Identifying LATS2 as a prognostic biomarker relevant to immune infiltrates in human esophageal squamous cell carcinoma.

According to the TIMER database, large tumor suppressor 2 (LATS2) is differentially expressed in various tumors. However, the correlation between LATS2 and esophageal squamous cell carcinoma (ESCC) and the association between LATS2 and immune infiltration in ESCC remain unclear. Our synthetic research on LATS2 in ESCC revealed that the expression was low in esophageal squamous epithelium tissues, revealing the pernicious and adverse prognosis of ESCC. The Kaplan-Meier survival investigation pointed out that low LATS2 expression would result in an adverse prognosis. Biological investigation indicated that LATS2 was engaged in cell migration, adhesion, and junction. To further explore the relationship between LATS2 and tumor immunity, we utilized CIBERSORT to assess immune infiltration. The findings revealed that specimens with lower LATS2 expression showed higher immune infiltration, including T-cell follicular helper cells, M0 macrophages, M1 macrophages, and myeloid dendritic cell resting. An association investigation indicated that LATS2 was negatively relevant to immune checkpoints that restrain operative antitumor immune reactions. We also conducted immunohistochemical staining to explore the link between LATS2 expression and immunophenotype. The indicated association between low LATS2 expression and an immunophenotype is conducive to our understanding of ESCC mini-environments and might offer new indications for enhancing new therapeutic targets.

Interleukin-17A attenuates photoreceptor cell apoptosis in streptozotocin-induced diabetic mouse model.

Diabetic retinopathy (DR) represents an important microvascular complication of diabetes, which is the top etiology of vision impairment worldwide. Although interleukin (IL)-17A is increasingly implicated in DR development, the underlying cellular mechanisms remain poorly defined. This work aims to evaluate IL-17A levels in the retina of streptozotocin (STZ)-induced diabetic mice and elucidate their potential roles. We found IL-17A was upregulated in diabetic retina after intraperitoneal injection of STZ and high-glucose (HG)-cultured primary Müller cells. IL-17A knockout (IL-17A-/-) downregulated glial fibrillary acidic protein (GFAP) and inhibited the conversion of proneurotrophin-3 (proNT-3) to mature NT-3 in retinal specimens from diabetic mice as well as in Müller cells cultured under HG conditions. Induced apoptosis and upregulated Bax and cleaved caspase-3 were observed in retinal specimens from IL-17A-/- diabetic mice and photoreceptor (661 W) cells after co-culture with IL-17A-/- Müller cells. Moreover, RNA interference-induced gene silencing of tyrosine kinase C receptor (TrkC) in 661 W cells reversed the anti-apoptotic effect of IL-17A under HG conditions. Taken together, our findings suggest that IL-17A/NT-3/TrkC axis regulation suppresses apoptosis in photoreceptor cells, providing a new treatment strategy for DR.

Regulation of inflammation by VEGF/BDNF signaling in mouse retinal Müller glial cells exposed to high glucose.

The inflammatory changes seem to play an important role in the development of diabetic retinopathy (DR). Anti-VEGF therapy has been testified to inhibit inflammation in animal models of diabetes, but the detailed mechanisms during this process are not yet clear. Müller glial cells (MGCs) in the mammalian retina are deeply involved in DR, while the BDNF overexpression reduces inflammation in diabetic mice. In this research, we aimed to explore the relationship between VEGF and BDNF in mouse retinal MGCs during inflammation of diabetes. We examined the expression of glutamine-synthetase (GS), glial fibrillary acidic protein (GFAP), vascular-endothelial growth factor (VEGF), interleukin-1beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α) at different time points after mouse retinal MGCs exposed to high glucose (25 mM). We also explored changes in the expression of brain-derived neurotrophic factor (BDNF), nuclear factor kappa B (NF-κB), IL-1ß, and TNF-α in MGCs after treatments with anti-VEGF, VEGF siRNA, BDNF siRNA, BDNF recombination protein, and NF-κB inhibitor. In mouse retinal MGCs exposed to high glucose, BDNF was increased after treatments with anti-VEGF or VEGF siRNA. BDNF was decreased in MGCs from VEGF overexpressed mice. Moreover, the expressions of NF-κB, IL-1ß, and TNF-α changed with BDNF: NF-κB, IL-1ß, and TNF-α were increased after treatments with BDNF siRNA; NF-κB, IL-1ß, and TNF-α were decreased after treatments with BDNF recombination protein. VEGF may regulate cytokines (IL-1ß and TNF-α) by BDNF/NF-κB signaling pathway. The regulation of the VEGF/BDNF/NF-κB signaling pathway may be a significant therapeutic strategy for DR.

Tumor microenvironment characterization in esophageal cancer identifies prognostic relevant immune cell subtypes and gene signatures.

Esophageal cancer (ESCA) is a common malignancy in the digestive system with a high mortality rate and poor prognosis. Tumor microenvironment (TME) plays an important role in the tumorigenesis, progression and therapy resistance of ESCA, whereas its role in predicting clinical outcomes has not been fully elucidated. In this study, we comprehensively estimated the TME infiltration patterns of 164 ESCA patients using Gene Set Variation Analysis (GSVA) and identified 4 key immune cells (natural killer T cell, immature B cell, natural killer cell, and type 1 T helper cell) associated with the prognosis of ESCA patients. Besides, two TME groups were defined based on the TME patterns with different clinical outcomes. According to the expression gene set between two TME groups, we built a model to calculate TMEscore based on the single-sample gene-set enrichment analysis (ssGSEA) algorithm. TMEscore systematically correlated the TME groups with genomic characteristics and clinicopathologic features. In conclusion, our data provide a novel TMEscore which can be regarded as a reliable index for predicting the clinical outcomes of ESCA.

Study on Microstructure and Fatigue Properties of FGH96 Nickel-Based Superalloy.

In this study, using synchrotron radiation X-ray imaging, the microstructure, tensile properties, and fatigue properties of FGH96 nickel-based superalloy were tested, and the fatigue damage mechanism was analyzed. An analysis of the experimental results shows that the alloy structure is dense without voids or other defects. It was observed that the primary γ' phase is distributed on the grain boundary in a chain shape, and the secondary γ' phase is found inside the crystal grains. The X-ray diffraction (XRD) pattern indicates that no other phases were seen except for the γ and γ' phases. The tensile strength of the alloy is 1570 MPa and the elongation is 12.1%. Using data fitting and calculation, it was found that the fatigue strength of the alloy under the condition of 5 × 106 cycles is 620.33 MPa. A fatigue fracture has the characteristics of secondary crack, cleavage step, fatigue stripe, tire indentation, and dimple. The fracture is a mix of cleavage fracture and ductile fracture. Through a three-dimensional reconstruction of the alloy synchrotron radiation imaging area, it was found that the internal defects are small and mostly distributed at the edge of the sample. The dimple morphology is formed by cavity aggregation and cavity germination resulting from defects in the material itself, fracture of the second-phase particles, and separation of the second-phase particles from the matrix interface. By analyzing the damage mechanism of fatigue fractures, it is concluded that the cleavage step is formed by the intersection of cleavage planes formed by branch cracks, with the main crack of the confluence extending forward to form a cleavage fracture. The crack propagation path was also analyzed, and under the action of cyclic load and tip passivation, the crack shows Z-shaped propagation.

Ferroptosis-Related Gene Signature and Patterns of Immune Infiltration Predict the Overall Survival in Patients With Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is a malignant tumor with high heterogeneity and poor prognosis. Ferroptosis, a form of regulated cell-death-related iron, has been proven to trigger inflammation-associated immunosuppression in the tumor microenvironment, which promotes tumor growth. Therefore, the clinical prognostic value of ferroptosis-related genes in LUAD needs to be further explored. Method: In this study, we downloaded the mRNA expression profiles and corresponding clinical data of LUAD patients from the Cancer Genome Atlas database. The least absolute shrinkage and selection operator (LASSO) Cox regression model was utilized to construct ferroptosis-related gene signature. Based on these, we established the nomograms for prognosis prediction and validated the model in the GSE72094 dataset. The cell type was identified using the CIBERSORT algorithm for estimating relative subsets of RNA transcripts, which was then used to screen significant tumor immune-infiltrating cells associated with the LUAD prognosis prediction model. Subsequently, we applied co-expression analysis to reveal the relationship between ferroptosis-related genes and significant immune cells. Results: The univariate COX regression analysis showed that 20 genes were associated with the overall survival (OS) as prognostic differentially expressed genes (DEGs) (FDR <0.05). Patients were divided into two risk groups using a 13-gene signature, with the high-risk group having a significantly worse OS than their low-risk counterparts (p < 0.001). We used receiver operating characteristic (ROC) curve analysis to confirm the predictive capacity of the signature. Besides, we identified seven pairs of ferroptosis-related genes and tumor-infiltrating immune cells associated with the prognosis of LUAD patients. Conclusion: In this study, we construct a ferroptosis-related gene signature that can be used for prognostic prediction in LUAD. In addition, we reveal a potential connection between ferroptosis and tumor-infiltrating immune cells.

CircPUM1 promotes hepatocellular carcinoma progression through the miR-1208/MAP3K2 axis.

Hepatocellular carcinoma (HCC) is a common disease with a significant mortality, and there is no effective treatment for advanced patients. Growing evidence indicates that circRNAs are closely related to HCC progression, may be used as biomarkers and targets for the diagnosis and treatment of HCC. Recent researches have shown that circPUM1 may play an oncogene role in a variety of human cancers, but its role in HCC development has not been reported. Our study found that circPUM1 could promote the proliferation, migration and invasion of HCC cells in vitro. In addition, in vivo studies showed that circPUM1 could increase the development of HCC tumours and regulate the expression of EMT-related proteins. Furthermore, we demonstrated that circPUM1 could promote the development of HCC by up-regulating the expression of MAP3K2 via sponging miR-1208. Our study suggested that circPUM1 may be a potential therapeutic target for HCC.

Circulating microRNAs as biomarkers for severe coronary artery disease.

Coronary artery disease (CAD) is the second leading cause of death after stroke in China. Percutaneous coronary intervention (PCI) significantly improves the prognosis of CAD patients. This study aimed to evaluate the diagnostic value of circulating microRNAs (miRNAs) in patients with severe CAD requiring PCI. The plasma miRNA profiles were determined using miRNA microarray. The relative expression levels of differentially expressed miRNA were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Nine miRNAs (ebv-miR-BART12, ebv-miR-BART16, let-7i-5p, miR-130a-3p, miR-26a-5p, miR-3149, miR-3152-3p, miR-32-3p, and miR-149-3p) were differentially expressed between severe CAD and control groups. Four miRNAs (let-7i-5p, miR-32-3p, miR-3149, and miR-26a-5p) validated by qRT-PCR showed good diagnostic accuracy, with the area under the receiver operating characteristic curves (AUCs) of 0.634 (95% confidence interval [CI] 0.528-0.739), 0.745 (95%CI 0.649-0.84), 0.795 (95%CI 0.709-0.88), and 0.818 (95%CI 0.739-0.897), respectively. Furthermore, the combination of these 4 miRNAs exhibited better diagnostic performance compared with any individual miRNA, with an AUC of 0.837 (95%CI 0.763-0.911). These data indicate that plasma let-7i-5p, miR-32-3p, miR-3149, and miR-26a-5p have promising diagnostic value for severe CAD.

Müller cells derived neurotrophin-3 inhibits hypoxia-induced photoreceptor apoptosis via the TrkC/ERK pathway.

Neurotrophin-3 (NT-3), a neurotrophic factor that mainly binds to the tyrosine kinase C (trkC) receptor, has been shown to play a crucial role in proliferation, differentiation, and survival. However, the role of NT-3 in the hypoxia-induced retinopathy has not been investigated extensively. Here, we created a model of hypoxia (1% O2) in vitro and found that hypoxia promoted the apoptosis of mouse cone photoreceptor-derived 661W cells, increased the expression of TrkC and cleaved caspase-3. In contrast, the hypoxia-mediated 661W cell apoptosis was markedly alleviated by co-culturing with primary mouse Müller cells. Further mechanism studies revealed that hypoxia increased the synthesis and secretion of NT-3 by Müller cells, and exogenous NT-3 stimulation increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 by binding to TrkC in 661W cells. Besides, both siRNA knockdown of TrkC expression and incubation with an ERK-specific inhibitor PD98059 triggered apoptosis in hypoxic 661W cells. Altogether, these data suggest that NT-3 originating from Müller cells protects photoreceptors from hypoxia-induced apoptosis through a TrkC/ERK-dependent pathway. Our findings may facilitate future studies on the therapeutic implications of NT-3 in the treatment of hypoxia-relevant retinal diseases.

A novel thermo-sensitive hydrogel-based on poly(N-isopropylacrylamide)/hyaluronic acid of ketoconazole for ophthalmic delivery.

The aim of this study is to develop thermo-sensitive in situ gelling formulation of KCL based on poly(N-isopropylacrylamide)/hyaluronic acid. The prepared preparations were characterized for in vitro gelation, drug release and antifungal activity. In this study, drug content of prepared gels was found to be in the range of 91-96%. The pH value was in the range of 6.0-7.5. By measuring the gelation temperature of the prepared PN-HA thermogelling solutions, it was 33 °C. In vitro release showed that the release of KCL from in situ gels was moderate without burst effects. The KCL PN-HA in situ gels were well-tolerated by the rabbits, and no macroscopic signs of irritation, redness, or other toxic effects were observed. From in vivo antimicrobial study, KCL PN-HA in situ gels may be concluded to have a better cure percent in clinical profile and negative growth of Candida albicans in microbiological test. Therefore, this new formulation could prove to be a novel ocular dosage form able to prolong the residence time and to control the release of drug when administered into the eye.

Nanovalved Adsorbents for CH4 Storage.

A novel concept of utilizing nanoporous coatings as effective nanovalves on microporous adsorbents was developed for high capacity natural gas storage at low storage pressure. The work reported here for the first time presents the concept of nanovalved adsorbents capable of sealing high pressure CH4 inside the adsorbents and storing it at low pressure. Traditional natural gas storage tanks are thick and heavy, which makes them expensive to manufacture and highly energy-consuming to carry around. Our design uses unique adsorbent pellets with nanoscale pores surrounded by a coating that functions as a valve to help manage the pressure of the gas and facilitate more efficient storage and transportation. We expect this new concept will result in a lighter, more affordable product with increased storage capacity. The nanovalved adsorbent concept demonstrated here can be potentially extended for the storage of other important gas molecules targeted for diverse relevant functional applications.

Microwave-assisted synthesized SAPO-56 as a catalyst in the conversion of CO2 to cyclic carbonates.

SAPO-56 crystals were synthesized via microwave heating. The resultant crystals displayed high catalytic activity in the synthesis of chloropropene carbonate from CO2 and epichlorohydrin. The enhanced catalytic activity of SAPO-56 crystals was related to their high CO2 adsorption capacity, small crystal size, and the presence of acid sites.