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Abstract The proteasome inhibitor bortezomib (BTZ) is the first‐line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin‐33 (IL‐33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti‐MM effect of IL‐33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL‐33 expression levels were downregulated in MM, and that BTZ‐treated MM patients with high IL‐33 levels had better prognosis than those with low IL‐33 levels. Moreover, the patients with high IL‐33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL‐33 can enhance the anti‐MM immunity. IL‐33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF‐κB‐p65, thereby decreasing the transcription of target stemness‐related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N‐acetylcysteine. In conclusion, our results indicated that IL‐33 enhanced the sensitivity of MM to BTZ through ROS‐mediated inhibition of nuclear factor kappa‐B (NF‐κB) signal and stemness properties.

Introduction:Despite the abundance of research indicating the participation of immune cells in prostate cancer development, establishing a definitive cause-and-effect relationship has proven to be a difficult undertaking.Methods:This study employs Mendelian randomization (MR), leveraging genetic variables related to immune cells from publicly available genome-wide association studies (GWAS), to investigate this association. The primary analytical method used in this study is inverse variance weighting (IVW) analysis. Comprehensive sensitivity analyses were conducted to assess the heterogeneity and horizontal pleiotropy of the results.Results:The study identifies four immune cell traits as causally contributing to prostate cancer risk, including CD127- CD8+ T cell %CD8+ T cell (OR = 1.0042, 95%CI:1.0011–1.0073, p = 0.0077), CD45RA on CD39+ resting CD4 regulatory T cell (OR = 1.0029, 95%CI:1.0008–1.0050, p = 0.0065), CD62L− Dendritic Cell Absolute Count (OR = 1.0016; 95%CI:1.0005–1.0026; p = 0.0039), CX3CR1 on CD14+ CD16− monocyte (OR = 1.0024, 95%CI:1.0007–1.0040, p = 0.0060). Additionally, two immune cell traits are identified as causally protective factors: CD4 on monocyte (OR = 0.9975, 95%CI:0.9958–0.9992, p = 0.0047), FSC-A on plasmacytoid Dendritic Cell (OR = 0.9983, 95%CI:0.9970–0.9995, p = 0.0070). Sensitivity analyses indicated no horizontal pleiotropy.Discussion:Our MR study provide evidence for a causal relationship between immune cells and prostate cancer, holding implications for clinical diagnosis and treatment.

Abstract The most common kind of acute leukemia in adults is acute myeloid leukemia (AML), which is often treated with induction chemotherapy regimens followed by consolidation or allogeneic hematopoietic stem cell transplantation (HSCT). However, some patients continue to develop relapsed or refractory AML (R/R-AML). Small molecular targeted drugs require long-time administration. Not all the patients hold molecular targets. Novel medicines are therefore needed to enhance treatment outcomes. T cells and natural killer (NK) cells engineered with chimeric antigen receptors (CARs) that target antigens associated with AML have recently been produced and are currently being tested in both pre-clinical and clinical settings. This review provides an overview of CAR-T/NK treatments for AML.

Abstract Background Ferroptosis is an iron-dependent mode of cell death that could be induced by erastin and exert antitumor effects. However, the clinical and biological roles of ferroptosis-related gene (FRG) signature and the therapeutic value of erastin in multiple myeloma (MM) remained unknown. Methods Clinical and gene expression data of MM subjects were extracted from the Gene Expression Omnibus (GEO) public database. Univariable cox analysis was applied to determine FRGs related to survival and the least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a prognostic model. Prediction accuracy of the model was estimated by receiver operating characteristic (ROC) curves. Functional pathway enrichments and infiltrating immune status were also analyzed. We conducted in vitro experiments to investigate the combination therapy of erastin and doxorubicin. Results 17 FRGs were strongly associated with patient survival and 11 genes were identified to construct the prognostic model. ROC curves indicated great predictive sensitivity and specificity of the model in all cohorts. Patients were divided into low- and high-risk groups by median risk score in each cohort and the survival of the low-risk group was significantly superior than that of the high-risk group. We also observed a close relevance between functional pathways and immune infiltration with risk scores. Moreover, we combined erastin and doxorubicin in our in vitro experiments and found synergetic antitumor effects of the two agents, and the underlying mechanism is the overgeneration of intracellular Reactive Oxygen Species (ROS). Conclusions We demonstrated the important value of ferroptosis in patient prognosis and as a potential antitumor target for MM.

Abstract Purpose The interaction between tumor cells and tumor microenvironment (TME) has an important impact on progression and prognosis of multiple myeloma (MM), and has been proven to be promising therapeutic targets. This study intended to explore the relationship between TME and prognosis and identify valuable biomarkers of MM. Methods The transcriptomic and clinical information of MM retrieved from the Gene Expression Omnibus (GEO) were used to establish the model. The curve of Kaplan–Meier survival and the time-dependent receiver operating characteristic (ROC) were used to appraise the predictive ability. A nomogram was established for clinical application. Furthermore, the CIBERSORT algorithm was used to investigate the relation between IRGPI with the infiltration of immune cells. We also used histology, as well as in vitro and in vivo experiments to validate these findings. Results The results demonstrated an immune-related gene-based prognostic index (IRGPI) combined with clinical information. Patients were separated into high- and low-risk groups based on risk score, which had significantly difference in survival status and immune infiltrations. Furthermore, we identified CXCL11 as a key factor, which positively promotes the progression of MM and correlate with macrophage M2-like polarization and tumor immune cells infiltration. Conclusion Our findings suggest the IRGPI significantly demonstrate the differential prognosis and prediction of immune cells infiltration. It provides some insights into the complex interaction between myeloma tumor cells and the TME, as well as in the development of a novel biomarker target for anti-MM therapy.

PurposeThis study investigated the relationship between serum lipid levels and clinical outcomes in acute myeloid leukemia (AML) by establishing a predictive risk classification model.MethodA total of 214 AML patients who were pathologically diagnosed and treated with standard induction chemotherapy at Sun Yat-Sen University Cancer Center were included. The patients were randomly divided into the training (n = 107) and validation (n=107) cohorts. Univariate and multivariate Cox analyses were used to assess the value of triglyceride (TG), Apolipoprotein B (Apo B), Apo Apolipoprotein A-I (Apo A-I), cholesterol (CHO), and high-density lipoprotein (HDL) as prognostic factors for AML.ResultsAfter a series of data analyses, a five-factor model was established to divide the patients into high- and low-risk groups. Kaplan-Meier survival analysis showed that the high-risk group had a poor prognosis (P

PurposePyroptosis is an inflammation-based programmed cell death that holds great potential as a novel cancer therapeutic target in patients with multiple myeloma (MM). However, thus far, the function of pyroptosis-related genes (PRGs) in MM and their prognostic relevance remains undetermined.MethodsThe model was established by the LASSO analysis, based on the Gene Expression Omnibus (GEO) dabatase, and its efficacy was verified using two external datasets. The model’s predictive ability was assessed by the Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) curves. Finally, a nomogram was established for clinical application. We also confirmed the validity of our model using specimens and in vitro experiments.ResultsWe established an 11-PRG signature profile, and verified its efficacy using two validation cohorts (VCs). In both cohorts, patients were separated into two subpopulations, according to their median risk scores (RS). Our analysis revealed that high-risk (HR) patients experienced considerably lower overall survival (OS), compared to the low-risk (LR) patients. Using functional enrichment and immune infiltration analyses, we demonstrated that the immunologic status was strongly related to RS. Furthermore, using a pyroptosis inhibitor Q-VD-OPh, we revealed that MM cell proliferation and progression was drastically suppressed and the doxorubicin (DOX)-induced apoptosis was reversed.ConclusionBased on our analysis, pyroptosis not only serves as a measure of MM treatment efficiency and patient prognosis, but is also a possible target for anti-MM therapy.

Hepatocellular carcinoma (HCC) is the second most lethal malignant tumor worldwide, with an increasing incidence and mortality. Due to general resistance to antitumor drugs, only limited therapies are currently available for advanced HCC patients, leading to a poor prognosis with a 5-year survival rate less than 20%. Pyroptosis is a type of inflammation-related programmed cell death and may become a new potential target for cancer therapy. However, the function and prognostic value of pyroptosis-related genes (PRGs) in HCC remain unknown. Here, we identified a total of 58 PRGs reported before and conducted a six-PRG signature via the LASSO regression method in the GEO training cohort, and model efficacy was further validated in an external dataset. The HCC patients can be classified into two subgroups based on the median risk score. High-risk patients have significantly shorter overall survival (OS) than low-risk patients in both training and validation cohorts. Multivariable analysis indicated that the risk score was an independent prognostic factor for OS of HCC patients. Functional enrichment analysis and immune infiltration evaluation suggested that immune status was more activated in the low-risk group. In summary, PRGs can be a prediction factor for prognosis of HCC patients and targeting pyroptosis is a potential therapeutic alternative in HCC.

The Ni-WC coatings were prepared on the surface of 6082-T6 aluminum alloy by plasma spraying. The effect of WC content on the microstructure, mechanical properties and wear performance of the coatings was investigated. The wear mechanism was discussed according to the wear surface morphology and phase composition. The results show that with the increase of the WC content, the microhardness of Ni-WC coatings increases and the bond strength first increases and then decreases sharply. The Ni-20WC coating shows the highest bond strength. The friction coefficient decreases with increasing the WC content, while the wear rate first reduces and then increases as the WC content rises. The wear mechanism of Ni-WC coatings is a mixture of adhesive wear and oxidation wear. With WC content increasing from 10 wt% to 20 wt.%, the friction coefficient and wear rate reduce mainly due to the formation of the continuous oxide film on the wear surface. When the WC content reaches to 30 wt%, the severe oxidation and the defects of the coating such as some microcracks and holes, lead to the increase of the wear rate.