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Supplementary Data from Activation of β-Catenin by Hypoxia in Hepatocellular Carcinoma Contributes to Enhanced Metastatic Potential and Poor Prognosis

Purpose: Aberrant activation of β-catenin contributes to the malignant phenotype in hepatocellular carcinoma (HCC). Hypoxia is also known to promote HCC invasion and metastasis. However, the association between β-catenin and the proinvasive role of hypoxia remains unclear. We investigated the role of β-catenin in the proinvasive consequences of hypoxia in HCC.Experimental Design: We established in vitro and in vivo hypoxic models to investigate the expression of β-catenin in hypoxic HCC cells and its role in hypoxia-induced aggressiveness. The clinical significance of β-catenin and/or hypoxia-induced factor-1α (HIF-1α) was evaluated using HCC tissue microarrays.Results: Hypoxia induced β-catenin overexpression and/or intracellular accumulation in four HCC cell lines through downregulating the endogenous degradation machinery, and promoted in vitro invasion and in vivo metastasis of MHCC97 and Hep3B cells. Besides morphologic changes, hypoxic MHCC97 and Hep3B cells exhibited molecular alterations consistent with epithelial-mesenchymal transition, characterized by the loss of epithelial cell markers (E-cadherin and plakoglobin) and upregulation of mesenchymal markers (vimentin and N-cadherin), as well as the increase of matrix metalloproteinase 2. However, silencing β-catenin in these hypoxic cells reversed epithelial-mesenchymal transition and repressed metastatic potential. Positive expression of β-catenin in HCC tissue microarray was associated with the expression of HIF-1α (P = 0.034), and coexpression of β-catenin and HIF-1α in HCC was correlated with shorter overall survival and time to recurrence.Conclusion: β-Catenin in HCC is activated by hypoxia and contributes to hypoxia-induced metastatic potential. Clin Cancer Res; 16(10); 2740–50. ©2010 AACR.

The present study explored the physiological mechanism of the effects of different pH treatments on the growth, physiological characteristics, and stachydrine biosynthesis of Leonurus japonicus to provide references for the cultivation and quality control of L. japonicus. Under hydroponic conditions, different pH treatments(pH 5,6,7,8) were set up. The growth, physiology, and the content of stachydrine and total alkaloids of L. japonicus, as well as the content of key intermediate products in stachydrine biosynthesis pathway(i.e., pyruvic acid, α-ketoglutaric acid, glutamic acid, and ornithine) were monitored to explore the physiological mechanism of the effects of pH on the growth and active components of L. japonicus. The results showed that L. japonicus. could grow normally in the pH 5-8 solution. The pH treatment of neutral acidity was more conducive to the accumulation of photosynthetic pigments and the increase in soluble protein in leaves of L. japonicus. to promote its growth and yield. However, since stachydrine is a nitrogen-containing pyrrolidine alkaloid, its synthesis involves the two key rate-limiting steps of nitrogen addition: reductive ammoniation reaction and Schiff base formation reaction. High pH treatments promote the synthesis and accumulation of substrates and products of the above two reactions, indicating that the alkaline environment can promote the nitrogen addition reaction, thereby promoting the biosynthesis and accumulation of stachydrine.

The flow losses owing to friction and unstable flow patterns in Francis turbines will cause a drop in their efficiency. The traditional approach to evaluating the hydraulic losses of Francis turbine via the pressure drop cannot determine the exact locations at which the high energy loss occurs. In this paper, a full analysis for flow losses in a Francis turbine with the entropy production method has been implemented. Firstly, the prediction of hydraulic efficiency between entropy production theory and the model test is compared. Secondly, distribution of entropy production in different parts and flow components is analyzed. Finally, detailed distribution of local entropy production rate (LEPR) in spiral casing, stay/guide vanes, runner and draft tube is investigated. It is found that hydraulic losses of the turbine are closely related to flow separation and the vortex motion as well as backflow. Meanwhile, draft tube accounts for the greatest proportion of entropy production followed by the runner. It is concluded that the entropy production method adopted in this paper can be feasible to explore where the energy dissipation happens and how it is distributed in Francis turbine passage under different operating conditions within a certain reasonable range of error.

Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery. We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression. PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5 years) of PanNETs after curative resection (P = 0.019, P

The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial.A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9.The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The TS-CD9 risk-level system was used to stratify patients with different survival levels. The combination of TS-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort.Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

The energy harvesting performance of symmetrical flapping hydrofoil varying with thickness, shape and position of pitching axis was numerical investigated via immersed boundary method at a Reynolds number of 1100. The foil performs the given sinusoidal heaving and cosine-curvilinear pitching motions. The center of the hydrofoil is the intersection of the chord line and vertical line at maximum thickness. α is the ratio of the length between the leading edge and the center to the length of chord. β is the ratio of the length between the upper edge and the center to the length of chord. x p is the length between the leading edge and the pitching axis. It is found that enhancing the thickness of the foil can modestly increase the energy harvesting efficiency in the range of 0.03 ≤ β ≤ 0.06 , however, it is in contrast in the range of 0.06 ≤ β ≤ 0.105 . It is also found that the higher the value of α, the higher the extracting energy when α ≤ 0 . 4 . The optimal foil thickness is β = 0.06. The optimal pitching axis is located at the foil center when α ≤ 0 . 35 , and it is x p = 0.35 l when 0.35 α ≤ 0 . 50 .The highest energy harvesting efficiency of 41.71% is achieved when α = 0.4 .

Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.

ObjectiveThis study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs).MethodsTumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells.ResultsTINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set.ConclusionIntratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

BACKGROUND Systemic inflammation and nutrition status play an important role in cancer metastasis. The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP), consisting of haemoglobin, albumin, lymphocytes, and platelets, is considered as a novel marker to reflect both systemic inflammation and nutrition status. However, no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection. AIM To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients. METHODS The preoperative serum levels of hemoglobin, albumin, lymphocyte counts, and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection. The relationship between postoperative survival and the preoperative level of HALP was investigated. RESULTS Low levels of HALP were significantly associated with lymph node metastasis (P = 0.002), poor tumor differentiation (P = 0.032), high TNM stage (P = 0.008), female patients (P = 0.005) and tumor location in the head of the pancreas (P < 0.001). Low levels of HALP were associated with early recurrence [7.3 mo vs 16.3 mo, P < 0.001 for recurrence-free survival (RFS)] and short survival [11.5 mo vs 23.6 mo, P < 0.001 for overall survival (OS)] in patients with resected pancreatic adenocarcinoma. A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location. CONCLUSION Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer and has devastating consequences on affected families and society. Its dismal prognosis is attributed to poor specificity of symptoms during early stages. It is widely believed that PDAC patients with the wildtype (WT) KRAS gene benefit more from currently available treatments than those with KRAS mutations. The oncogenic genetic changes alternations generally found in KRAS wildtype PDAC are related to either the KRAS pathway or microsatellite instability/mismatch repair deficiency (MSI/dMMR), which enable the application of tailored treatments based on each patient's genetic characteristics. This review focuses on targeted therapies against alternative tumour mechanisms in KRAS WT PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial "network" to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.

BACKGROUND Platelets have been reported to participate in tumor cell growth, extravasation, epithelial–mesenchymal transition, metastasis, and drug resistance. However, the importance of platelets in pancreatic neuroendocrine tumor (pNET) lacks adequate literature support. The predictive value of tumor-infiltrating platelets (TIPs) in pNET remains unclear. AIM To investigate the relationship between TIPs and the prognosis of patients with pNET following radical resection. METHODS In total, 113 patients who had undergone radical surgical resection with a pathologic diagnosis of pNET were enrolled in this study. Immunohistochemical analysis of cluster of differentiation 42b (CD42b) expression in the tumor specimens was performed to determine the presence of TIPs. Univariate and multivariate analyses were used to analyze the prognostic value of TIPs. RESULTS TIPs were observed in intratumoral areas in 54 patients. Neither basic characteristics nor preoperative platelet-associated indicators showed a significant relationship with the presence of TIPs (all P > 0.05). Patients with positive intratumoral CD42b expression had worse overall survival (P = 0.005) and recurrence-free survival (P < 0.001) than those with negative intratumoral CD42b expression. Multivariate analysis demonstrated that TIPs were independent prognostic factors for overall survival (P = 0.049) and recurrence-free survival (P = 0.003). Nevertheless, platelet count, mean platelet volume, and platelet-to-lymphocyte ratio were not associated with postoperative survival or recurrence in pNET patients (all P > 0.05). CONCLUSION TIPs are a useful prognostic biomarker for patients with resectable pNET, and their detection represents a promising tool for pNET treatment strategy decisions.

Sugarcane is an important sugar and energy crop worldwide. It utilises highly efficient C4 photosynthesis and accumulates sucrose in its culms. The sucrose content in sugarcane culms is a quantitative trait controlled by multiple genes. The regulatory mechanism underlying the maximum sucrose level in sugarcane culms remains unclear. We used transcriptome sequences to identify the potential regulatory genes involved in sucrose accumulation in Saccarum officinarum L. cv. Badila. The sucrose accumulating internodes at the elongation and mature growth stage and the immature internodes with low sucrose content at the mature stage were used for RNA sequencing. The obtained differentially expressed genes (DEGs) related to sucrose accumulation were analysed. Results showed that the transcripts encoding invertase (beta-fructofuranosidase, EC: 3.2.1.26) which catalyses sucrose hydrolysis and 6-phosphofructokinase (PFK, EC: 2.7.1.11), a key glycolysis regulatory enzyme, were downregulated in the high sucrose accumulation internodes. The transcripts encoding key enzymes for ABA, gibberellin and ethylene synthesis were also downregulated during sucrose accumulation. Furthermore, regulated protein kinase, transcription factor and sugar transporter genes were also obtained. This research can clarify the molecular regulation network of sucrose accumulation in sugarcane.

Time-delay displacement and velocity feedback of different types of active control in a cantilever beam carrying an lumped mass is investigated in this paper. Based on Euler–Bernoulli beam theory, the nonlinear governing equation is studied with damping, harmonic distribution, displacement delay, velocity delay and two time delays. The multiple scales perturbation method is applied to obtain the frequency response equations near primary, superharmonic and subharmonic resonances. A thorough study on the stability is proposed, with a particular emphasis on delay feedback. The results show that the hardening and softening behaviors of the system depend on the location of lumped mass. Furthermore, the displacement feedback gain coefficient only makes the peak amplitude move to the low frequency, yet velocity feedback coefficient and their time delays can be used to effectively enhance the stability and quench the nonlinear vibration of the cantilever beam. Thus, reasonable selection of the control system parameters can effectively improve the level of vibration control for the mechanical system.

Friction stir welded lap joints of 5083 aluminum alloy plates with thickness of 2mm and T2 pure copper plates with thickness of 3mm were prepared, and the microstructures and properties of lap joints were investigated. The results showed that Al and Cu interdiffusion occurred at the interface of the lap joints, the grains in the stir zone of Al were refined and the microhardness increased sharply. The joint of Cu can be divided into four parts, including the nugget zone (NZ), thermo-mechanically affected zone (TMAZ), heat affected zone (HAZ) and base metal (BM). Using the optimum welding parameters (rotation speed of 900rpm and welding speed of 100mm/min), the lap joints were well formed. There were fewer welding defects and the average shear tensile force reached 3.155KN. Also, the ductile-brittle hybrid fracture occurred at the transitional zone of the advancing side of the Al plates. XRD results showed that intermetallic compounds (IMCS) mainly composed of Al2Cu and AlCu4 were produced in the interface of the lap joints during welding.

This paper developed a horizontal axis micro-hydrokinetic river turbine (HAMHRT) technology for local renewable energy applications. Firstly, a hydrofoil shape was selected, and the hydrodynamic and cavitation characteristics of the hydrofoils were analyzed, then the chord length and twist angle for different blade location were optimal, and finally a 2 m diameter with 3-bladed HAMHRT was designed. Then, the numerical computational model of a hydrodynamic analysis for the prototype HAMHRT was carried out to determine force distributions along the blade under normal and extreme operating conditions, including the non-designed conditions, different tip speed ratios as well as the different pitch angles. The rotor has a maximum efficiency of 25.2% at the river current speed of 0.8 m/s, pitch angle of 4° and TSR of 6. It is ensured that the rotor performance does not deteriorate in a relative large scope even if the current speed changes or if the TSR deviates from the design values. Finally, the unsteady behaviors of hydrodynamics of this HAMHRT were analyzed farther. From the output performance of this turbine, the designed rotor was found to have stable power output and good efficiency at current speeding conditions.

Purpose: The systemic inflammation response index (SIRI), based on peripheral neutrophil, monocyte, and lymphocyte counts, was recently emerged and used as a novel tool in predicting prognosis in different types of cancer. Our aim was to investigate the clinical significance of preoperative SIRI in patients with resectable pancreatic ductal adenocarcinoma (PDAC). Materials and methods: The SIRI was developed in a training cohort of 371 PDAC patients undergoing radical surgery between 2010 and 2013 and validated in a validation cohort of 310 patients from 2014 to 2015. Baseline clinicopathologic characteristics, preoperative laboratory parameters and follow-up information were collected. The optimal cutoff value of SIRI was determined by receiver operating characteristic curve. Univariate and multivariate analysis were performed to analyze the prognostic value of SIRI. Results: The optimal cutoff value of SIRI stratified patients into low SIRI group (≤0.69) and high SIRI group (>0.69). Survival analysis showed that the median overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients with low SIRI. The SIRI was an independent predictor of OS and RFS in multivariate analysis. In addition, SIRI remained its prognostic significance both in patients with early-stage diseases and in patients with normal carbohydrate antigen 19-9 levels. High SIRI indicated poor treatment response for patients who received postoperative adjuvant chemotherapy. Conclusion: Preoperative SIRI was an independent prognostic indicator of poor outcomes in PDAC patients after radical resection. It might assist clinicians to identify high-risk patients and choose the optimal individualized treatment strategy.

Simple Summary The immunosuppressive microenvironment is closely related to the poor prognosis of patients with PDAC. Tfh cells play an anti-tumor function in various malignant solid tumors; however, the role of Tfh cells in PDAC has not been determined. In this study, we aimed to explore the function of Tfh cells in PDAC, and revealed a novel immunosuppressive mechanism mediated by Tfh cells. Tfh cells promoted the formation of an immunoactive tumor microenvironment by secreting CXCL13 and IL-21, and the high infiltration of Tfh cells correlated with better patient prognosis. However, the anti-tumor function of Tfh cells was inhibited by the PD-L1/PD-1 signaling pathway. Neoadjuvant chemotherapy could further reverse the function of Tfh cells. Our results provided new strategies to remodel the immunoactive tumor microenvironment of PDAC. Abstract Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.