chemosensitivity to GEM to improve the prognosis of PanCa patients.

LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α.

Rationale: Hypoxia has been proved to contribute to aggressive phenotype of cancers, while functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of hypoxia on pancreatic cancer (PC) tumorigenesis is incompletely understood. The aim of this study was to uncover the regulatory and functional roles for hypoxia-induced lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) in the regulation of PC tumorigenesis. Methods: A lncRNA microarray confirmed MTA2TR expression in tissues of PC patients. The effects of MTA2TR on proliferation and metastasis of PC cells and xenograft models were determined, and the key mechanisms by which MTA2TR promotes PC were further dissected. Furthermore, the expression and regulation of MTA2TR under hypoxic conditions in PC cells were assessed. We also assessed the correlation between MTA2TR expression and PC patient clinical outcomes. Results: We found that metastasis associated protein 2 (MTA2) transcriptional regulator lncRNA (MTA2TR) was overexpressed in PC patient tissues relative to paired noncancerous tissues. Furthermore, we found that depletion of MTA2TR significantly inhibited PC cell proliferation and invasion both in vitro and in vivo. We further demonstrated that MTA2TR transcriptionally upregulates MTA2 expression by recruiting activating transcription factor 3 (ATF3) to the promoter area of MTA2. Consequentially, MTA2 can stabilize the HIF-1α protein via deacetylation, which further activates HIF-1α transcriptional activity. Interestingly, our results revealed that MTA2TR is transcriptionally regulated by HIF-1α under hypoxic conditions. Our clinical samples further indicated that the overexpression of MTA2TR was correlated with MTA2 upregulation, as well as with reduced overall survival (OS) in PC patients. Conclusions: These results suggest that feedback between MTA2TR and HIF-1α may play a key role in regulating PC tumorigenesis, thus potentially highlighting novel avenues PC treatment.

Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells.

BACKGROUND: Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. However, its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. A strategy of combined chemo-regimens is widely employed in clinical settings in attempt to reduce the chance of developing therapeutic resistance. Valproic acid (VPA) has been reported as a promising anticancer drug in various clinical trials and studies. However, the clinical value and potential dose-effect of VPA in combination with gemcitabine for pancreatic cancer treatment are under investigated. RESULTS: In this study, we determined the synergistic effect of VPA and gemcitabine and found that high-dose VPA significantly and dose-dependently enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Intriguingly, low-dose VPA potentiated the migration and invasion of pancreatic cancer cells that already showed gemcitabine-induced motility. Moreover, low-dose VPA increased the reactive oxygen species (ROS) production, which activated AKT to further stimulate the activation of STAT3, Bmi1 expression and eventually promoted the migration and invasion of pancreatic cancer cells induced by gemcitabine. Whereas high-dose VPA stimulated excessive ROS accumulation that promoted p38 activation, which suppressed the activation of STAT3 and Bmi1. CONCLUSION: Pancreatic cancer cells respond differentially towards low- or high-dose of VPA in combination with gemcitabine, and a low VPA further potentiate pancreatic cancer cell to migrate and invade. Our results suggest that STAT3/Bmi1 signaling cascade, which is regulated by ROS-dependent, AKT- or p38-modulated pathways, primarily mediated the sensitivity and motility of pancreatic cancer cells towards combined gemcitabine and VPA regimen. These findings suggest a highly clinically relevant new mechanism of developing resistance against combined chemo-regimens, warranting further mechanistic and translational exploration for VPA in combination with gemcitabine and other chemotherapies.

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.

High glucose promotes pancreatic cancer cells to escape from immune surveillance via AMPK-Bmi1-GATA2-MICA/B pathway.

BACKGROUND: Modulation of cell surface expression of MHC class I chain-related protein A/B (MICA/B) has been proven to be one of the mechanisms by which tumor cells escape from NK cell-mediated killing. Abnormal metabolic condition, such as high glucose, may create a cellular stress milieu to induce immune dysfunction. Hyperglycemia is frequently presented in the majority of pancreatic cancer patients and is associated with poor prognosis. In this study, we aimed to detect the effects of high glucose on NK cell-mediated killing on pancreatic cancer cells through reduction of MICA/B expression. METHODS: The lysis of NK cells on pancreatic cancer cells were compared at different glucose concentrations through lactate dehydrogenase release assay. Then, qPCR, Western Blot, Flow cytometry and Immunofluorescence were used to identify the effect of high glucose on expression of MICA/B, Bmi1, GATA2, phosphorylated AMPK to explore the underlying mechanisms in the process. Moreover, an animal model with diabetes mellitus was established to explore the role of high glucose on NK cell-mediated cytotoxicity on pancreatic cancer in vivo. RESULTS: In our study, high glucose protects pancreatic cancer from NK cell-mediated killing through suppressing MICA/B expression. Bmi1, a polycomb group (PcG) protein, was found to be up-regulated by high glucose, and mediated the inhibition of MICA/B expression through promoting GATA2 in pancreatic cancer. Moreover, high glucose inhibited AMP-activated protein kinase signaling, leading to high expression of Bmi1. CONCLUSION: Our findings identify that high glucose may promote the immune escape of pancreatic cancer cells under hyperglycemic tumor microenvironment. In this process, constitutive activation of AMPK-Bmi1-GATA2 axis could mediate MICA/B inhibition, which may serve as a therapeutic target for further intervention of pancreatic cancer immune evasion.