Identification of a six-gene signature to predict survival and immunotherapy effectiveness of gastric cancer

BackgroundGastric cancer (GC) ranks as the fifth most prevalent malignancy and the second leading cause of oncologic mortality globally. Despite staging guidelines and standard treatment protocols, significant heterogeneity exists in patient survival and response to therapy for GC. Thus, an increasing number of research have examined prognostic models recently for screening high-risk GC patients.MethodsWe studied DEGs between GC tissues and adjacent non-tumor tissues in GEO and TCGA datasets. Then the candidate DEGs were further screened in TCGA cohort through univariate Cox regression analyses. Following this, LASSO regression was utilized to generate prognostic model of DEGs. We used the ROC curve, Kaplan-Meier curve, and risk score plot to evaluate the signature’s performance and prognostic power. ESTIMATE, xCell, and TIDE algorithm were used to explore the relationship between the risk score and immune landscape relationship. As a final step, nomogram was developed in this study, utilizing both clinical characteristics and a prognostic model.ResultsThere were 3211 DEGs in TCGA, 2371 DEGs in GSE54129, 627 DEGs in GSE66229, and 329 DEGs in GSE64951 selected as candidate genes and intersected with to obtain DEGs. In total, the 208 DEGs were further screened in TCGA cohort through univariate Cox regression analyses. Following this, LASSO regression was utilized to generate prognostic model of 6 DEGs. External validation showed favorable predictive efficacy. We studied interaction between risk models, immunoscores, and immune cell infiltrate based on six-gene signature. The high-risk group exhibited significantly elevated ESTIMATE score, immunescore, and stromal score relative to low-risk group. The proportions of CD4+ memory T cells, CD8+ naive T cells, common lymphoid progenitor, plasmacytoid dentritic cell, gamma delta T cell, and B cell plasma were significantly enriched in low-risk group. According to TIDE, the TIDE scores, exclusion scores and dysfunction scores for low-risk group were lower than those for high-risk group. As a final step, nomogram was developed in this study, utilizing both clinical characteristics and a prognostic model.ConclusionIn conclusion, we discovered a 6 gene signature to forecast GC patients’ OS. This risk signature proves to be a valuable clinical predictive tool for guiding clinical practice

Effect of mass distribution on curving performance for a loaded wagon

The location of wagon gravity center for a loaded wagon is underestimated in a vehicle–track coupled system. The asymmetric wheel load distribution due to loading offset significantly affects the wheel-rail contact state and seriously deteriorates the curving performance in conjunction with the height of gravity center and cant deficiency. Optimizing the location of gravity center and cruising velocity, therefore, is of interest to prevent the derailment and promote the transport capacity of railway wagons. This study aims to reveal the three-dimensional influencing mechanism of mass distribution on vehicle curving performance under different velocities. The wheel unloading ratio is regarded as the evaluation index. A simplified quasi-static model is established considering essential assumptions to highlight the influence of lateral and vertical offset on curving performance. For a more accurate description, the MBS models with various locations of wagon gravity center are built and then negotiate curves in different simulation cases. The simulation results reveal that the distribution of wheel unloading ratio determined by loading offset is like contour lines of ‘basin’. Based on the conclusions of quasi-static analysis and dynamics simulations, the regression equation is proposed and the fitting parameters are calculated for each simulation case. This paper demonstrates the necessity of optimizing the location of wagon gravity center according to the running condition and offers a novel strategy to load and transport the cargo by railway wagons.TU Berlin, Open-Access-Mittel – 202

Climate Change Impacts on Coastal and Offshore Petroleum Infrastructure and the Associated Oil Spill Risk: A Review

Climate change has been observed worldwide in recent decades, posing challenges to the coastal and offshore oil and gas infrastructure. It is crucial to identify how climate change affects these infrastructures and the associated oil spill risk. This paper provides an analysis of the vulnerability of coastal and offshore oil and gas infrastructure in response to climate change. The paper examines oil spill incidents worldwide and addresses climate change’s possible influences on oil spill risk. Moreover, available oil spill modeling and decision support tools for oil spill response are reviewed considering climate change. The paper signals the need for emerging decision and modeling tools considering climate change effects, which can help decision-makers to evaluate the risk on time and provide early warnings to adapt or prevent the unforeseen impacts on the oil industry partially resulting from global warming, including oil spill accidents

Climate Change Impacts on Coastal and Offshore Petroleum Infrastructure and the Associated Oil Spill Risk: A Review

Climate change has been observed worldwide in recent decades, posing challenges to the coastal and offshore oil and gas infrastructure. It is crucial to identify how climate change affects these infrastructures and the associated oil spill risk. This paper provides an analysis of the vulnerability of coastal and offshore oil and gas infrastructure in response to climate change. The paper examines oil spill incidents worldwide and addresses climate change’s possible influences on oil spill risk. Moreover, available oil spill modeling and decision support tools for oil spill response are reviewed considering climate change. The paper signals the need for emerging decision and modeling tools considering climate change effects, which can help decision-makers to evaluate the risk on time and provide early warnings to adapt or prevent the unforeseen impacts on the oil industry partially resulting from global warming, including oil spill accidents

MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways

Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway

The expression level and diagnostic value of microRNA-22 in HCC patients

AbstractBackground Involvements of microRNA-22 (miR-22) in cancer have attracted much attention, but its role in diagnosis of hepatocellular carcinoma (HCC) is still largely unknown. Therefore, the aim of this study was to investigate the expression level and the prognostic value of miR-22 in HCC patients.Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate serum level of miR-22 in 108 HCC patients and 67 healthy controls. The relationship between miR-22 expression level and clinicopathologic characteristics was analysed via chi-square test. Receiver operating characteristic (ROC) curve was built to estimate the diagnostic value of serum miR-22 in HCC.Results miR-22 expression was significantly down-regulated in HCC compared to that in healthy controls (p < .05). And the low miR-22 expression was significantly associated with vein invasion (p = .002), TNM stage (p = .013) and high serum levels of AFP (α-fetoprotein), ALT (alanine aminotransferase), AST (aspartate aminotransferase) and ALP (alkaline phosphatase. miR-22 had a high diagnostic value with area under the curve of 0.866 corresponding with a sensitivity of 89.3% and a specificity of 68.9%, respectively.Conclusion miR-22 expression was down-regulated in HCC patients. Serum miR-22 might be a novel diagnostic marker in HCC

Alternative coatings to cyanide silver coatings with low infrared emissivity for tokamak components

Alternative to cyanide silver coatings with low infrared emissivity for tokamak components were prepared by cyanide-free silver plating on nuclear-grade 304L stainless steel. The surface morphology, coating adhesion and emissivity were characterized and optimized. The experimental results indicate that the developed cyanide-free silver coating is a viable alternative to cyanide silver coating. The adhesion of silver coating was enhanced by the reactivating of nickel plating. The emissivity was reduced by decreasing surface roughness and increasing coating thickness. Both optimizations reach limit at 0.4 μm and 0.6 μm, respectively. Further decrease in surface roughness and increase in coating thickness did not contribute to decreasing emissivity. To sum up, the obtained cyanide-free silver coatings showed sufficient adhesion with emissivity as low as 0.02, thus providing an eco-friendly alternative solution to fusion energy application

Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation

Abstract Background Higher matrix stiffness affects biological behavior of tumor cells, regulates tumor-associated gene/miRNA expression and stemness characteristic, and contributes to tumor invasion and metastasis. However, the linkage between higher matrix stiffness and pre-metastatic niche in hepatocellular carcinoma (HCC) is still largely unknown. Methods We comparatively analyzed the expressions of LOX family members in HCC cells grown on different stiffness substrates, and speculated that the secreted LOXL2 may mediate the linkage between higher matrix stiffness and pre-metastatic niche. Subsequently, we investigated the underlying molecular mechanism by which matrix stiffness induced LOXL2 expression in HCC cells, and explored the effects of LOXL2 on pre-metastatic niche formation, such as BMCs recruitment, fibronectin production, MMPs and CXCL12 expression, cell adhesion, etc. Results Higher matrix stiffness significantly upregulated LOXL2 expression in HCC cells, and activated JNK/c-JUN signaling pathway. Knockdown of integrin β1 and α5 suppressed LOXL2 expression and reversed the activation of above signaling pathway. Additionally, JNK inhibitor attenuated the expressions of p-JNK, p-c-JUN, c-JUN and LOXL2, and shRNA-c-JUN also decreased LOXL2 expression. CM-LV-LOXL2-OE and rhLOXL2 upregulated MMP9 expression and fibronectin production obviously in lung fibroblasts. Moreover, activation of Akt pathway contributed to LOXL2-induced fibronectin upregulation. LOXL2 in CM as chemoattractant increased motility and invasion of BMCs, implicating a significant role of LOXL2 in BMCs recruitment. Except that, CM-LV-LOXL2-OE as chemoattractant also increased the number of migrated HCC cells, and improved chemokine CXCL12 expression in lung fibroblasts. The number of HCC cells adhered to surface of lung fibroblasts treated with CM-LV-LOXL2-OE was remarkably higher than that of the control cells. These results indicated that the secreted LOXL2 facilitated the motility of HCC cells and strengthened CTCs settlement on the remodeled matrix “soil”. Conclusion Integrin β1/α5/JNK/c-JUN signaling pathway participates in higher matrix stiffness-induced LOXL2 upregulation in HCC cells. The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation