NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

OLFM4 promotes the progression of intestinal metaplasia through activation of the MYH9/GSK3ß/ß-catenin pathway.

BACKGROUND: Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression. METHODS: In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM. RESULTS: Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3ß and resulted in increased ß-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells. CONCLUSIONS: OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.

Identification and validation of a PD-L1-related signature from mass spectrometry in gastric cancer.

BACKGROUND: According to the guidelines, PD-L1 expression is a critical indicator for guiding immunotherapy application. According to certain studies, regardless of PD-L1 expression, immunotherapy could be advantageous for individuals with gastric cancer. Therefore, new scoring systems or biomarkers are required to enhance treatment strategies. METHODS: Mass spectrometry and machine learning were used to search for strongly related PD-L1 genes, and the NMF approach was then used to separate gastric cancer patients into two categories. Differentially expressed genes (DEGs) between the two subtypes identified in this investigation were utilized to develop the UBscore predictive model, which was verified by the Gene Expression Omnibus (GEO) database. Coimmunoprecipitation, protein expression, and natural killing (NK) cell coculture experiments were conducted to validate the findings. RESULTS: A total of 123 proteins were identified as PD-L1 interactors that are substantially enriched in the proteasome complex at the mRNA level. Using random forest, 30 UPS genes were discovered in the GSE66229 cohort, and ANAPC7 was experimentally verified as one of 123 PD-L1 interactors. Depending on the expression of PD-L1 and ANAPC7, patients were separated into two subgroups with vastly distinct immune infiltration. Low UBscore was related to increased tumor mutation burden (TMB) and microsatellite instability-high (MSI-H). In addition, chemotherapy medications were more effective in individuals with a low UBscore. Finally, we discovered that ANAPC7 might lead to the incidence of immunological escape when cocultured with NK-92 cells. CONCLUSION: According to our analysis of the PD-L1-related signature in GC, the UBscore played a crucial role in prognosis and had a strong relationship with TMB, MSI, and chemotherapeutic drug sensitivity. This research lays the groundwork for improving GC patient prognosis and treatment response.

Review of Research Progress on Mo-Si-B Alloys.

Mo-Si-B alloys are a crucial focus for the development of the next generation of ultra-high-temperature structural materials. They have garnered significant attention over the past few decades due to their high melting point and superior strength and oxidation resistance compared to other refractory metal alloys. However, their low fracture toughness at room temperature and poor oxidation resistance at medium temperature are significant barriers limiting the processing and application of Mo-Si-B alloys. Therefore, this review was carried out to compare the effectiveness of doped metallic elements and second-phase particles in solving these problems in detail, in order to provide clear approaches to future research work on Mo-Si-B alloys. It was found that metal doping can enhance the properties of the alloys in several ways. However, their impact on oxidation resistance and fracture toughness at room temperature is limited. Apart from B-rich particles, which significantly improve the high-temperature oxidation resistance of the alloy, the doping of second-phase particles primarily enhances the mechanical properties of the alloys. Additionally, the application of additive manufacturing to Mo-Si-B alloys was discussed, with the observation of high crack density in the alloys prepared using this method. As a result, we suggest a future research direction and the preparation process of oscillatory sintering, which is expected to reduce the porosity of Mo-Si-B alloys, thereby addressing the noted issues.

Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer.

Immune escape is a major challenge in tumour immunotherapy. Pleckstrin-2(PLEK2) plays a critical role in tumour progression, but its role in immune escape in gastric cancer (GC) remains uncharacterized. RNA sequencing was used to explore the differentially expressed genes in a GC cell line that was resistant to the antitumor effect of Natural killer (NK) cells. Apoptosis and the expression of IFN-γ and TNF-α were detected by flow cytometry (FCM). PLEK2 expression was examined by Western blotting and immunohistochemistry (IHC). PLEK2 was upregulated in MGC803R cells that were resistant to the antitumor effect of NK cells. PLEK2 knockout increased the sensitivity of GC cells to NK cell killing. PLEK2 expression was negatively correlated with MICA and positively correlated with MT1-MMP expression both in vitro and in vivo. PLEK2 promoted Sp1 phosphorylation through the PI3K-AKT pathway, thereby upregulating MT1-MMP expression, which ultimately led to MICA shedding. In mouse xenograft models, PLEK2 knockout inhibited intraperitoneal metastasis of GC cells and promoted NK cell infiltration. In summary, PLEK2 suppressed NK cell immune surveillance by promoting MICA shedding, which serves as a potential therapeutic target for GC.

Construction of a hypoxia-immune-related prognostic panel based on integrated single-cell and bulk RNA sequencing analyses in gastric cancer.

Introduction: Gastric cancer (GC) is the fifth most common tumor, contributing to the third-highest number of cancer-related deaths. Hypoxia is a major feature of the tumor microenvironment. This study aimed to explore the influence of hypoxia in GC and establish a hypoxia-related prognostic panel. Methods: The GC scRNA-seq data and bulk RNA-seq data were downloaded from the GEO and TCGA databases, respectively. AddModuleScore() and AUCell() were used to calculate module scores and fractions of enrichment for hypoxia-related gene expression in single cells. Least absolute shrinkage and selection operator cox (LASSO-COX) regression analysis was utilized to build a prognostic panel, and hub RNAs were validated by qPCR. The CIBERSORT algorithm was adopted to evaluate immune infiltration. The finding of immune infiltration was validated by a dual immunohistochemistry staining. The TIDE score, TIS score and ESTIMATE were used to evaluate the immunotherapy predictive efficacy. Results: Hypoxia-related scores were the highest in fibroblasts, and 166 differentially expressed genes were identified. Five hypoxia-related genes were incorporated into the hypoxia-related prognostic panel. 4 hypoxia-related genes (including POSTN, BMP4, MXRA5 and LBH) were significantly upregulated in clinical GC samples compared with the normal group, while APOD expression decreased in GC samples. Similar results were found between cancer-associated fibroblasts (CAFs) and normal fibroblasts (NFs). A high hypoxia score was associated with advanced grade, TNM stage, N stage, and poorer prognosis. Decreased antitumor immune cells and increased cancer-promoting immune cells were found in patients with high hypoxia scores. Dual immunohistochemistry staining showed high expression of CD8 and ACTA2 in gastric cancer tissue. In addition, the high hypoxia score group possessed higher TIDE scores, indicating poor immunotherapy benefit. A high hypoxia score was also firmly related to sensitivity to chemotherapeutic drugs. Discussion: This hypoxia-related prognostic panel may be effective in predicting the clinical prognosis, immune infiltrations, immunotherapy, and chemotherapy in GC.

Dual-Attitude Decision-Making Processes of Construction Worker Safety Behaviors: A Simulation-Based Approach.

Workplace accidents are of great concern in the construction industry. Most of those accidents are caused by unsafe behavior in the workplace. Many previous studies have analyzed the causes of workers' unsafe behaviors, but few have investigated workers' feelings of insecurity from the perspective of systematic psychological theory. This study developed an attitude-behavior-intervention feedback loop mechanism of construction workers and used the dual-attitude theory to explain the occurrence mechanisms of unsafe behavior. Using this mechanism, an active-intervention system-dynamics model and a passive-intervention system-dynamics model were designed and simulated. The coefficient of the system dynamics equation in the simulation model involved meta-analysis to combine the correlation coefficients of existing studies, which increased the sample size and improved the statistical test efficiency. The results show that an implicit safety attitude has a more significant impact on safety behavior, and the effect of an active intervention is stronger than that of a passive intervention. Based on these results, this paper presents some feasible suggestions to reduce the probability of unsafe worker behaviors occurring.

Syntaxin-6, a Reliable Biomarker for Predicting the Prognosis of Patients with Cancer and the Effectiveness of Immunotherapy.

Syntaxin-6 (STX6), a vesicular transport protein, is a direct target of the tumor suppressor gene P53, supporting cancer growth dependent on P53. However, STX6's function in the tumor microenvironment has yet to be reported. In this research, we comprehensively explored the role of the oncogene STX6 in pan-cancer by combining data from several databases, including the Cancer Genome Atlas, CPTAC, cBioPortal, and TIMER. Then, we verified the carcinogenic effect of STX6 in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) through a series of experiments in vitro and in vivo. Bioinformatics analysis demonstrated that STX6 is an oncogene for several cancers and is mainly involved in the cell cycle, epithelial-mesenchymal transition, oxidative phosphorylation, and tumor immune modulation, especially for tumor-associated fibroblasts (CAFs) and NKT cells. Additionally, a high level of STX6 could indicate patients' resistance to immunotherapy. Our own data indicated that the STX6 level was upregulated in HCC and CRC. Knockdown of the STX6 levels could arrest the cell cycle and restrain cell proliferation, migration, and invasion. RNA-seq indicated that STX6 was significantly involved in pathways for cancer, such as the MAPK signal pathway. In a mouse model, knockdown of STX6 inhibited tumor growth and potentiated anti-PD-1 efficacy. In light of the essential roles STX6 plays in carcinogenesis and cancer immunology, it has the potential to be a predictive biomarker and a target for cancer immunotherapy.

Cross-Talk of Focal Adhesion-Related Gene Defines Prognosis and the Immune Microenvironment in Gastric Cancer.

Background: Focal adhesion, as the intermediary between tumor cells and extracellular matrix communication, plays a variety of roles in tumor invasion, migration, and drug resistance. However, the potential role of focal adhesion-related genes in the microenvironment, immune cell infiltration, and drug sensitivity of gastric cancer (GC) has not yet been revealed. Methods: The genetic and transcriptional perspectives of focal adhesion-related genes were systematically analyzed. From a genetic perspective, the focal adhesion index (FAI) was constructed based on 18 prognosis-related focus adhesion-related genes to evaluate the immune microenvironment and drug sensitivity. Then three prognosis-related genes were used for consistent clustering to identify GC subtypes. Finally, use FLT1, EGF, COL5A2, and M2 macrophages to develop risk signatures, and establish a nomogram together with clinicopathological characteristics. Results: Mutations in the focal adhesion-related gene affect the survival time and clinical characteristics of GC patients. FAI has been associated with a shorter survival time, immune signaling pathways, M2 macrophage infiltration, epithelial-mesenchymal transition (EMT) signaling, and diffuse type of GC. FAI recognizes ALK, cell cycle, and BMX signaling pathways inhibitors as sensitive agents for the treatment of GC. FLT1, EGF, and COL5A2 may distinguish GC subtypes. The established risk signature is of great significance to the prognostic evaluation of GC based on FLT1, EGF, and COL5A2 and M2 macrophage expression. Conclusion: The focal adhesion-related gene is a potential biomarker for the evaluation of the immune microenvironment and prognosis. This work emphasizes the potential impact of the focal adhesion pathway in GC therapy and highlights its guiding role in prognostic evaluation.