The causal relationship between blood cell indices and 28-day mortality in sepsis: a retrospective study and bidirectional Mendelian randomization analysis.

BACKGROUND: Despite emerging evidence linking blood cell indices (BCIs) to sepsis mortality, the inconsistency of observational studies obscures the clarity of these associations. This study aims to clarify the causal influence of BCIs on 28-day mortality rates in sepsis patients. METHODS: Utilizing univariable and multivariable Mendelian randomization (MR) analyses, we examined the impact of BCIs on sepsis mortality by analyzing data from extensive genome-wide association studies. The inverse-variance weighted (IVW) method was our primary analytic tool, complemented by several robustness checks to mitigate pleiotropy, including weighted median, mode-based estimates, MR-Egger regression, and MR-PRESSO. Subsequently, we conducted a retrospective study to further explore the correlation between platelet indices and 28-day mortality of sepsis using real-world data. RESULTS: Our findings highlight a significant causal relationship between platelet distribution width (PDW) and 28-day mortality in sepsis, with the univariable Mendelian randomization approach yielding an odds ratio of 1.12 (95% CI, 1.06-1.26; P < 0.05). Multivariable analysis further substantiated PDW's robust association with mortality risk (OR 1.23; 95% CI, 1.03-1.48; P < 0.05). Conversely, our analysis did not uncover significant correlations between the genetic predispositions to other BCIs-including red blood cell count, erythrocyte distribution width, platelet count, mean platelet volume, white blood cell count, neutrophil count, neutrophil percentage, lymphocyte count, and lymphocyte percentage-and 28-day mortality in sepsis. Additionally, an inverse MR analysis did not establish a causal impact of 28-day mortality in sepsis on PDW (OR 1.00; 95% CI, 1.00-1.07; P = 0.29). Moreover, a similar result was observed in the retrospective study. CONCLUSIONS: The study underscores the independent causal role of PDW in predicting 28-day mortality in sepsis, suggesting its potential utility in early patient assessment, risk stratification, and tailoring of therapeutic interventions.

Pan-cancer analysis reveals that G6PD is a prognostic biomarker and therapeutic target for a variety of cancers.

Background: Despite accumulating evidence revealing that Glucose-6-phosphate dehydrogenase (G6PD) is highly expressed in many tumor tissues and plays a remarkable role in cancer tumorigenesis and progression, there is still a lack of G6PD pan-cancer analysis. This study was designed to analyze the expression status and prognostic significance of G6PD in pan-cancer. Methods: G6PD expression data were obtained from multiple data resources including the Genotype-Tissue Expression, the Cancer Genome Atlas, and the Tumor Immunity Estimation Resource. These data were used to assess the G6PD expression, prognostic value, and clinical characteristics. The ESTIMATE algorithms were used to analyze the association between G6PD expression and immune-infiltrating cells and the tumor microenvironment. The functional enrichment analysis was also performed across pan-cancer. In addition, the GDSC1 database containing 403 drugs was utilized to explore the relationship between drug sensitivity and G6PD expression levels. Furthermore, we also performed clinical validation and in vitro experiments to further validate the role of G6PD in hepatocellular carcinoma (HCC) cells and its correlation with prognosis. The R software was used for statistical analysis and data visualization. Results: G6PD expression was upregulated in most cancers compared to their normal counterparts. The study also revealed that G6PD expression was a prognostic indicator and high levels of G6PD expression were correlated with worse clinical prognosis including overall survival, disease-specific survival, and progression-free interval in multiple cancers. Furthermore, the G6PD level was also related to cancer immunity infiltration in most of the cancers, especially in KIRC, LGG, and LIHC. In addition to this, G6PD expression was positively related to pathological stages of KIRP, BRCA, KIRC, and LIHC. Functional analysis and protein-protein interactions network results revealed that G6PD was involved in metabolism-related activities, immune responses, proliferation, and apoptosis. Drug sensitivity analysis showed that IC50 values of most identified anti-cancer drugs were positively correlated with the G6PD expression. Notably, in vitro functional validation showed that G6PD knockdown attenuated the phenotypes of proliferation in HCC. Conclusion: G6PD may serve as a potential prognostic biomarker for cancers and may be a potential therapeutic target gene for tumor therapy.

The Regulation of let-7c-5p on the Biological Characteristics of Lung Adenocarcinoma Cells by Targeting AURKB.

To study the modulatory mechanism of let-7c-5p on the biological characteristics of lung adenocarcinoma (LUAD) cells by targeting AURKB. Differentially expressed genes (DEGs) were screened by bioinformatics analysis. CCK-8, colony formation, scratch healing, Transwell, and flow cytometry assays were employed to test biological functions of LUAD cells. Western Blot was undertaken to assay the protein level of AURKB, and qRT-PCR was undertaken to test AURKB mRNA and let-7c-5p expression. Dual-luciferase reporter gene method was applied to detect the interaction between AURKB and let-7c-5p. Let-7c-5p was much likely to target AURKB expression. Let-7c-5p was poorly expressed in LUAD cells and suppressed AURKB. Silencing AURKB or overexpressing let-7c-5p both could suppress proliferation, migration, and invasion and stimulate apoptosis, while overexpressing the two simultaneously could reverse such effect. Forced expression of let-7c-5p inhibited proliferation, migration, and invasion and accelerated apoptosis of LUAD cells by inhibiting AURKB, which may provide a new way to understand the malignant progression of LUAD.

MiR-224-5p Targeting OCLN Promotes the Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma Cells.

A number of studies reported that miR-224-5p is involved in a variety of cancer-related cellular processes, yet its physiological role in clear cell renal cell carcinoma (ccRCC) remains unclear. In order to clarify the function of miR-224-5p in ccRCC, real-time quantitative-PCR was conducted to compare the expression of miR-224-5p in human normal renal tubular epithelial cell lines and ccRCC cell lines first, and a strikingly upregulated expression was observed in ccRCC cell lines. Inhibition of miR-224-5p expression by microRNA inhibitors could inhibit the proliferation, migration, and invasion of ccRCC cells. Besides, it was validated by dual-luciferase assay in which miR-224-5p directly targeted OCLN gene. The expression of OCLN was downregulated in ccRCC cells, and overexpression of miR-224-5p could inhibit the mRNA and protein expression levels of OCLN. Overexpression of OCLN could reduce the proliferation, migration, and invasion of ccRCC cells, while overexpressed miR-224-5p could partially reverse that inhibitory effect. Therefore, the promotive effect of miR-224-5p on the proliferation, invasion, and migration of ccRCC cell lines was at least partly due to the inhibition of OCLN expression. These findings highlighted the important function of miR-224-5p, which was promoting cell proliferation, migration, and invasion by downregulating OCLN, in the pathogenesis of ccRCC, and provided a potential treatment strategy.

miR-129-5p inhibits clear cell renal cell carcinoma cell proliferation, migration and invasion by targeting SPN.

OBJECTIVE: Our study aims to investigate the mechanism of the miR-129-5p/SPN axis in clear cell renal cell carcinoma (ccRCC), providing a novel direction for the targeted therapy of ccRCC. METHODS: Bioinformatics methods were implemented to find the differentially expressed genes (DEGs) associated with ccRCC from TCGA database. qRT-PCR was performed to detect miR-129-5p and SPN mRNA expression, while western bot was carried out for the detection of protein expression of SPN. Bioinformatics analysis was used to predict the binding sites of miR-129-5p on SPN 3'UTR, while dual-luciferase assay was conducted to verify their binding relationship. CCK-8 assay, colony formation assay, wound healing assay and Transwell assay were employed to measure ccRCC cell proliferative ability, cell formation ability, cell migratory and invasive abilities. Flow cytometry was implemented to assess cell cycle and apoptosis. RESULTS: miR-129-5p exhibited a significantly down-regulated expression level in ccRCC, while SPN showed a remarkably up-regulated expression level. Overexpressed miR-129-5p inhibited ccRCC cell proliferative, invasive and migratory capacities while induced cell cycle arrest in G0/G1 phase and promoted cell apoptosis. Dual-luciferase assay confirmed that there was a binding relationship between miR-129-5p and SPN. Moreover, overexpressed miR-129-5p remarkably reduced SPN expression in cancer cells, weakened the promoting effect of SPN on cell proliferation, migration, invasion and cell cycle progress, and led to enhanced cell apoptotic activity. CONCLUSIONS: Our study proves the regulatory effect of the miR-129-5p/SPN axis in ccRCC, and provides a novel potential target for precise treatment of patients with ccRCC.

Surfactant-enhanced remediation of oil-contaminated soil and groundwater: A review.

Oil leakage, which is inevitable in the process of extraction, processing, transportation and storage, seriously undermines the soil and groundwater environment. Surfactants can facilitate the migration and solution of oil contaminants from nonaqueous phase liquid (NAPL) or solid phase to water by reducing the (air/water) surface tension, (oil/water) interfacial tension and micellar solubilization. They can effectively enhance the hydrodynamic driven remediation technologies by improving the contact efficiency of contaminants and liquid remediation agents or microorganism, and have been widely used to enhance the remediation of oil-contaminated sites. This paper summarizes the characteristics of different types of surfactants such as nonionic, anionic, biological and mixed surfactants, their enhancements to the remediation of oil-contaminated soil and groundwater, and examines the factors influencing surfactant performance. The causes of tailing and rebound effects and the role of surfactants in suppressing them are also discussed. Laboratory researches and actual site remediation practices have shown that various types of surfactants offer diverse options. Biosurfactants and mixed surfactants are superior and worth attention among the surfactants. Using surfactant foams, adding shear-thinning polymers, and combining surfactants with in-situ chemical oxidation are effective ways to resolve tailing and rebound effects. The adsorption of surfactants on soils and aquifer sediments decreases remediation efficiency and may cause secondary pollution, Therefore the adsorption loss should be noticed and minimized.

Insights into the phosphate adsorption behavior onto 3D self-assembled cellulose/graphene hybrid nanomaterials embedded with bimetallic hydroxides.

3D self-assembled cellulose/graphene hybrids (3D cell/GO hybrids) were used as the host for encapsulating the Zr and La hydroxides, forming the Zr/La-cell/GO hybrids. After phosphate adsorption, the crystallization peaks of LaPO4·xH2O in saturated Zr/La-cell/GO hybrids were observed and they were reduced with the increase in pHs. Especially, a low crystallization was observed at pH 10.0 as compared with those at pH 3.0 and 6.0; this also corresponded well to the varied adsorption capacity as a function of pHs. The increased humic acid (HA) amounts (150 mg/L) only resulted in a low capacity loss (16.3%) in phosphate uptake from 25.3 to 21.2 mg/g. A noticeable La leach (2.1 mg/L) was observed at the HA level of 150 mg/L but no Zr leach was detected, and therefore, complexation of La with HA seemed a potential explanation for the increased La leaching. The interference of different coexisting anions on phosphate uptake followed the order as F- > SiO32- > HCO3- > SO42- > NO3- > Cl-. Phosphate uptake by Zr/La-cell/GO hybrids was significantly reduced at the co-existing fluoride partially due to the stronger electro-negativity of fluoride to combine with the protonated Zr/La hydroxides. In addition, Ca2+ laden on the Zr/La-cell/GO hybrids significantly enhanced the adsorption of phosphate by Zr/La-cell/GG hybrids due to the formation of calcium phosphate precipitation in framework of Zr/La-cell/GG hybrids.

ß-catenin regulates IRF3-mediated innate immune signalling in colorectal cancer.

OBJECTIVE: ß-catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage-associated molecular patterns (DAMPs) and primes the anti-tumour adaptive responses. While the function of ß-catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of ß-catenin in inhibiting RIG-I-like receptor (RLR)-mediated IFN-ß signalling in colorectal cancer. MATERIALS AND METHODS: Immunohistochemical staining and western blotting were conducted to study the expression of ß-catenin, IRF3 and phospho-IRF3 (p-IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of ß-catenin on IFN-ß signalling. The inhibition of ß-catenin on RLR-mediated IFN-ß signalling was further studied by real-time analyses and reporter assays in the context of lentiviral-mediated ß-catenin stably knocking down. Lastly, co-immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between ß-catenin and IRF3. RESULTS: We found that high expression of ß-catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of ß-catenin increased the viral replication. Conversely knocking down of ß-catenin inhibited viral replication. Furthermore, our data demonstrated that ß-catenin could inhibit the expression of IFN-ß and interferon-stimulated gene 56 (ISG56). Mechanistically, we found that ß-catenin interacted with IRF3 and blocked its nuclear translocation. CONCLUSION: Our study reveals an unprecedented role of ß-catenin in enabling innate immune evasion in CRC.

Mcl-1 suppresses abasic site repair following bile acid-induced hepatic cellular DNA damage.

In cholestasis, increases in bile acid levels result in the generation of reactive oxygen species and the induction of DNA damage and mutation. It is believed that bile acid accumulation is associated with liver tumorigenesis. However, the mechanism that underpins this phenomenon remains to be elucidated. Mcl-1, which is overexpressed in hepatic cells, is a pro-survival member of the Bcl-2 family. In this study, we observed that Mcl-1 potently suppresses the repair of bile acid-induced abasic (apurinic/apyrimidinic) sites in DNA lesions. Upon exposure of hepatic cells to glycochenodeoxycholate, one of the major conjugated human bile acids, we observed an increase in AP site accumulation along with induction of poly(ADP-ribose) polymerase and XRCC1 ( X-Ray Repair Cross Complementing 1). In addition, accumulation of Mcl-1 was observed in the nuclei of QGY-7703 cells in response to glycochenodeoxycholate stimulation. Knockdown of endogenous Mcl-1 by RNA interference significantly accelerated the repair of DNA lesions in glycochenodeoxycholate-treated cells. However, unlike XRCC1, poly(ADP-ribose) polymerase was induced following Mcl-1 knockdown. Conversely, poly(ADP-ribose) polymerase suppression was observed following glycochenodeoxycholate treatment of cells overexpressing Mcl-1. Moreover, AP-site counting analyses revealed that DNA repair activity was enhanced in cells overexpressing poly(ADP-ribose) polymerase under glycochenodeoxycholate stress conditions. It is well known that poly(ADP-ribose) polymerase plays a crucial role in the base excision repair pathway. Thus, our findings suggest that Mcl-1 suppresses base excision repair by inhibiting poly(ADP-ribose) polymerase induction following glycochenodeoxycholate-induced DNA damage. These results potentially explain how bile acid accumulation results in genetic instability and carcinogenesis.