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A quantitative comparative analysis of PM accumulation on boles, branches and leaves is necessary to better understand the reduction of airborne PM by trees. This study compared the total water-insoluble particle accumulation mass per unit area, the distribution of water-insoluble particle size fractions, and the accumulation masses and compositions of water-soluble ions among different vegetative organs. The average accumulation capacity of water-insoluble particles was as follows: leaf epicuticular wax (11.1 ± 4.4 μg/cm2), leaf surfaces (22.0 ± 3.2 μg/cm2), terminal branch surfaces (101.6 ± 47.0 μg/cm2), perennial branch surfaces (92.7 ± 20.0 μg/cm2), and bark surfaces (1719.9 ± 684.7 μg/cm2). Bole bark surfaces tended to accumulate the largest proportion of large particles, averaging 88 ± 4%. Branch surfaces and leaf epicuticular wax accumulated the largest proportions of fine particles, averaging 15 ± 5%. The total masses of water-soluble ions were 18 ± 10%, 33 ± 13% and 32 ± 6% of the total water-insoluble particles on boles, terminal branches and leaves, respectively. Leaf surfaces accumulated 2.2–6.0 times more SO2- 4 and NO 3 than did branch and bark surfaces. Image 1014832 • PM accumulation differed significantly among vegetative organs. • Stem bark surfaces tended to accumulate large particles. • Branch surfaces and leaf epicuticular wax accumulated more fine particles. • Leaf surfaces accounted for greater proportion of water-soluble ions. [ABSTRACT FROM AUTHOR]

Background: An optimal method for intracorporeal esophagojejunostomy has not yet been standardized. This study sought to introduce intracorporeal hand-sewn end-to-side esophagojejunostomy after totally laparoscopic total gastrectomy.Methods: The author conducted a consecutive series of 100 intracorporeal hand-sewn esophagojejunostomies after totally laparoscopic total gastrectomy for upper third gastric cancer from September 2012 to December 2016.Results: All patients were successfully operated on without conversion to open- or laparoscope-assisted surgery. The mean reconstruction time was 45 min, and the time until first flatus was 4 days. The time to start a soft diet was 7 days. The length of postoperative hospital stay was 8 days. The overall postoperative morbidity was 8%, including one anastomotic leak, and the mortality was zero. The median follow-up duration was 13 months; no anastomotic strictures were encountered.Conclusions: Intracorporeal hand-sewn end-to-side esophagojejunostomy after totally laparoscopic total gastrectomy is a safe and feasible procedure. This method can identify negative margins with intraoperative frozen sections before reconstruction and could be a good option for performing intracorporeal esophagojejunostomy with an advanced endoscopic suture technique. [ABSTRACT FROM AUTHOR]

Rainfall influences removal of airborne particulate matter (PM) from leaf surfaces through a process called wash off resulting in throughfall that carries PM to the ground. The present study examined the effects of rainfall characteristics on PM wash-off mass and rate from the foliage of four broadleaf species, to investigate retention of PM pollution. In a controlled rainfall simulation experiment, rainfall intensity was set to 15, 30, and 50 mm h − 1 , and sampling intervals for the three rainfall intensities were divided into 10, 5, and 3 min, respectively. Of the plants examined, the evergreen shrub Euonymus japonicus had the greatest surface PM accumulation before rainfall (165 μg cm − 2 ), maximum wash-off during the first 2.5 mm of rain (30 μg cm − 2 ), and maximum surface PM retention after rainfall (24 μg cm − 2 ). Fitting observations with the Box Lucas regression model, cumulative PM wash-off rates increased with cumulative rainfall amount, until the curves tended to become steady after rain exceeded 12.5 mm. Wash off removed 51 to 70% of surface PM accumulation. As rainfall intensity increased, the duration of PM wash-off decreased, and wash-off rates were highest during the first rainfall interval. However, there was no significant difference between PM wash-off rates for rainfall intensities of 30 and 50 mm h − 1 in each rainfall interval. In addition, rain did not remove all PM completely, and PM retention following rainfall differed with rainfall intensity, except for Populus tomentosa . [ABSTRACT FROM AUTHOR]

Two isostructural heterometallic MOFs [Cd3M6(TDPAT)2(H2O)9]·0.75H2O·4DMF·2MeOH (1 M = K; 2 M = Rb) were synthesized via solvothermal reaction. MOFs 1 and 2 are 3D chiral frameworks constructed by interpenetration of two identical 3D cage nets, which feature a giant double-walled heterometallic cage M36Cd24(TDPAT)8@M54Cd24(TDPAT)8. The luminescence properties of 1 and 2 including the quantum yield and lifetime values were also investigated. [ABSTRACT FROM AUTHOR]

Background: Nuclear receptor coactivator 6 (NCoA6) is overexpressed in various cancers and considered a multifunctional coactivator of various transcription factors and nuclear receptors. However, the role of NCoA6 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Methods: NCoA6 expression data in PDAC were extracted from TCGA and GTEx databases, and their correlation with survival outcomes were analyzed using the Kaplan–Meier plotter database. NCoA6 protein expression in PDAC tissues was evaluated using immunohistochemistry. RNA‐sequencing technology was used to sequence the transcriptome of NCoA6‐silenced PANC‐1 cells, followed by differential expression, GO/KEGG and GSEA analyses. The effects of NCoA6 on cell proliferation, migration, invasion, cell cycle, and apoptosis were determined in two representative cell lines (PANC‐1 and SW1990). Western blotting, qPCR, and co‐immunoprecipitation were performed to explore the mechanism of action of NCoA6 in PDAC cells. Results: NCoA6 expression was markedly increased in PDAC tissues, and high NCoA6 expression was associated with poor survival prognosis. However, there was no significant relationship between NCoA6 expression and metastasis in PDAC patients. Our RNA‐sequencing data analysis found 1194 significant differentially expressed genes between the control and NCoA6‐silenced PANC‐1 cells. GO/KEGG analysis results mainly focused on cytokine production, cytokine activity, and cytokine‐cytokine receptor interactions. GSEA results showed that the knockdown of NCoA6 affected the expression of histone deacetylase 1 (HDAC1) targeted genes. NCoA6 knockdown suppressed proliferation, migration, and invasion of PDAC cells. Finally, western blotting, qPCR, and co‐immunoprecipitation results showed that NCoA6 interacted with HDAC1 and that NCoA6 expression was negatively correlated with F‐box and WD repeat domain‐containing 7 (FBW7) and caudal‐related homeobox transcription factor 2 (CDX2) expression in pancreatic cancer. Conclusions: NCoA6 has a profound effect on cell proliferation, migration, invasion, and prognosis of PDAC and is potentially related to the expression of HDAC1, FBW7, and CDX2. Our results may provide novel therapeutic strategies for PDAC patients. [ABSTRACT FROM AUTHOR]

Background: Central pancreatectomy has been accepted as an alternative procedure for treating benign or low-grade malignant tumors in the pancreatic neck or proximal body of the pancreas, which preserves pancreatic parenchyma and function. In this study, we present our experience of laparoscopic central pancreatectomy with pancreaticojejunostomy. Patients and Methods: From April 2011 to February 2013, 8 patients underwent laparoscopic central pancreatectomy with a Roux-en-Y modified 'dunking' or duct-to-mucosa pancreaticojejunostomy for benign or low-grade malignant tumors in the pancreatic neck or proximal body of the pancreas at the Department of General Surgery, Sir Run Run Shaw Hospital, Hangzhou, China. Surgical procedure, postoperative course, and follow-up data were collected. Results: Laparoscopic central pancreatectomy was performed successfully in all the patients. The pancreaticojejunostomy was executed with a modified 'dunking' pancreaticojejunostomy ( n=7) or duct-to-mucosa pancreaticojejunostomy ( n=1). The mean operative time was 286±27 minutes (range, 250-330 minutes), with a mean blood loss of 57±21 mL (range, 30-100 mL). Mortality was 0%, and perioperative morbidity was 37.5% (pancreatic fistula [grade A], bleeding of a splenic vein branch, and retroperitoneal infection). The median postoperative hospital stay was 10 days (range, 6-38 days). At a median follow-up of 7.5 months (range, 2-24 months), all patients were alive without any exocrine or endocrine insufficiency or recurrence. Conclusions: Laparoscopic central pancreatectomy is feasible and safe. The modified 'dunking' pancreaticojejunostomy can be performed safely in this approach. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic wedge resection is widely accepted as a choice of treatment for gastric submucosal tumors (SMTs). But it cannot easily be applied to tumors located near the esophagogastric junction (EGJ) due to the high risk of causing deformity or stenosis in the gastric inlet. We evaluated our laparoscopic transgastric surgical technique for gastric SMTs located near the EGJ and clinical outcomes. Methods: Twelve consecutive patients with gastric intraluminal SMTs located 3 cm or less from the EGJ underwent laparoscopic transgastric resection at our institution from June 2010 to November 2012. The clinicopathological results of these 12 cases were analyzed. Results: Laparoscopic transgastric resection was successfully performed on all the patients. The mean operation time was 125 ± 25 min (range, 85-160 min) and the mean blood loss was 53 ± 32 mL (range, 10-120 mL). There was no death in our series. One patient experienced a postoperative complication of upper gastrointestinal tract bleeding due to the errhysis along the staple line treated with an endoscopic hemostatic clip. The mean postoperative length of hospital stay was 5.1 ± 1.2 days (range, 3-7 days). All patients received complete resection with a negative margin. Histopathologic diagnoses were gastrointestinal stromal tumor in seven cases, leiomyoma in four, and heterotopic pancreas in one. There was no tumor recurrence or evidence of stenosis of the EGJ during a mean follow-up of 15.3 ± 9.6 months (range, 1-30 months). Conclusions: Laparoscopic transgastric resection is simple, safe, and effective for gastric intraluminal SMTs located near the EGJ. [ABSTRACT FROM AUTHOR]

Background: The relationship between nutritional risk and postoperative recovery of patients with major laparoscopic abdominal surgery is still unclear. The present study was designed to assess the value of the nutritional risk screening in predicting the postoperative outcomes in this cohort of patients. Methods: Data from a consecutive series of 75 patients undergoing various elective major laparoscopic abdominal operations was prospectively collected. Nutritional risk was defined by the Nutritional Risk Screening 2002 (NRS 2002) score and correlated to the incidence of postoperative complications and hospital stay. Multivariate regression identified factors associated with 30-day complications [odds ratio (95 % confidence interval)]. Results: The overall incidence of nutritional risk was 34.7 %. There was a significantly higher infectious complication rate of 38.5 % in patients at nutritional risk, compared to 12.2 % in patients at no risk ( p = 0.008). No significant difference of postoperative hospital stay and overall complications was found in patients at nutritional risk or not. Nutritional risk was identified as an independent predictor of postoperative infectious complications (odds ratio 4.87 [1.33-17.84]; p = 0.017). Conclusions: The present study reinforces the value of the NRS 2002 to identify patients at higher risk of infectious complications after major laparoscopic abdominal surgery. In the era of minimally invasive surgery, the problem of nutritional risk still deserves our attention and concern. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic radical pancreatectomy is safe and beneficial for recectable pancreatic cancer, but the extent of resection for early-stage tumors remains controversial. Methods: Consecutive patients with left-sided pancreatic cancer who underwent either laparoscopic radical antegrade modular pancreatosplenectomy (LRAMPS, n = 54) or laparoscopic distal pancreatosplecnectomy (LDP, n = 131) between October 2020 and December 2022 were reviewed. The preoperative radiological selection criteria were as follows: (1) tumor diameter ≤ 4 cm; (2) located ≥ 1 cm from the celiac trunk; (3) didn't invade the fascial layer behind the pancreas. Results: After 1:1 propensity score matching (LRAMPS, n = 54; LDP, n = 54), baseline data were well-balanced with no differences. LRAMPS resulted in longer operation time (240.5 vs. 219.0 min, P = 0.020) and higher intraoperative bleeding volume (200 vs. 150 mL, P = 0.001) compared to LDP. Although LRAMPS harvested more lymph nodes (16 vs. 13, P = 0.008), there were no statistically significant differences in lymph node positivity rate (35.2% vs. 33.3%), R0 pancreatic transection margin (94.4% vs. 96.3%), and retroperitoneal margin (83.3% vs. 87.0%) rate. Postoperative complications did not significantly differ between the two groups. However, LRAMPS was associated with increased drainage volume (85.0 vs. 40.0 mL, P = 0.001), longer time to recover semi-liquid diet compared to LDP (5 vs. 4 days, P < 0.001) and increased daily bowel movement frequency. Tumor recurrence pattern and recurrence-free survival were comparable between the two groups, but the adjuvant chemotherapy regimens varied, and the completion rate of the 6-month intravenous chemotherapy was lower in the LRAMPS group compared to the LDP group (51.9% vs. 75.9%, P = 0.016). Conclusions: LRAMPS did not provide oncological benefits over LDP for left-sided pancreatic cancer within the selection criteria, but it increased operation time, intraoperative bleeding, and postoperative bowel movement frequency. These factors impacted the regimen selection and completion of adjuvant chemotherapy, consequently compromising the potential benefits of LRAMPS in achieving better local control. [ABSTRACT FROM AUTHOR]

Pancreatic cancer cells have a much higher metabolic demand than that of normal cells. However, the abundant interstitium and lack of blood supply determine the lack of nutrients in the tumour microenvironment. Although pancreatic cancer has been reported to supply extra metabolic demand for proliferation through autophagy and other means, the specific regulatory mechanisms have not yet been elucidated. In this study, we focused on transcription factor EB (TFEB), a key factor in the regulation of autophagy, to explore its effect on the phenotype and role in the unique amino acid utilisation pattern of pancreatic cancer cells (PCCs). The results showed that TFEB, which is generally highly expressed in pancreatic cancer, promoted the proliferation and metastasis of PCCs. TFEB knockdown inhibited the proliferation and metastasis of PCCs by blocking the catabolism of branched‐chain amino acids (BCAAs). Concerning the mechanism, we found that TFEB regulates the catabolism of BCAAs by regulating BCAT1, a key enzyme in BCAA metabolism. BCAA deprivation alone did not effectively inhibit PCC proliferation. However, BCAA deprivation combined with eltrombopag, a drug targeting TFEB, can play a two‐pronged role in exogenous supply deprivation and endogenous utilisation blockade to inhibit the proliferation of pancreatic cancer to the greatest extent, providing a new therapeutic direction, such as targeted metabolic reprogramming of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Postoperative pancreatic fistula (POPF) is the most prevalent complications following minimally invasive pancreaticoduodenectomy (MIPD). Only one model related to MIPD exists, and previous POPF scoring prediction methods are based on open pancreaticoduodenectomy patients. Our objectives are to determine the variables that may increase the probability of pancreatic fistula following MIPD and to develop and validate a POPF predictive risk model. Methods: Data from 432 patients who underwent MIPD between July 2015 and May 2022 were retrospectively collected. A nomogram prediction model was created using multivariate logistic regression analysis to evaluate independent factors for POPF in patients undergoing MIPD in the modeling cohort. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) and the calibration curve were used to verify the nomogram prediction model internally and externally within the modeling cohort and the verification cohort. Results: Multivariate logistic regression analysis showed that body mass index (BMI), albumin, triglycerides, pancreatic duct diameter, pathological diagnosis and intraoperative bleeding were independent variables for POPF. On the basis of this information, a model for the prediction of risks associated with POPF was developed. In accordance with the ROC analysis, the modeling cohort's AUC was 0.819 (95% CI 0.747–0.891), the internal validation cohort's AUC was 0.830 (95% CI 0.747–0.912), and the external validation cohort's AUC was 0.793 (95% CI 0.671–0.915). Based on the calibration curve, the estimated values of POPF have a high degree of concordance with the actual values that were measured. Conclusions: This model for predicting the probability of pancreatic fistula following MIPD has strong predictive capacity and can provide a trustworthy predictive method for the early screening of high-risk patients with pancreatic fistula after MIPD and timely clinical intervention. [ABSTRACT FROM AUTHOR]

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Highlights: 1. Attempting to delineate the complex and multidimensional interplays between metabolites (or metabolic enzymes) and predominant immune cell populations. 2. Metabolic checkpoints of immune cells are described and the contribution of these metabolic targets to determine the metabolic adaptations of distinct immune cells in specific tissue environments is emphasized. 3. Proposed cancer-immunometabolism subcycle, enriching the theoretical foundation of the cancer-immunology field. 4. Metabolism-induced disturbances in the acid-base balance of the tumor microenvironment have non-redundant effects on immunotherapy. 5. Pending challenges and clinical concerns in metabolic insights were addressed. [ABSTRACT FROM AUTHOR]

Background: The incidence of postoperative pancreatic fistula (POPF) following enucleation is high, and prophylactic pancreaticojejunostomy (PPJ) is frequently performed. Minimally invasive enucleation (MEN) has been demonstrated to be safe and feasible, leaving most enucleation wounds exposed. Methods: The clinical data of 40 patients who underwent open enucleation with PPJ at our center between 2012 and 2021 were compared with those of 80 patients who underwent MEN. Results: The MEN group had better outcomes than the PPJ group in terms of intraoperative bleeding (50.0 versus 100.0 mL), postoperative semi‐liquid diet recovery (2.0 versus 5.0 days), and postoperative length of stay (7.7 versus 12.5 days). While the MEN group had higher rates of complex enucleation (60.0% versus 40.0%), main pancreatic duct repair (32.5% versus 10.0%), discharge with drains (48.8% versus 25.0%), and grade B POPFs (47.5% versus 17.5%). Both surgical methods effectively preserved pancreatic function; however, two patients in the PPJ group experienced severe haemorrhaging and died. Additionally, during the follow‐up period, gastrointestinal bleeding was found and discomfort in the surgical area was reported. Conclusion: Pancreatic enucleation combined with PPJ should be avoided, and although a biochemical or grade B POPF may develop after MEN, it can be compensated for by preserving pancreatic function and ensuring a good long‐term quality of life in the patients. [ABSTRACT FROM AUTHOR]

Background: ALDOA is a glycolytic enzyme found mainly in developing embryos, adult muscle and various malignant tumours, including pancreatic tumours. Our previous study revealed that ALDOA, an oncogene, can promote the proliferation and metastasis of pancreatic tumours. Furthermore, ALDOA could predict poor prognosis in patients with pancreatic tumours. Methods: IHC analysis of PDAC tissues was conducted. Western blotting, PCR, cellular IF experiments and cell cycle assessment were conducted utilizing cell lines. GSEA and KEGG pathway analysis were used to identify potential downstream pathways. Results: To explore the effects of ALDOA on the occurrence and development of pancreatic tumours, we analysed the RNA sequencing results and found that ALDOA could inhibit the DDR. Under normal circumstances, when DNA is damaged, initiation of the DDR causes cell cycle arrest, DNA repair or cell apoptosis. Further experiments showed that ALDOA could inhibit DNA repair and reverse cell cycle arrest induced by DNA damage so that DNA damage persisted to promote the occurrence and progression of cancer. Conclusions: Regarding the molecular mechanism, we found that ALDOA inhibited the DDR and improved activation of the cell cycle checkpoint PLK1 by suppressing ATM, which promotes tumour cell progression. Consequently, ALDOA has a profound effect on pancreatic cancer development. [ABSTRACT FROM AUTHOR]

Background: There is no evidence supporting the feasibility of laparoscopic pancreaticoduodenectomy (LPD) compared to open pancreatoduodenectomy (OPD) following neoadjuvant chemotherapy (NACT) for pancreatic ductal adenocarcinoma (PDAC). Methods: The clinical data of consecutive patients with borderline resectable PDAC who received NACT and underwent either LPD or OPD between January 2020 and December 2022 at Fudan University Shanghai Cancer Center was prospectively collected and retrospectively analyzed. Results: The analysis included 57 patients in the OPD group and 20 in the LPD group. Following NACT, the LPD group exhibited a higher median CA19-9 decrease rate compared to the OPD group (85.3% vs. 66.9%, P = 0.042). Furthermore, 3 anatomically borderline PDACs in the LPD group and 5 in the OPD group were downstaged into resectable status (30.0% vs. 12.3%, P = 0.069). According to RECIST criteria, 51 (66.2%) patients in the entire cohort were evaluated as having stable disease. The median operation time for the LPD group was longer than the OPD group (419 vs. 325 min, P < 0.001), while the venous resection rate was 35.0% vs. 43.9%, respectively (P = 0.489). There was no difference in the number of retrieved lymph nodes, with a median number of 18.5 in the LPD group and 22 in the OPD group, and the R1 margin rate (15.0% vs. 12.3%) was also comparable. The incidence of Clavien-Dindo complications (35.0% vs. 66.7%, P = 0.018) was lower in the LPD group compared to the OPD group. Multivariable regression analysis revealed that a tumor diameter > 3 cm before NACT (HR 2.185) and poor tumor differentiation (HR 1.805) were independent risk factors for recurrence-free survival, and a decrease rate of CA19-9 > 70% (OR 0.309) was a protective factor for early tumor recurrence and overall survival. Conclusions: LPD for PDAC following NACT is feasible and oncologically equivalent to OPD. Effective control of CA19-9 levels is beneficial in reducing early tumor recurrence and improving overall survival. [ABSTRACT FROM AUTHOR]

Particulate matter (PM), one of the most important pollutants of traffic emission, threatens the health of urban ecosystems and citizens. Roadside trees play an important role in trapping PM, and the foliar PM load is a useful indicator for air PM pollution in road systems. To detect the relationships of foliar PM load with road structures, urbanization, and meteorology in road systems, we studied a widely-planted tree Sophora japonica L. in 100 roads and 10 yards of Beijing, China, and found that the foliar PM loads increased with the distances from the urban centre (DUC) linearly, while decreased with the road density. All-subsets regression analysis indicated that DUC, average monthly relative humidity, average monthly wind speed, and mean annual wind speed were the most important factors in predicting foliar PM load, rather than general situation of buildings and road cleanliness. The monthly relative humidity and monthly wind speed had a negative correlation to foliar PM, while the annual relative humidity and annual wind speed had a positive correlation to foliar PM. Suburban areas and these effective factors should be highlighted in PM control in Beijing. [ABSTRACT FROM AUTHOR]

Background: As an oncogene, SETD8 can promote tumour growth and tumour cell proliferation. This study aims to reveal the relationship between SETD8 and ferroptosis in pancreatic cancer and its role in pancreatic cancer to provide a possible new direction for the comprehensive treatment of pancreatic cancer. Methods: The downstream targets were screened by RNA sequencing analysis. Western blot, Real-time Quantitative PCR (qPCR) and immunohistochemistry showed the relationship between genes. Cell proliferation analysis and cell metabolite analysis revealed the function of genes. Chromatin immunoprecipitation (CHIP) assays were used to study the molecular mechanism. Results: The potential downstream target of SETD8, RRAD, was screened by RNA sequencing analysis. A negative correlation between SETD8 and RRAD was found by protein imprinting, Real-time Quantitative PCR (qPCR) and immunohistochemistry. Through cell proliferation analysis and cell metabolite analysis, it was found that RRAD can not only inhibit the proliferation of cancer cells but also improve the level of lipid peroxidation of cancer cells. At the same time, chromatin immunoprecipitation analysis (CHIP) was used to explore the molecular mechanism by which SETD8 regulates RRAD expression. SETD8 inhibited RRAD expression. Conclusions: SETD8 interacts with the promoter region of RRAD, which epigenetically silences the expression of RRAD to reduce the level of lipid peroxidation in pancreatic cancer cells, thereby inhibiting ferroptosis in pancreatic cancer cells and resulting in poor prognosis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

During the course of pancreatic neuroendocrine tumors (NETs), they generally become more heterogeneous with individual cells exhibiting distinct molecular fingerprints. This heterogeneity manifests itself through an unequal distribution of genetically-variant, tumor cell subpopulations within disease locations (i.e., spatial heterogeneity) or changes in the genomic landscape over time (i.e., temporal heterogeneity); these characteristics complicate clinical diagnosis and treatment. Effective, feasible tumor heterogeneity detection and eradication methods are essential to overcome the clinical challenges of pancreatic NETs. This review explores the molecular fingerprints of pancreatic NETs and the spectrum of tumoral heterogeneity. We then describe the challenges of assessing heterogeneity by liquid biopsies and imaging modalities and the therapeutic challenges for pancreatic NETs. In general, navigating these challenges, refining approaches for translational research, and ultimately improving patient care are available once we have a better understanding of intratumoral spatiotemporal heterogeneity. [ABSTRACT FROM AUTHOR]

Objective. To develop a multimodal model that combines multiphase contrast-enhanced computed tomography (CECT) imaging and clinical characteristics, including experts’ experience, to preoperatively predict lymph node metastasis (LNM) in pancreatic cancer patients. Methods. We proposed a new classifier fusion strategy (CFS) based on a new evidential reasoning (ER) rule (CFS-nER) by combining nomogram weights into a previous ER rule-based CFS. Three kernelled support tensor machine-based classifiers with plain, arterial, and venous phases of CECT as the inputs, respectively, were constructed. They were then fused based on the CFS-nER to construct a fusion model of multiphase CECT. The clinical characteristics were analyzed by univariate and multivariable logistic regression to screen risk factors, which were used to construct correspondent risk factor-based classifiers. Finally, the fusion model of the three phases of CECT and each risk factor-based classifier were fused further to construct the multimodal model based on our CFS-nER, named MMM-nER. This study consisted of 186 patients diagnosed with pancreatic cancer from four clinical centers in China, 88 (47.31%) of whom had LNM. Results. The fusion model of the three phases of CECT performed better overall than single and two-phase fusion models; this implies that the three considered phases of CECT were supplementary and complemented one another. The MMM-nER further improved the predictive performance, which implies that our MMM-nER can complement the supplementary information between CECT and clinical characteristics. The MMM-nER had better predictive performance than based on previous classifier fusion strategies, which presents the advantage of our CFS-nER. Conclusion. We proposed a new CFS-nER, based on which the fusion model of the three phases of CECT and MMM-nER were constructed and performed better than all compared methods. MMM-nER achieved an encouraging performance, implying that it can assist clinicians in noninvasively and preoperatively evaluating the lymph node status of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Ferroptosis inhibits tumor progression in pancreatic cancer cells, while PITX2 is known to function as a pro-oncogenic factor in various tumor types, protecting them from ferroptosis and thereby promoting tumor progression. In this study, we sought to investigate the regulatory role of PITX2 in tumor cell ferroptosis within the context of pancreatic cancer. We conducted PITX2 knockdown experiments using lentiviral infection in two pancreatic cancer cell lines, namely PANC-1 and BxPC-3. We assessed protein expression through immunoblotting and mRNA expression through RT-PCR. To confirm PITX2 as a transcription factor for GPX4, we employed Chromatin Immunoprecipitation (ChIP) and Dual-luciferase assays. Furthermore, we used flow cytometry to measure reactive oxygen species (ROS), lipid peroxidation, and apoptosis and employed confocal microscopy to assess mitochondrial membrane potential. Additionally, electron microscopy was used to observe mitochondrial structural changes and evaluate PITX2's regulation of ferroptosis in pancreatic cancer cells. Our findings demonstrated that PITX2, functioning as a transcription factor for GPX4, promoted GPX4 expression, thereby exerting an inhibitory effect on ferroptosis in pancreatic cancer cells and consequently promoting tumor progression. Moreover, PITX2 enhanced the invasive and migratory capabilities of pancreatic cancer cells by activating the WNT signaling pathway. Knockdown of PITX2 increased ferroptosis and inhibited the proliferation of PANC-1 and BxPC-3 cells. Notably, the inhibitory effect on ferroptosis resulting from PITX2 overexpression in these cells could be countered using RSL3, an inhibitor of GPX4. Overall, our study established PITX2 as a transcriptional regulator of GPX4 that could promote tumor progression in pancreatic cancer by reducing ferroptosis. These findings suggest that PITX2 may serve as a potential therapeutic target for combating ferroptosis in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs. Here, we found that patients with high stromal proportion had poor prognosis, especially for that with infiltrating stroma (stroma and tumor cells that presented an infiltrative growth pattern and no regular boundary). In addition, myofibroblastic CAFs (myCAFs), characterized by FAP+ and α-SMAhigh, were spatially closer to tumor cells and promoted the EMT and tumor growth. Intriguingly, only tumor cells which were spatially closer to myCAFs underwent EMT. We further elucidated that myCAFs stimulate TGF-β expression in nearby tumor cells. Then, TGF-β promoted the EMT in adjacent tumor cells and promoted the expression of myCAFs marker genes in tumor cells, resulting in distant metastasis. Our results indicate that myCAFs cause spatial heterogeneity of EMT, which accounts for liver metastasis of NF-PanNETs. The findings of this study might provide possible targets for the prevention of liver metastasis. • The spatial distribution of stroma in NF-PanNETs tissues is heterogeneous. • myCAFs induce adjacent tumor cells to express and secrete TGF-β. • myCAFs cause spatial heterogeneity of EMT in NF-PanNETs via TGF-β signaling. • Highly aggressive tumor cells exhibit the characteristics of myCAFs. [ABSTRACT FROM AUTHOR]

Lipid rafts are cholesterol‐ and sphingolipid‐enriched specialized membrane domains within the plasma membrane. Lipid rafts regulate the density and activity of signal receptors by compartmentalizing them, promoting signalling cascades that play important roles in the survival, death and metastasis of cancer cells. In this review, we emphasize the current concept initially postulated by F. Mollinedo and C. Gajate on the importance of lipid rafts in cancer survival, death and metastasis by describing representative signalling pathways, including the IGF system and the PI3K/AKT, Fas/CD95, VEGF/VEGFR2 and CD44 signalling pathways, and we also discuss the concept of CASMER (cluster of apoptotic signalling molecule‐enriched rafts), coined, originally introduced and further advanced by F. Mollinedo and C. Gajate in the period 2005–2010. Then, we summarize relevant research progress and suggest that lipid rafts play important roles in the survival, death and metastasis of cancer cells, making them promising targets for cancer therapy. [ABSTRACT FROM AUTHOR]

The baseline is referring to the patient before therapy administration gl Interesting, VEGF promotes gemcitabine resistance in pancreatic cancer cells (Figures 2A and 2B). Finally, we silenced c-Myc in VEGF-stimulated MIA PaCa-2 and SW1990 cells, and found that c-Myc suppression or knockdown could reverse the effects of VEGF on the IC50 values of gemcitabine of pancreatic cancer cells (Figures S2E and S2F). The baseline is referring to the patient before therapy administration. gl GLO:F2H7/01aug21:ctm2398-sup-0002-FigureS2.jpg PHOTO (COLOR): Figure S2 Silencing c-Myc reverses the effect of VEGF on RRM1. Dear Editor, The regimen of nab-paclitaxel and gemcitabine (AG) has been widely used as the first-line chemotherapy for advanced pancreatic cancer; the prolonged survival time is still less than 2 months.1 Kim et al demonstrated that paclitaxel can induce vascular endothelial growth factor-A (VEGF) expression which could facilitate the survival of neoplastic and tumor cells, thus protecting both endothelial and stroma cells from cytotoxic death while promoting angiogenesis.2-4 To explore the neovascularization in patients with pancreatic ductal adenocarcinoma (PDAC) treated with AG or gemcitabine alone, we first examined the I K SP trans sp i value in the tumor by Dynamic contrast enhancement magnetic resonance imaging (DCE-MRI). [Extracted from the article]

Constitutive ERK1/2 activation has been frequently observed in pancreatic adenocarcinoma (PDAC). How ERK1/2 activation status been potentiated and maintained by epigenetic mechanisms has seldom been discussed in PDAC. In this study, we first examined the expression status of p-ERK1/2 in PDAC tissues by immunohistochemical staining and then screened possible epigenetic factors that displayed different expression status between p-ERK1/2 high and low groups by RNA profiling, and found that SETD8 displayed an increased expressional pattern in p-ERK1/2high patient group. Then the impact of SETD8 on the proliferation of PDAC cells were investigated on the basis of gain or loss-of-function assays. RNA sequencing assays were performed to screen potential SETD8 downstream targets that contribute to ERK1/2 activation. Mass spectrometry and transcriptional analysis, including dual-luciferase assay and chromatin immunoprecipitation assay (ChIP), were used to explore the molecular mechanisms that governing SETD8-mediated ERK1/2 activation. In vitro cell line studies and in vivo xenograft mouse model studies indicated that SETD8 promoted cell proliferation and increased tumor formation capacity of PDAC cell lines. Mechanism explorations uncovered that SETD8 suppressed the expression of DUSP10, which was responsible for dephosphorylation of ERK1/2. Mass spectrometry and transcriptional analysis results demonstrated that STAT3 interacted with SETD8 and recruited SETD8 to the promoter region of DUSP10, leading to epigenetic silencing of DUSP10 and the resultant activation of ERK1/2. In conclusion, SETD8 interacts with STAT3 on DUSP10 promoter region and epigenetically silences DUSP10 expression. Decreased DUSP10 expression in PDAC potentiates activation of ERK1/2 phosphorylation, resulting in unfavorable prognosis of PDAC. [ABSTRACT FROM AUTHOR]

The ubiquitin-proteasome system is an important post-translational modification system involved in numerous biological processes, such as cell cycle regulation, gene transcription, signal transduction, apoptosis, differentiation and development. F-box/WD repeat-containing protein 7 (FBXW7) is one of the most studied F-box (FBX) proteins, serving as substrate recognition component of S phase kinase-associated protein 1-Cullin 1-FBX protein complexes. As a tumor suppressor, FBXW7 recognizes numerous proto-oncoproteins and promotes their ubiquitination and subsequent proteasomal degradation. FBXW7 is regulated at different levels, leading to tunable and specific control of the activity and abundance of its substrates. Therefore, genetic mutations or decreases in its expression serve an important biological role in tumor development. In-depth studies and identification of additional substrates targeted by FBXW7 have suggested a signaling network regulated by FBXW7, including its tumor-inhibitory role. The present review focused on the role of FBXW7 in tumor suppression and its application in cancer therapy. [ABSTRACT FROM AUTHOR]

Objectives: Accumulated evidence suggests that Pin1 contributes to oncogenesis of diverse cancers. However, the underlying mechanism of oncogenic function of Pin1 in PDAC requires further exploration. Materials and Methods: IHC was performed using PDAC tissues. Western blot, PCR, immunofluorescence and transwell were performed using cell lines. GSEA were applied for possible downstream pathways. ChIP assay and dual luciferase were used for assessment of transcriptional activity. Results: Both Pin1 and IL‐18 levels are increased in primary PDAC tissues and that their levels are positively correlated. High expression of IL‐18 is a predictor of poor prognoses. Pin1 promoted pancreatic cancer cell proliferation and motility by increasing IL‐18 expression, while Pin1 knockdown also inhibited the tumour‐promoting effect of IL‐18. Both Pin1 and IL‐18 could enhance the NFκB activity in pancreatic cancer cells. When bound to the p65 protein, Pin1 promoted p65 phosphorylation and its nuclear translocation. In the nucleus, Pin1 and p65 simultaneously bound to the IL‐18 promoter and enhanced IL‐18 transcription. In addition, recruitment of p65 to the IL‐18 promoter was decreased in Pin1‐silenced cells. Conclusions: Our study improves the understanding of Pin1 in tumour‐promoting inflammation in PDAC, which is a hallmark of cancer; Pin1 interacted with p65 in PDAC and enhanced NF‐κB signalling and downstream transcriptional activation of IL‐18, with increased IL‐18 continuously activating NF‐κB signalling, which then forms a positive feedback loop. [ABSTRACT FROM AUTHOR]

Ferroptosis is a recently defined, non‐apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron‐containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy‐dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy. [ABSTRACT FROM AUTHOR]

UHRF1 (ubiquitin like with plant homeodomain and ring finger domains 1) is an epigenetic modifier that is overexpressed in some cancers, including pancreatic cancer, and mediates silencing of tumor suppressor genes. However, the role of UHRF1 in regulating pancreatic cancer metabolism and metastasis is not clear. In the present study, we demonstrated that silencing UHRF1 significantly inhibited aerobic glycolysis in pancreatic cancer cells. Furthermore, we demonstrated that UHRF1 knockdown decreased hypoxia inducible factor (HIF)1α levels and HIF1α targeted glycolytic genes. The Cancer Genome Atlas dataset analysis supported this observation. The Sirtuin (SIRT) family members regulate aerobic glycolysis in many cancers. We analyzed the correlation between UHRF1 and SIRT3-5 expression and found a significant negative correlation between UHRF1 and SIRT4. Further transcriptional and functional analysis demonstrates that SIRT4 is a downstream target of UHRF1 and negatively regulated aerobic glycolysis, cell proliferation and tumor growth. Our study identified a novel UHRF1/SIRT4 axis in regulation of pancreatic cancer cell proliferation, metabolism, and metastasis. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the roles of the homeodomain‐interacting protein kinase (HIPK) family of proteins in pancreatic cancer prognosis and the possible molecular mechanism. Materials and Methods: The expression of HIPK family genes and their roles in pancreatic cancer prognosis were analysed by using The Cancer Genome Atlas (TCGA). The roles of HIPK2 in pancreatic cancer proliferation and glycolysis were tested by overexpression of HIPK2 in pancreatic cancer cells, followed by cell proliferation assay, glucose uptake analysis and Seahorse extracellular flux analysis. The mechanism of action of HIPK2 in pancreatic cancer proliferation and glycolysis was explored by examining its effect on the ERK/cMyc axis. Results: Decreased HIPK2 expression indicated worse prognosis of pancreatic cancer. Overexpression of HIPK2 in pancreatic cancer cells decreased cell proliferation and attenuated aerobic glycolysis, which sustained proliferation of cancer cells. HIPK2 decreased cMyc protein levels and expression of cMyc‐targeted glycolytic genes. cMyc was a mediator that regulated HIPK2‐induced decrease in aerobic glycolysis. HIPK2 regulated cMyc protein stability via ERK activation, which phosphorylated and controlled cMyc protein stability. Conclusions: HIPK2 suppressed proliferation of pancreatic cancer in part through inhibiting the ERK/cMyc axis and related aerobic glycolysis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a global health problem and one of the most common malignant tumors. Recent studies have shown that noncoding RNAs (ncRNAs) contribute to the pathogenesis of hepatocellular carcinoma (HCC). These RNAs may be involved in a variety of pathological processes such as cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. In addition, abnormal expression of ncRNAs in HCC may provide potential prognostic or diagnostic biomarkers. This review provides an overview of the role and potential applications of ncRNAs, miRNAs, lncRNAs, circRNAs, and snoRNAs in liver cancer. [ABSTRACT FROM AUTHOR]

Ten new and 13 known prenylated 2,5-diketopiperazines (2,5-DKPs) were identified from co-culture of Penicillium sp. DT-F29 with Bacillus sp. B31. The constitutions and relative configurations of new compounds were established by 1D and 2D NMR spectroscopic data analysis. The isolated 2,5-DKPs in bioactivity test showed bromodomain-containing protein 4 (BRD4) inhibitory activities, and compound 14 , with IC 50 values of 6.54 μ M, was potential for BRD4 inhibitor discovery. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic distal pancreatectomy (LDP) showed advantage of perioperation outcomes for benign and low-grade tumor of the pancreas. The application of LDP for pancreatic ductal adenocarcinoma (PDAC) didn't gain popular acceptance and the number of LDP for PDAC remains low. We designed a case-matched study to analysis the short- and long-term outcomes of the patients undergoing either Laparoscopic distal pancreatectomy or open distal pancreatectomy for PDAC.Method: From 2003 to 2013, 17 patients were underwent LDP and 34 patients were underwent ODP for PDAC were matched by tumor size, age and body mass index (BMI). The two groups' demographic information, perioperative outcomes and survival data were compared.Results: Baseline characteristics were comparable between the LDP and ODP groups. The intraoperative blood loss, first flatus, first oral intake and postoperative hospital stay were significantly less in LDP group than ODP group (50 ml vs400ml, P = 0.000; 3d vs 4d, P = 0.001; 3d vs 4d, P = 0.003; 13d vs 15.5d, P = 0.022). The mean operation time, overall postoperative morbidity and postoperative pancreatic fistula rates were similar in the two groups. 5 patients (29.4 %) in LDP group and 7 patients (20.6 %) in ODP group underwent extended resections. There were no significant differences in tumor sizes (3.5 cm vs 3.9 cm, P = 0.664) and number of harvested lymph nodes (9 vs8 P = 0.534). The median overall survival for both groups was 14.0 months. Cox proportional hazards analysis showed extended resections, R1 resection, perineural invasion and tumor differentiation were associated with worse survival.Conclusion: LDP is technically feasible and safe for PDAC in selected patients and the short-term oncologic outcomes were not inferior to ODP in this small sample study. However the long-term oncologic safety of LDP for PDAC has to be further evaluated by multicenter or randomized controlled trials. [ABSTRACT FROM AUTHOR]

Introduction: Flag leaf width (FLW) is directly related to photosynthetic capacity and yield potential in wheat. In a previous study, Qflw.nau- 5A controlling FLW was detected on chromosome 5A in the interval possessing Fhb5 for type I Fusarium head blight (FHB) resistance using a recombinant inbred line population derived from Nanda2419 × Wangshuibai. Materials and methods: Qflw.nau- 5A near-isogenic line (NIL) with the background of Mianyang 99-323 and PH691 was developed and evaluated. FLW inheritance was investigated using two F populations developed from crossing the Qflw.nau- 5A NILs with their recurrent parents. One hundred ten and 28 recombinants, which included 10 and 5 types of recombinants, were identified from 2816 F plants with Mianyang 99-323 background and 1277 F plants with PH691 background, respectively, and phenotyped in field trials for FLW and type I FHB resistance. Deletion bin mapping was applied to physically map Qflw.nau- 5A. Results and conclusions: The introduction of Wangshuibai Qflw.nau- 5A allele reduced the FLW up to 3 mm. In the F populations, Qflw.nau- 5A was inherited like a semi-dominant gene, and was therefore designated as TaFLW1. The FLW of the recombinant lines displayed a distinct two-peak distribution. Recombinants with wider leaves commonly have Mianyang 99-323 or PH691 chromatin in the 0.2 cM Xwmc492- Xwmc752 interval that resided in the 5AL12-0.35-0.57 deletion bin, and recombinants with narrow leaves were Wangshuibai genotype in this interval. Phenotypic recombination between FLW and type I FHB resistance was identified, implying TaFLW1 was in close linkage with Fhb5. These results should aid wheat breeders to break the linkage drag through marker-assisted selection and assist in the map-based cloning of TaFLW1. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a rapidly progressing disease with a poor prognosis. We still have many questions about the pathogenesis, early diagnosis and precise treatment of this disease. Organoids, a rapidly emerging technology, can simulate the characteristics of pancreatic tumors. Using the organoid model of pancreatic cancer, we can study and explore the characteristics of pancreatic cancer, thereby effectively guiding clinical practice and improving patient prognosis. This review introduces the development of organoids, comparisons of organoids with other preclinical models and the status of organoids in basic research and clinical applications for pancreatic cancer. Unlabelled Image [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer continues to be one of the most aggressive malignant tumors. Work in recent years in cancer molecular biology has revealed that metabolic reprogramming is an additional hallmark of cancer that is involved in the pathogenesis of cancers, and is intricately linked to gene mutations. Main text: However, though oncogenes such as KRAS and c-Myc play important roles in the process, and have been extensively studied, no substantial improvements in the prognosis of pancreatic cancer have seen. Therefore, some scientists have tried to explain the mechanisms of abnormal cancer metabolism from the perspective of tumor suppressor genes. In this paper, we reviewed researches about how metabolic reprogramming was regulated by tumor suppressor genes in pancreatic cancer and their clinical implications. Conclusion: Abnormal metabolism and genetic mutations are mutually causal and complementary in tumor initiation and development. A clear understanding of how metabolic reprogramming is regulated by the mutated genes would provide important insights into the pathogenesis and ultimately treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Galectins constitute a family of β-galactoside-binding proteins, which influence various hallmarks of pancreatic cancer, including cell proliferation, invasion and migration; immune escape; and angiogenesis. Although many studies have concentrated on the role of galectins in pancreatic cancer, the results remain controversial. Hence, we performed a comprehensive meta-analysis to clarify the precise diagnostic and prognostic value of galectins in pancreatic cancer. Methods: PubMed/MEDLINE, EMBASE and Web of Science were used to search related published literature up to July 2019. Pooled hazard ratios (HRs), diagnostic accuracy variables and related 95% confidence intervals (CIs) were calculated using STATA 14.0 software. Results: Eleven studies including 1227 participants met our inclusion criteria. High expression of galectin family was not correlated with overall survival (OS) in pancreatic cancer (HR, 1.19; 95% CI 0.67–2.11). According to subgroup analysis, high levels of galectin-1 were significantly correlated with worse OS in pancreatic cancer (HR, 4.77; 95% CI 2.47–9.21), while high levels of tandem-repeat galectins (galectin-4 or galectin-9) predicted both better OS (HR, 0.63; 95% CI 0.46–0.86) and disease-free survival (DFS) (HR, 0.63; 95% CI 0.48–0.83). The expression levels of galectin-3 did not directly correlate with prognosis (HR, 0.99; 95% CI 0.40–2.46). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratios of galectin-3 were 0.64 (95% CI 0.41–0.82), 0.76 (95% CI 0.59–0.88), 2.70 (95% CI 1.21–6.1), and 0.47 (95% CI 0.23–0.98), respectively. The area under the curve (AUC) of galectin-3 was 0.77. Conclusion: Taken together, our results suggest that high expression of galectin-1 and low levels of galectin-4 or galectin-9 are predictors of worse prognosis in pancreatic cancer patients. The expression of galectin-3 was not directly related to OS and other clinical characteristics. Although galectin-3 exhibited some diagnostic value in patients with pancreatic cancer in this meta-analysis, clinical application prospects remain to be validated. Further studies are warranted to confirm and strengthen these findings. [ABSTRACT FROM AUTHOR]

Background: The introduction of laparoscopic technology has greatly promoted the development of surgery, and the trend of minimally invasive surgery is becoming more and more obvious. However, there is no consensus as to whether laparoscopic pancreaticoduodenectomy (LPD) should be performed routinely. Main body: We summarized the development of laparoscopic pancreaticoduodenectomy (LPD) in recent years by comparing with open pancreaticoduodenectomy (OPD) and robotic pancreaticoduodenectomy (RPD) and evaluated its feasibility, perioperative, and long-term outcomes including operation time, length of hospital stay, estimated blood loss, and overall survival. Then, several relevant issues and challenges were discussed in depth. Conclusion: The perioperative and long-term outcomes of LPD are no worse and even better in length of hospital stay and estimated blood loss than OPD and RPD except for a few reports. Though with strict control of indications, standardized training, and learning, ensuring safety and reducing cost are still and will always the keys to the healthy development of LPD; the best times for it are coming. [ABSTRACT FROM AUTHOR]

Background: The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism. Methods: Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of 18F-FDG (fluorodeoxyglucose) uptake by PET/CT (positron emission tomography/computed tomography) imaging were used to verify the role of PRMT5 in aerobic glycolysis, which sustains cell proliferation. The regulatory effect of PRMT5 on cMyc, a master regulator of oncogenesis and aerobic glycolysis, was explored by quantitative PCR and protein stability measurements. Results: PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells. Conclusions: The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Hepatocyte nuclear factor 4α (HNF4α) is a tissue-specific transcription factor that regulates the expression of numerous genes in hepatocytes and pancreatic β cells. HNF4α has been reported to affect cell proliferation and chemoresistance in several cancers. However, the role of HNF4α in pancreatic adenocarcinoma (PDAC) has not been studied extensively and remains unclear. Methods: By utilizing immunohistochemical (IHC) staining, we measured the expression of HNF4α in PDAC tissues. By silencing HNF4α in PDAC cell lines, we assessed the impact of HNF4α on pancreatic cancer cell proliferation and gemcitabine sensitivity. We used CCK8 and colony formation assays to examine the effect of HNF4α on cell proliferation. A flow cytometry assay was used to assess cell apoptosis. The expression of gemcitabine-related genes was detected by quantitative real‑time PCR (qRT-PCR) and Western blotting. IHC was utilized to assess the correlation between HNF4α and human equilibrative nucleoside transporter 1 (hENT1) expression in PDAC patients. Chromatin immunoprecipitation (ChIP) and dual‑luciferase reporter assays were used to confirm that hENT1 is a target gene of HNF4α. Results: Increased HNF4α expression was detected in PDAC tissues; patients with higher HNF4α expression displayed worse prognosis. To elucidate the function of HNF4α, we examined its role in pancreatic cancer cell proliferation, apoptosis and gemcitabine resistance. In HNF4α-silenced Capan-1 and MiaPaCa-2 cells, we observed decreased cell proliferation and increased sensitivity to gemcitabine compared to those of controls. The mechanism of HNF4α in gemcitabine-related chemosensitivity was then explored. In response to HNF4α silencing, the expression levels of gemcitabine-related proteins, hENT1 and deoxycytidine kinase (dCK) were significantly increased. Additionally, hENT1 was negatively correlated with HNF4α in PDAC tissue samples. Moreover, we identified hENT1 as a downstream target of HNF4α. Conclusion: HNF4α is a prognostic marker for overall survival, is required for pancreatic cancer cell proliferation and promotes resistance to gemcitabine by downregulating hENT1. Therefore, targeting HNF4α might reverse gemcitabine resistance and provide novel treatment strategies for PDAC. [ABSTRACT FROM AUTHOR]