Sepsis is a common critical condition caused by the body’s overwhelming response to certain infective agents. Many biomarkers, including the serum lactate level, have been used for sepsis diagnosis and guiding treatment. Recently, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) recommended the Sequential Organ Failure Assessment (SOFA) and the quick SOFA (qSOFA) rather than lactate for screening sepsis and assess prognosis. Here, we aim to explore and compare the prognostic accuracy of the lactate level, the SOFA score and the qSOFA score for mortality in septic patients using the public Medical Information Mart for Intensive Care III database (MIMIC III). The baseline characteristics, laboratory test results and outcomes for sepsis patients were retrieved from MIMIC III. Survival was analysed by the Kaplan-Meier method. Univariate and multivariate analysis was performed to identify predictors of prognosis. Receiver operating characteristic curve (ROC) analysis was conducted to compare lactate with SOFA and qSOFA scores. A total of 3713 cases were initially identified. The analysis cohort included 1865 patients. The 24-h average lactate levels and the worst scores during the first 24 h of ICU admission were collected. Patients in the higher lactate group had higher mortality than those in the lower lactate group. Lactate was an independent predictor of sepsis prognosis. The AUROC of lactate (AUROC, 0.664 [95% CI, 0.639–0.689]) was significantly higher than that of qSOFA (AUROC, 0.547 [95% CI, 0.521–0.574]), and it was similar to the AUROC of SOFA (AUROC, 0.686 [95% CI, 0.661–0.710]). But the timing of lactate relative to SOFA and qSOFA scores was inconsistent. Lactate is an independent prognostic predictor of mortality for patients with sepsis. It has superior discriminative power to qSOFA, and shows discriminative ability similar to that of SOFA.

Sorafenib is currently the first-line treatment for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a significant challenge. Aberrant AKT signaling activation is a crucial mechanism driving sorafenib resistance in HCC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital role in antitumor immune responses. In this study, we demonstrate that aberrant PCSK9 upregulation promotes cell proliferation and sorafenib resistance in HCC by inducing AKT-S473 phosphorylation. After palmitoylation at cysteine 600, the binding affinity between PCSK9 and tensin homolog (PTEN) is dramatically increased, inducing lysosome-mediated PTEN degradation and subsequent AKT activation. We identify zinc finger DHHC-type palmitoyltransferase 16 (ZDHHC16) as a palmitoyltransferase that promotes PCSK9 palmitoylation at cysteine 600. We also develop a biologically active PCSK9-derived peptide that competitively inhibits PCSK9 palmitoylation, suppressing AKT phosphorylation and augmenting the antitumor effects of sorafenib in HCC.

Pancreatic cancer is a deadly disease with little response to standard therapies. Irreversible electroporation (IRE) has emerged as a novel ablative technique for the clinical treatment of pancreatic cancer. Combinations of IRE and immunotherapies, including anti‐programmed death 1 (αPD1) immune checkpoint blockade, have shown promising efficacy in both preclinical and clinical studies. However, tumor recurrence remains an obstacle that needs to be overcome. It herein is shown that IRE induces a substantial infiltration of neutrophils into pancreatic tumors. These neutrophils are then polarized into a protumor phenotype by immunosuppressive cues, in particular transforming growth factor β (TGF‐β). Using glutathione‐responsive degradable mesoporous silica nanoparticles loaded with SB525334, an inhibitor of TGF‐β1 receptor, it is demonstrated that local inhibition of TGF‐β within the tumor microenvironment promotes neutrophil polarization into an antitumor phenotype, enhances pancreatic cancer response to combined IRE and αPD1 therapy, and induces long‐term antitumor memory. The therapeutic efficacy is also attributed to tumor infiltration by CD8⁺ cytotoxic T cells, depletion of regulatory T cells, and maturation of antigen‐presenting dendritic cells. Thus, modulating neutrophil polarization with nanomedicine is a promising strategy for treating pancreatic cancer.

Background: Recent studies have reported that Integrin alpha 2 (ITGA2) plays an essential role in tumor cell proliferation, invasion, metastasis, and angiogenesis. An abnormally expressed ITGA2 correlates with unfavorable prognoses in multiple types of cancer. However, the specific mechanism of how ITGA2 contributes to tumorigenesis remains unclear.Methods: The GEPIA web tool was used to find the clinical relevance of ITGA2 in cancer, and this significance was verified using Western blotting analysis of paired patient tissues and immunohistochemistry of the pancreatic cancer tissue. Functional assays, such as the MTS assay, colony formation assay, and transwell assay, were used to determine the biological role of ITGA2 in human cancer. The relationship between ITGA2 and programmed death-ligand 1 (PD-L1) was examined using Western blot analysis, RT-qPCR assay, and immunohistochemistry. The protein-protein interaction between ITGA2 and STAT3 was detected via co-immunoprecipitation.Results: Our study showed that ITGA2 was markedly overexpressed in several malignant tumor cells and clinical tissues. Blocking ITGA2 inhibited the proliferation and invasion ability of cancer cells significantly, whereas overexpressed ITGA2 increased the degree of those processes considerably. Additionally, the RNA-seq assay indicated that ITGA2 transcriptionally regulated the expression of PD-L1 in pancreatic cancer. We also demonstrated that ITGA2 interacted with STAT3 and up-regulated the phosphorylation of STAT3; this interaction might involve the mechanism of ITGA2 inducing PD-L1 expression in cancer cells. Our results suggest that ITGA2 plays a critical role in cancer cell progression and the regulation of PD-L1 by activating the STAT3 pathway.Conclusions: We identified a novel mechanism by which ITGA2 plays a critical role in modulating cancer immune response by transcriptionally increasing the expression of PD-L1 in cancer cells. Thus, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy against cancer.