Search

Hot spot gene mutations in splicing factor 3b subunit 1 (SF3B1) are observed in many types of cancer and create abundant aberrant mRNA splicing, which is profoundly implicated in tumorigenesis. Here, we identified that the SF3B1 K700E (SF3B1K700E) mutation is strongly associated with tumor growth in pancreatic ductal adenocarcinoma (PDAC). Knockdown of SF3B1 significantly retarded cell proliferation and tumor growth in a cell line (Panc05.04) with the SF3B1K700E mutation. However, SF3B1 knockdown had no notable effect on cell proliferation in two cell lines (BxPC3 and AsPC1) carrying wild‐type SF3B1. Ectopic expression of SF3B1K700E but not SF3B1WT in SF3B1‐knockout Panc05.04 cells largely restored the inhibitory role induced by SF3B1 knockdown. Introduction of the SF3B1K700E mutation in BxPC3 and AsPC1 cells also boosted cell proliferation. Gene set enrichment analysis demonstrated a close correlation between SF3B1 mutation and aerobic glycolysis. Functional analyses showed that the SF3B1K700E mutation promoted tumor glycolysis, as evidenced by glucose consumption, lactate release, and extracellular acidification rate. Mechanistically, the SF3B1 mutation promoted the aberrant splicing of PPP2R5A and led to the activation of the glycolytic regulator c‐Myc via post‐translational regulation. Pharmacological activation of PP2A with FTY‐720 markedly compromised the growth advantage induced by the SF3B1K700E mutation in vitro and in vivo. Taken together, our data suggest a novel function for SF3B1 mutation in the Warburg effect, and this finding may offer a potential therapeutic strategy against PDAC with the SF3B1K700E mutation., SF3B1 mutations have been previously implicated in tumorigenesis. Here, we investigate the role of SF3B1K700E mutation in pancreatic ductal adenocarcinoma (PDAC). SF3B1K700E led to aberrant splicing of PPP2R5A, coupled with c‐Myc activation higher aerobic glycolysis rate and growth advantage of tumor cells. Taken together, our data describe a novel function for SF3B1 K700E mutations in the Warburg effect. Inhibition of SF3B1 K700E mutation may potentially serve as a novel therapeutic strategy for patients with PDAC.

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils., Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease characterized by an immunosuppressive microenvironment. Here the authors show that a subset of P2RX1-negative neutrophils with immunosuppressive properties accumulate in PDAC metastatic liver tissues and promote tumor growth.

Background: Infection by multi–drug-resistant (MDR) bacteria is a high-risk factor for poor clinical results. Pancreatoduodenectomy (PD) has been associated with a high rate of complications, inclu...

Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism.The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms.We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression.Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion–triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. Significance: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.

Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

Mercury speciation is of significant importance in environmental and biological analysis because its toxicity and metabolic behavior in the human body differ among species. Nanomaterial-assisted optical sensors are widely used for mercury ion detection but rarely applied in mercury speciation analysis. In this work, we develop a novel colorimetric sensing strategy for mercury speciation based on mercury-stimulated peroxidase mimetic activity of gold nanoparticles with the assistance of different reductants. In the presence of a weak reductant, only inorganic mercury can be reduced to Hg0, whereas both inorganic mercury and organic mercury can be reduced to Hg0 in the presence of a strong reductant. Due to the high affinity between Hg and Au, Hg0 deposits on the AuNP surface in the form of a Au-Hg amalgam, leading to a remarkable enhancement of peroxidase mimetic activity of gold nanoparticles. On the basis of this effect, inorganic mercury and total mercury can be detected by using 3,3',5,5'-tetramethylbenzidine (TMB) as the substrate. The limits of detection for inorganic mercury and total mercury are 1.9 and 0.9 nM within 5-100 nM, respectively. The selectivity of this sensing system is high due to the specificity of Au-Hg interaction. Its practical applications are further demonstrated by organic mercury analysis in a fish sample and mercury speciation in a human hair sample.

Synchronous resection of primary pancreatic ductal adenocarcinoma (PDAC) and liver metastases in highly selective patients is being accepted based on oncology research progress showing safe surgical outcomes with low morbidity and mortality. We also tried to determine patients who would benefit from the operation.From January 2012 to October 2017, 48 patients who underwent synchronous resection of primary PDAC and liver metastases were retrospectively evaluated. Twenty-three of them underwent oligometastatic synchronous resection.The majority of synchronous resection PDAC patients underwent hepatic wedge resection, and no oligometastatic patient was treated with hemihepatectomy. The median overall survival (OS) of the synchronous resection patients was 7.8 months. Hepatic oligometastatic PDAC patients had a longer OS than that of non-oligometastatic synchronous resection patients, systemic chemotherapy patients and palliative patients (16.1 vs 6.4 months, P = 0.02; 16.1 vs 7.6 months, P = 0.02; 16.1 vs 4.3 months, P 0.0001; respectively). Further analysis showed that localized pancreatic body/tail PDAC had a better OS in oligometastatic patients than in non-oligometastatic synchronous resection patients (16.8 months vs 7.05 months, P = 0.0004) and systemic chemotherapy patients (16.8 months vs 8 months, P = 0.003).Patients with pancreatic body/tail PDAC with liver oligometastases can benefit from synchronous resection.

A novel sensor array based on a (+)AuNP/AuNC nanocomposite was constructed for the selective discrimination of 10 types of Gram-negative bacteria (including 3 types of antibiotic-resistant strains) at a low concentration level of OD600 = 0.015. By recognizing the triple optical patterns of Gram-negative bacteria with the assistance of LDA, the sensor array is able to group the bacteria with respect to their species to each other.

Owing to the lack of early diagnosis, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal tumours. Because acinar-to-ductal metaplasia (ADM) is a critical process to pancreatic regeneration and PDAC initiation, we applied GSE65146, a dataset composed of transcripts at different time points in wild-type and Kras

The discrimination of various sulfur -containing species helps us to deeply understand how sulfur affects cellular signaling and other physiological events. Herein, we present a three-dimensional sensor array based on simultaneous variation of the optical properties (fluorescence, light scattering, and UV–vis absorption) of gold–silver alloy nanocluster (AuAgNCs)–gold nanoparticle (AuNPs) composite for the rapid identification of 13 sulfur-containing species and sulfur-oxidizing bacteria. The sensor array is fabricated based on the strong coordination interactions between sulfur-containing compounds and AuAgNCs on the surface of AuNPs. The sulfur species of interest exhibit different affinities toward AuAgNCs and generate unique optical properties. These response patterns could divide the analytes into three categories including organic sulfide, inorganic sulfide, and thiols. Thirteen types of sulfur species including cystine, methionine, GSSG, S2–, SO32–, S2O32–, S2O72–, S2O82–, S4O62–, GSH, N-acetyl-l-c...

Background and aimsPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.MethodsThe Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.ResultsGABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression.ConclusionsOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

Background. Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) serves as an effector for tumor growth in human malignancies. However, the mechanism of ERO1L on promoting metastasis of pancreatic ductal adenocarcinoma (PDAC) remains to be further explored. Methods. Bioinformatics analysis of public databases and large-scale metastatic PDAC sequencing was performed to determine the expression profile and prognostic value of ERO1L in PDAC. The effect of ERO1L on metastasis of PDAC was analyzed in vitro and in vivo, via cell biological, molecular, and biochemical approaches. Results. ERO1L in PDAC hepatic metastatic tissues were highly expressed and related to disease-free survival (DFS). Genetic silencing and pharmacological inhibition of ERO1L with EN460 suppressed cell migration and invasion of PDAC. Furthermore, EN460 also suppressed hepatic metastasis of PDAC in vivo. Using shRNAs and EN460 to inhibit the ERO1L expression in Capan-2 and MiaPaca-2 led to the remarkable change of EMT-related protein Vimentin and E-cadherin, which indicated that EMT acted as a key pathway for ERO1L to promote invasion, dissemination, colonization, and growth of hepatic metastasis in PDAC. Conclusion. Our findings uncover ERO1L contributes to hepatic metastasis in PDAC via epithelial-mesenchymal transition (EMT) process and indicate a promising therapeutic strategy for PDAC hepatic metastasis.

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in the liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity. Results We conduct exome sequencing and RNA sequencing for synchronous surgically resected primary tumors and the paired hepatic metastases from 17 hepatic oligometastatic pancreatic ductal adenocarcinoma and validate our findings in specimens from 35 of such cases. The comprehensive analysis of somatic mutations, copy number alterations, and gene expressions show high similarity between primary tumors and hepatic metastases. However, hepatic metastases also show unique characteristics, such as a higher degree of 3p21.1 loss, stronger abilities of proliferation, downregulation of epithelial to mesenchymal transition activity, and metabolic rewiring. More interesting, altered tumor microenvironments are observed in hepatic metastases, especially a higher proportion of tumor infiltrating M2 macrophage and upregulation of complement cascade. Further experiments demonstrate that expression of C1q increases in primary tumors and hepatic metastases, C1q is mainly produced by M2 macrophage, and C1q promotes migration and invasion of PDAC cells. Conclusion Taken together, we find potential factors that contribute to different stages of PDAC metastasis. Our study broadens the understanding of molecular mechanisms driving PDAC metastasis.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor in southern China. Cucurbitacin B (CuB) is a tetracyclic triterpene compound isolated from Cucurbitaceae plants which has anti-inflammation and antitumor properties and low toxic side effects. In this study, we use a series of wet experiments and network pharmacology analyses to explore the effects of CuB on cell proliferation, migration, invasion, and apoptosis of highly metastatic 5-8F NPC cells. The findings suggest that CuB inhibits NPC cells in a time- and dose-dependent manner and that cancer migration and invasion abilities decrease significantly after CuB treatments. Mechanistically, CuB could increase the proportion of cells in the G2/M phase and reduce it in the G0/G1 phase, leading to apoptosis. The network pharmacological analyses and wet experiments uncovered that the MAPK pathway is a central target by pathway enrichment analysis, affecting the fate of cancer cells and influencing proliferation and apoptosis. Taken together, our study reveals that CuB could effectively inhibit 5-8F NPC cell proliferation, migration, and invasion via cell cycle blockage and cell apoptosis. Collectively, we have shown that CuB is a promising anti-NPC candidate compound for future preclinical study.

Perineural invasion (PNI) is a prominent characteristic of pancreatic ductal adenocarcinoma (PDAC). PNI is associated with tumor progression, local recurrence and neuropathic pain; therefore, the identification of biomarkers associated with PNI may be beneficial in assessing the prognosis for patients with PDAC. Using an in vivo model of PNI, five pancreatic cancer cell lines (PANC-1, CFPAC-1, CAPAN-2, SW1990 and ASPC-1) were divided into two groups: High-(comprising PANC-1, CFPAC-1 and CAPAN-2) and low PNI (comprising SW1990 and ASPC-1). Differentially expressed genes (DEGs) between the two groups were identified using the GSE26088 dataset, and were regarded as PNI-associated genes. A total of 445 DEGs associated with PNI (fold change >1.5 or

Background: Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC) and is one of the important causes of local recurrence in resected pancreatic cancer, but the molecular mechanism remains largely unexplored. Methods: Here, we used immunohistochemistry staining to determine the expression of CD74. Then the in vivo PNI model, in vitro neuroplasticity assay, cell proliferation assay, wound healing and Transwell-based invasion assay were performed to examine the function of CD74 in pancreatic cancer cell lines. ChIP assay and Luciferase reporter assay were used to illustrate the mechanism underlying CD74 induced GDNF expression. Findings: We confirmed that the expression level of CD74 was an independent predictor of PNI and poor prognosis for PDAC. Moreover, we found that upregulation of CD74 on PDAC enhanced its migration and invasive capabilities and potentiated the secretion of neurotrophic factor GDNF to promote the neuroplasticity. Mechanistically, CD74 promoted GDNF production via the AKT/EGR-1/GDNF axis in PDAC. Interpretation: Taken together, our findings suggest a supportive role of CD74 in the PNI of PDAC, and deepen our understanding of how cancer cells promote neuroplasticity in the microenvironment of PDAC. Funding: This work was supported by grants from National Natural Science Foundation of China No.81401931 (Jun-Feng Zhang), 81602414(Jian-Yu Yang), 81702739 (Xue-Liang Fu), 81802317(Min-Wei Yang), and additional grants from Science and Technology funds of School of Medicine, Shanghai Jiao Tong University No. 14XJ10022 (Jun-Feng Zhang), Scientific research project of Shanghai municipal health and Family Planning Commission No. 201740218 (Jun-Feng Zhang). Conflict of Interest: The authors have no conflicts of interest to declare. Ethical Approval: All the patients provided written informed consent before admission, and the study was approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University.

A suitable As(III)-binding ligand is the key to realize selective and sensitive As(III) sensing. In this study, phage display technique was used for the screening of As(III)-binding peptide. By negative screening against some representative metal cations and positive screening against target As(III), phages that bind to foreign metal cations were eliminated, while those bearing As(III)-binding peptides were kept and enriched. After DNA sequencing and phage ELISA analysis, 5 sets of As(III)-binding peptides were identified, with high content of N-containing functional groups as their predominate feature. A highly specific peptide (sequence: T-Q-S-Y-K-H-G) with the highest frequency of occurrence and best selectivity for As(III) was finally chosen. This peptide with a cysteine added at the C-terminal induces the aggregation of gold nanoparticles (AuNPs), whereas the competitive binding of As(III) to the peptide prevents the aggregation of AuNPs. Based on this observation, a simple and sensitive colorimetric sensing assay was developed, with a limit of detection (LOD) of 54 nM (4 μg L −1 ) for As(III). The As(III) sensor showed high selectivity over other metal ions including As(V), and was validated by As(III) analysis in certified reference material and environmental water samples.

Dysregulated potassium (K+) channels have previously been shown to promote the development and progression of many types of cancers. Meanwhile, K+ channels are particularly important in regulating the endocrine and exocrine functions of pancreas. However, the expression pattern and prognostic significance of K+ channels in pancreatic ductal adenocarcinoma (PDAC) remain unknown. In this study, by screening a GEO dataset containing 36 microdissected PDAC and matching normal pancreatic tissue samples, four differentially expressed K+ channels (KCNJ5, KCNJ16, KCNN4 and KCNK1) were identified in PDAC. by immunohistochemical analysis of pancreatic tissue sections from Pdx1-Cre; LSL-KrasG12D/+ mice (KC), Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ mice (KPC) and human PDAC tissue microarrays, we found that Ca2+-activated K+ channel KCNN4 was significantly elevated in pancreatic intraepithelial neoplasia (PanIN) and PDAC epithelia compared with untransformed pancreas tissues. Higher epithelial KCNN4 expression was closely correlated with advanced TNM stages and predicted a poor prognosis in patients with PDAC. Elevated KCNN4 expression was significantly associated with shorter survival in univariable and multivariable analyses. Collectively, the identification of expression pattern of K+ channels in PDAC and its precursor PanIN demonstrates the importance of KCNN4 channel during the malignant transformation of PDAC. On the basis of the prognostic signals from two independent cohorts, KCNN4 should be considered as a promising therapeutic target.

The finite element model (FE) of temperature field of straight thin-walled samples in laser cladding IN718 was established, and the growth of microstructure was simulated by cellular automata (CA) method through macro-micro coupling (CA-FE). The effects of different cooling conditions on microstructure, hardness, and properties of laser-cladding layer were studied by designing cooling device. The results show that the simulation results are in good agreement with the microstructure of the cladding layer observed by the experiment. With the scanning strategy of reducing laser power layer-by-layer, the addition of water cooling device and the processing condition of 0.7 mm Z-axis lift, excellent thin-walled parts can be obtained. With the increase of cladding layers, the pool volume increases, the temperature value increases, the temperature gradient, cooling rate, solidification rate, K value gradually decrease, and eventually tend to be stable, in addition, the hardness shows a fluctuating downward trend. Under the processing conditions of layer-by-layer power reduction and water cooling device, the primary dendrite arm spacing reduced to about 8.3 μm, and the average hardness at the bottom of cladding layer increased from 260 HV to 288 HV. The yield strength and tensile strength of the tensile parts prepared under forced water cooling increased to a certain extent, while the elongation slightly decreased.

FAM83B (family with sequence similarity 83, member B) seems to emerge as a new class of players involved in the development of a variety of malignant tumors. Yet the molecular mechanisms are not well understood. The present study is intended to investigate the expression and function of FAM83B in pancreatic ductal adenocarcinoma (PDAC). In this study, we found that the expression of FAM83B was significantly increased both in PDAC cell lines and PDAC tumor tissues. FAM83B expression was positively related with advanced clinical stage and poor vital status. Higher FAM83B expression predicted shorter overall survival in PDAC patients, regardless of lymphatic metastasis status and histological differentiation. Actually, FAM83B may act as an independent prognostic indicator as well. What's more, down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation. Finally, a subcutaneous xenograft model indicated that knockdown of FAM83B significantly reduced the tumor volume in vivo. Our findings have provided supporting evidence for the potential molecular biomarker role of FAM83B in PDAC. It's of great interest and broad significance to target FAM83B in PDAC, which may conduce to develop a meaningful and effective strategy in the diagnosis and treatment of PDAC.

Dickkopf-1(DKK-1), the downstream target of β-catenin/T-cell factor, participates in a negative feedback loop in the Wnt signaling and reported as an important biomarker in many tumors. In this study, we analyzed the expression of DKK-1 in pancreatic ductal adenocarcinoma (PDAC) patients at both mRNA and protein levels. We used real-time PCR to detect the expression of DKK-1 in 32 PDAC and paired adjacent non-tumor tissues, results suggested that the expression of DKK-1 was increased in PDAC tissues. We found the similar results in the analysis of 3 independent microarray data sets. Immunohistochemical staining of 311 pairs of PDAC tissues suggested that DKK-1 expression was significantly associated with T classification (P = 0.039) and lymph node metastasis (P = 0.035). Furthermore, Kaplan-Meier analysis for DKK-1 expression demonstrated that patients with higher DKK-1 level had shorter overall survival (OS) and relapse-free survival (RFS) time in Ren Ji cohort and online PDAC database at both mRNA and protein levels. Univariable and multivariable Cox regression analysis confirmed that DKK-1 as well as lymph node metastasis and histology were independent predictors of OS in patients with PDAC. This study demonstrated that DKK-1 may be a predictor for prognosis in PDAC patients.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancer types despite the improvement of modern medicine. In our present study, we found that dickkopf-related protein 2 (DKK2) shares a higher expression in PDAC compared with adjacent pancreas tissue in tissue microarray. In addition, an elevated expression of DKK2 predicts poorer prognosis of patients and positively correlated with poor tumor differentiation. Multivariate Cox regression analysis was also performed and confirmed that the expression of DKK2 is an independent prognostic factor in PDAC. A high expression of DKK2 correlates with cell migration and epithelial mesenchymal transition based on gene set enrichment analysis (GSEA) while knockdown of DKK2 in PDAC cells resulted in impaired cellular migration. Furthermore, GSEA predicts negative correlation between tumor immunity invasion and DKK2 expression. We then confirmed these results and demonstrated that a higher expression of DKK2 imparts the recruitment of CD8+ T cells. Our work suggested that DKK2 imparts tumor immune evasion and is associated with poor prognosis in pancreatic ductal adenocarcinoma.

Hypoxia and the hypovascular tumor microenvironment are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is of great importance to tumor survival and proliferation. There is little research regarding the role of Nuclear Factor of Activated T Cells 5 (NFAT5) in relation to carcinoma. Here, we explored the impact of NFAT5 on the biological behavior of PDAC and the underlying mechanism. We demonstrated that NFAT5 was highly expressed in PDAC and was related to poorer prognosis. Knockdown of NFAT5 lead to impaired proliferation of tumor cells caused by an aberrant Warburg effect. Mechanically, phosphoglycerate kinase 1 (PGK-1), which is the first enzyme generating ATP in glycolysis, was verified as a target gene of NFAT5. Over-expression of PGK1 compromised the aberrant oncological behavior caused by knockdown of NFAT5 both in vitro and in vivo. Clinical samples underwent positron emission tomography-computed tomography (PET-CT) examination and KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice were collected to support our conclusion.

Background Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown. Aim To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant. Methods We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR. Results Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without. Conclusion Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.

Mature brain-derived neurotrophic factor (mBDNF) has neuroprotection in cerebral ischemia. Conversely, the precursor of brain derived neurotrophic factor (proBDNF) has the opposite function to its mature form, inducing apoptosis. However, whether the neuroprotection of Panax notoginsenoside Rb1 (PNS-Rb1) on ischemic stroke is due to, at least partially, its modulation of suppressing proBDNF/P75NTR/sortilin or upregulation of mBDNF is not clear. To test this hypothesis, rats induced by photothrombotic stroke were treated with PNS-Rb1 100 mg/kg or nimodipine 1 mg/kg twice a day until 3, 7, and 14 days.Our data indicate that PNS-Rb1 significantly reduced cerebral infarction rate, proBDNF/P75NTR/sortilin, and plasminogen activator inhibitor-1 (PAI-1) protein levels, and improved sensorimotor dysfunctions induced by ischemic stroke, upregulation of BDNF/TrkB levels, and its processing enzymes (tissue plasminogen activator, tPA) in a time-dependent manner. Taken together, our findings indicate that the improvement of sensorimotor dysfunctions by PNS-Rb1 following ischemic stroke is made, at least partially, by activating the BDNF/TrkB and inhibiting proBDNF/sortilin/P75NTR. Refereed/Peer-reviewed

// Jun-Chao Guo 1, * , Jian Li 1, 3, * , Li Zhou 1, * , Jian-Yu Yang 4 , Zhi-Gang Zhang 5 , Zhi-Yong Liang 2 , Wei-Xun Zhou 2 , Lei You 1 , Tai-Ping Zhang 1 , Yu-Pei Zhao 1 1 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China 2 Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China 3 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China 4 Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China 5 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China * These authors have contributed equally to this work Correspondence to: Yu-Pei Zhao, email: zhao8028@263.net Tai-Ping Zhang, email: tpingzhang@yahoo.com Keywords: pancreatic cancer, invasive phenotype, prognosis, CXCL12, CXCR7, mTOR Received: March 18, 2016 Accepted: July 27, 2016 Published: August 17, 2016 ABSTRACT Chemokine (C-X-C motif) receptor 7 (CXCR7) and its ligand, chemokine (C-X-C motif) ligand 12 (CXCL12), were established to be involved in biological behaviors and associated with prognosis in many cancers. However, effects, underlying mechanisms of CXCL12-CXCR7 axis in invasive phenotype of pancreatic cancer (PC) and its clinicopathologic significances have not been comprehensively explored. In the present study, it was first found by tissue microarray-based immunohistochemistry that CXCL12 and CXCR7 staining scores were significantly associated with vessel invasion and overall survival in two independent cohorts of PC. Besides, co-expression of these proteins was an independent prognosticator in multivariate analysis in both cohorts. Then, migration and invasion, but not proliferation, were decreased in CXCR7-stably silenced PC cells, whereas opposite changes were observed in CXCR7-stably overexpressed cells, accompanied by alterations of mTOR and Rho/ROCK pathways. CXCL12 stimulated migration, invasion, CXCR7 expression and phosphorylation of key mTOR proteins. AMD3100 did not influence effects of CXCL12. Two mTOR inhibitors, rapamycin and Torin1, reversed enhanced invasive phenotypes and mTOR phosphorylation in CXCR7-overexpressed cells. Moreover, CXCR7 directly interacts with mTOR. Finally, liver metastasis, but not growth, was affected by CXCR7 status in orthotopically-implanted PC models in nude mice. Collectively, CXCL12-CXCR7 axis accelerates migration and invasion of PC cells through mTOR and Rho/ROCK pathways, and predicts poor prognosis of PC.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce CaOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

Fluorescent nanoparticles are widely used for sensing biologically significant species. However, there are only rare reports of the discrimination or speciation of metal species. In this work, we report for the first time the speciation of mercury (Hg2+) and methylmercury (CH3Hg+) by taking advantage of the fluorescence feature of folic-acid-capped gold nanoclusters (FA-AuNCs). FA-Au NCs exhibit an average size of 2.08 ± 0.15 nm and a maximum emission at λex/λem = 280/440 nm with a quantum yield of 27.3%. It is interesting that Hg2+ causes a significant quench of the fluorescence of FA-Au NCs, whereas CH3Hg+ leads to a remarkable fluorescence enhancement. On the basis of this discriminative fluorescent response between Hg2+ and CH3Hg+, a novel nanosensor for the speciation of CH3Hg+ and Hg2+ was developed, providing limits of detection (LODs) of 28 nM for Hg2+ and 25 nM for CH3Hg+ within 100–1000 nM. This sensing system is highly selective to mercury. Its practical applications were further demonstrated b...

The present study aimed to investigate the expression level of ubiquitin specific peptidase 9X (USP9X) and its clinical significance in Chinese patients with pancreatic ductal adenocarcinoma (PDAC). The mRNA expression levels of USP9X in 30 paired PDAC tissue samples were examined by reverse transcription-quantitative polymerase chain reaction. The protein expression of USP9X was analyzed by immunohistochemistry (IHC) in a tissue microarray containing 205 PDAC specimens. All analyses were performed by SPSS 20.0 and GraphPad Prism 5.0 software. The USP9X mRNA level was significantly decreased in 18/30 (60.0%) PDAC tissue samples compared with matched surrounding non-tumor tissue samples. The results of IHC revealed that decreased expression of USP9X was inversely associated with liver metastasis (P=0.032). Kaplan-Meier survival curves indicated that patients with high expression of USP9X presented a longer clinical overall survival time (P

Echinacea purpurea (EP), a globally popular herbal medicine, has been used to treat various diseases in human and animals. However, little has been reported about its effects in fish. In this study, crucian carp (Carassius auratus) were selected to evaluate the effects of EP on growth performance and antioxidant response and the expressions of microRNAs. The results showed EP could stimulate the growth of crucian carp with the best effect was observed at dose of 4 g kg−1. In serum, the content of hydroxyl radical (·OH) and malondialdehyde (MDA) decreased by EP supplementation, whereas the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) increased. Similarly, the content of ·OH decreased, and the activities of CAT, GPX and GR increased in liver of crucian carp. Furthermore, in livers of crucian carp, EP supplements upregulated the expressions of the microRNAs (miR-16, miR-21, miR-125b, miR-146a, miR-155, miR-181a and miR-223), which had been confirmed to participate in regulating antioxidant and immune function in mammals. Our results suggest EP supplements in diets stimulated growth performance and antioxidant response of crucian carp. In liver, the upregulation of specific miRNAs may participate in the antioxidant effects of EP diets.

Thus far, clinicopathologic and prognostic significance of mTOR signaling pathway in pancreatic ductal adenocarcinoma (PDAC) remains unclear, although it is involved in PDAC. In this study, total (t-) and phosphorylated (p-) mTOR, 4EBP1 and P70S6K, were investigated. It was found that most aforementioned proteins were related to malignant and progressive phenotypes, especially histological grade, in independent development and validation cohorts of PDAC. In the development cohort, high expression and/or phosphorylation of mTOR, 4EBP1 and P70S6K were all univariately associated with poor tumor-specific survival, whereas p-mTOR, p-4EBP1 and p-P70S6K, adjusted for clinicopathologic variables, unlike t-mTOR, t-4EBP1 and t-P70S6K, were shown to be independent prognostic factors in multivariate analysis. Interestingly and importantly, the independently significant impacts of p-mTOR and p-4EBP1 on tumor-specific survival were confirmed in the validation cohort. Contrarily, t-mTOR and t-4EBP1 were only univariately significant, while t-P70S6K and p-P70S6K were not prognostic. Finally, mTOR and EIF4EBP1, genes encoding mTOR and 4EBP1, also serve as prognostic indicators in the publicly available TCGA RNA-sequencing database. Our data indicate that expression and activation, especially the latter, of mTOR and 4EBP1, might have clinicopathologic and prognostic significance in PDAC.

Background: Invasion and metastasis are the distinct biologic characteristics of cancer, resulting in an exceptionally low 5-year survival rate in pancreatic ductal adenocarcinoma (PDAC). Understanding in detail the mechanisms underlying PDAC metastasis is critical for prevention and effective interventions. Long non-coding RNAs (lncRNAs) have been documented as having a critical role in cancer development and progression. Methods: We examined the expression levels of lncRNA ENST00000480739 and osteosarcoma amplified-9 (OS-9) mRNA in a cohort of 35 PDAC patients. Cell proliferation, invasion and migration were examined with and without ENST00000480739 overexpression in PDAC cells. Results: We determined that the ENST00000480739 expression level was remarkably decreased in tumorous tissues compared with their corresponding non-tumorous tissues. The expression of ENST00000480739 was negatively associated with tumour node metastasis stage and lymph node metastasis. In addition, ENST0000048073 was an independent prognostic factor of survival time in PDAC patients following surgery. Besides, enforced expression of ENST00000480739 suppressed PDAC cells' invasion in vitro. Overexpression of ENST00000480739 significantly increased both mRNA and protein levels of OS-9, and the luciferase assays confirmed that ENST00000480739 positively regulates OS-9 by activating the transcription level of the OS-9 promoter. We further found that ENST00000480739 may target hypoxia-inducible factor-1α (HIF-1α) expression by upregulating OS-9. Conclusions: These findings suggest that the frequently downregulated ENST00000480739 in PDAC contributes to tumour metastasis and progression by regulating HIF-1α. Long non-coding RNA ENST00000480739 may provide not only a therapeutic potential to suppress metastasis but it may also be a novel biomarker for risk prognostication and personal therapy screening of PDAC patients.

By investigating and examining one 40 years old girder arch bridge, this paper gets the current situation of the bridge. On account of these data, the reliability analysis and safety evaluation have been done, the reliability index was calculated, the dynamic reliability of the bridge was analyzed, and the disciplinarian of bearing capacity change with the deck pavement thickness and vehicle load level increasing was discuss. Moreover, the treatment project and strengthening measures was put forward.

Hybrid robot combines the advantages of serial and parallel structure and has the characteristics of large workspace, agile kinesis, good stiffness, compact structure, good kinematic performance and so on. To conduct the research on the performance of hybrid robot, this dissertation develop an experimental system based on the new 3-TPS hybrid robot which is develop by the research institute of advance manufacturing technology and automation in Northeast University to drive the robot and examine the operational position, and it is also applied in the demarcate experimental of 3-TPS hybrid robot. Through the application, it draws a conclusion that the experimental system has the characteristics of simple structure, good function, good compliance, simply to operate, high reliability and low cost. Consequently, it has high value of popularization and application to conduct the experiment and research on hybrid robot.

Pure Cu samples were subjected to equal channel angular pressing (ECAP), and the corrosion resistance of the samples was investigated by potentiodynamic polarization measurements and electrochemical impedance spectroscopy measurements in 3.5% NaCl solution. The results show that the corrosion rate of the ultrafine-grained Cu decreases, in comparison with the coarse-grained Cu.

This paper displays the crack load failure pattern and influences on crack load of reinforced ceramists concrete beams in different reinforcement ratio, concrete cover thickness and diameter of rebar through the experimental study of bending anti-cracking property of 8 reinforced ceramists concrete beams, and proposes the method of calculation cracking moment of normal section for ceramists concrete beam.

For many applications in wireless sensor network (WSN) node positioning by unmanned aerial vehicle (UAV) need a path planning algorithm optimizing positioning error. In this article, we present an algorithm combining Voronoi diagram and geometric dilution of precision (GDOP) to make track points, considering both the efficiency of flying and accuracy of positioning. Then, we connect all the track points using genetic algorithm and we get the minimized flight path.

In the light of the engineering curriculums characteristics, according to the author's teaching experience, this paper undertake discussing some way to inspiring students’ thinking in engineering specialized courses teaching; And explored the engineering specialized courses teaching about before class - class - after class three links, teaching contents, multimedia applications and the applications of self-study guide method. It has a certain guiding significance to further improve the reform of engineering classroom teaching reform.