Risk assessment model based on nucleotide metabolism-related genes highlights SLC27A2 as a potential therapeutic target in breast cancer.

PURPOSE: Breast cancer (BC) is the most prevalent malignant tumor worldwide among women, with the highest incidence rate. The mechanisms underlying nucleotide metabolism on biological functions in BC remain incompletely elucidated. MATERIALS AND METHODS: We harnessed differentially expressed nucleotide metabolism-related genes from The Cancer Genome Atlas-BRCA, constructing a prognostic risk model through univariate Cox regression and LASSO regression analyses. A validation set and the GSE7390 dataset were used to validate the risk model. Clinical relevance, survival and prognosis, immune infiltration, functional enrichment, and drug sensitivity analyses were conducted. RESULTS: Our findings identified four signature genes (DCTPP1, IFNG, SLC27A2, and MYH3) as nucleotide metabolism-related prognostic genes. Subsequently, patients were stratified into high- and low-risk groups, revealing the risk model's independence as a prognostic factor. Nomogram calibration underscored superior prediction accuracy. Gene Set Variation Analysis (GSVA) uncovered activated pathways in low-risk cohorts and mobilized pathways in high-risk cohorts. Distinctions in immune cells were noted between risk cohorts. Subsequent experiments validated that reducing SLC27A2 expression in BC cell lines or using the SLC27A2 inhibitor, Lipofermata, effectively inhibited tumor growth. CONCLUSIONS: We pinpointed four nucleotide metabolism-related prognostic genes, demonstrating promising accuracy as a risk prediction tool for patients with BC. SLC27A2 appears to be a potential therapeutic target for BC among these genes.

MGP+ and IDO1+ tumor-associated macrophages facilitate immunoresistance in breast cancer revealed by single-cell RNA sequencing.

Immunotherapy is widely applied for the treatment of breast cancer, but to which some patients respond poorly or develop resistance. Therefore, the mechanism needs to be further studied. Transcriptomic data of 31 breast cancer patients treated with anti-programmed death receptor 1 (PD-1) was downloaded from the VIB-KULeuven Center for Cancer Biology to analyze the changes in myeloid cells in tumor tissues before and after immunotherapy. And 24 cell populations that may be immune-related were further identified. Representative cell populations were also screened and validated through cellular and animal experiments to evaluate the relevant molecular expression and pathways of tumor-associated macrophages (TAMs) in the tumor microenvironment. The results demonstrated that MGP+ TAMs and IDO1+ TAMs influenced the efficacy of immunotherapy in breast cancer patients. After anti-PD-1 treatment, Increased numbers of MGP+ TAMs and IDO1+ TAMs in breast cancer patients upregulated pro-tumorigenic factors associated with resistance to immunosuppressive therapy. This study provides new biomarkers for immunotherapy to predict therapeutic responses and overcome potential resistance to immunotherapy. It is an important complement to the immunosuppression caused by TAMs after immunotherapy for breast cancer.

PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis.

BACKGROUND: As an emerging treatment strategy for triple-negative breast cancer (TNBC), immunotherapy acts in part by inducing ferroptosis. Recent studies have shown that protein arginine methyltransferase 5 (PRMT5) has distinct roles in immunotherapy among multiple cancers by modulating the tumor microenvironment. However, the role of PRMT5 during ferroptosis, especially for TNBC immunotherapy, is unclear. METHODS: PRMT5 expression in TNBC was measured by IHC (immunohistochemistry) staining. To explore the function of PRMT5 in ferroptosis inducers and immunotherapy, functional experiments were conducted. A panel of biochemical assays was used to discover potential mechanisms. RESULTS: PRMT5 promoted ferroptosis resistance in TNBC but impaired ferroptosis resistance in non-TNBC. Mechanistically, PRMT5 selectively methylated KEAP1 and thereby downregulated NRF2 and its downstream targets which can be divided into two groups: pro-ferroptosis and anti-ferroptosis. We found that the cellular ferrous level might be a critical factor in determining cell fate as NRF2 changes. In the context of higher ferrous concentrations in TNBC cells, PRMT5 inhibited the NRF2/HMOX1 pathway and slowed the import of ferrous. In addition, a high PRMT5 protein level indicated strong resistance of TNBC to immunotherapy, and PRMT5 inhibitors potentiated the therapeutic efficacy of immunotherapy. CONCLUSIONS: Our results reveal that the activation of PRMT5 can modulate iron metabolism and drive resistance to ferroptosis inducers and immunotherapy. Accordingly, PRMT5 can be used as a target to change the immune resistance of TNBC.

Development and validation of an endoplasmic reticulum stress-related molecular prognostic model for breast cancer.

Background: Breast cancer is the most frequently diagnosed cancer and a leading cause of cancer-related death in women. Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of several malignancies. However, the prognostic value of ERS-related genes in breast cancer has not been thoroughly investigated. Methods: We downloaded and analyzed expression profiling data for breast invasive carcinoma samples in The Cancer Genome Atlas-Breast Invasive Carcinoma (TCGA-BRCA) and identified 23 ERS-related genes differentially expressed between the normal breast tissue and primary breast tumor tissues. We constructed and validated risk models using external test datasets. We assessed the differences in sensitivity to common antitumor drugs between high- and low-scoring groups using the Genomics of Drug Sensitivity in Cancer (GDSC) database, evaluated the sensitivity of patients in high- and low-scoring groups to immunotherapy using the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm, and assessed immune and stromal cell infiltration in the tumor microenvironment (TME) using the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm. We also analyzed the expression of independent factors in the prognostic model using the Western-blot analysis for correlation in relation to breast cancer. Results: Using multivariate Cox analysis, FBXO6, PMAIP1, ERP27, and CHAC1 were identified as independent prognostic factors in patients with breast cancer. The risk score in our model was defined as the endoplasmic reticulum score (ERScore). ERScore had high predictive power for overall survival in patients with breast cancer. The high-ERScore group exhibited a worse prognosis, lower drug sensitivity, and lower immunotherapy response and immune infiltration than did the low-ERScore group. Conclusions based on ERScore were consistent with Western-blot results. Conclusion: We constructed and validated for the first time an endoplasmic reticulum stress-related molecular prognostic model for breast cancer with reliable predictive properties and good sensitivity, as an important addition to the prognostic prediction model for breast cancer.

Photothermal conversion hydrogel based mini-eye patch for relieving dry eye with long-term use of the light-emitting screen.

Purpose: The frequent usage of various lighting screens has made dry eye syndrome an increasingly serious phenomenon. To relieve this global problem, we have developed a photothermal conversion hydrogel based mini-eye patch. Methods: Gold nanoparticles (GNRs) were synthesized by a seed-mediated method, and then used as the inner cores to grow palladium (Pd) shell by PdCl42-reduction. Then, gelatin was added to prepare GNRs @ Pd hydrogel eye patch by genipin cross-linking. We implanted temperature sensitive ink (complex composed of amino resin and styrene maleic anhydride copolymer) in the eye patch, which could change color at different temperatures. Heating performance of the eye patch was accessed with an infrared temperature profile and the circulating temperature experiment. The safety assessment of the eye patch was conducted by H&E staining of the mouse's eyelid skin and CCK-8 assay. A Keratograph 5M noninvasive ocular surface analyzer was used to assess the impact of eye patches on dry eyes. Results: It was found that GNRs @ Pd hydrogel eye patches could sense various visible light and responded by heating up spontaneously. Results from the CCK-8 assay and H&E staining showed that the eye patch has good safety performance. Measurements of the first noninvasive tear break-up time (NITBUT), the average NITBUT, the tear meniscus height (TMH), combined with red eye analysis, further demonstrated the patch's eye-protective properties. Conclusion: After being pasted to the lacrimal gland, the hydrogel patch converted various light irradiations into heat and stimulated the lacrimal gland to produce more tears to relieve dry eye. The built-in temperature-sensitive ink can play an important role in warning people of their excessive eye usage. Because this recyclable strategy does not interfere with normal eye use, it is thus more environmentally friendly and convenient than ordinary infrared eyewear.

Metal-Organic Framework and Hydrogel Based Strategy as a Universal First-Aid Treatment of Three Different Typical Snake Bites.

Snake bite envenoming is a worldwide problem which affects the health and safety of the public. The classical antivenom methods are difficult to be used immediately and accurately. Based on this situation, a new metal-organic framework and hydrogel based first-aid treatment was first set up in this study as a facile, economic, effective, and universal alternative strategy. According to the subsequent in vitro and in vivo experiments, this dual effective (block and absorption) strategy was proven to be useful in dealing with three different representative snake venoms (Bungarus fasciatus, Protobothrops mucrosquamatus, and cobra venom).

Identification of DNA methylation prognostic signature of acute myelocytic leukemia.

BACKGROUND: The aim of this study is to find the potential survival related DNA methylation signature capable of predicting survival time for acute myelocytic leukemia (AML) patients. METHODS: DNA methylation data were downloaded. DNA methylation signature was identified in the training group, and subsequently validated in an independent validation group. The overall survival of DNA methylation signature was performed. Functional analysis was used to explore the function of corresponding genes of DNA methylation signature. Differentially methylated sites and CpG islands were also identified in poor-risk group. RESULTS: A DNA methylation signature involving 8 DNA methylation sites and 6 genes were identified. Functional analysis showed that protein binding and cytoplasm were the only two enriched Gene Ontology terms. A total of 70 differentially methylated sites and 6 differentially methylated CpG islands were identified in poor-risk group. CONCLUSIONS: The identified survival related DNA methylation signature adds to the prognostic value of AML.

CAT104 silence behaves as a tumor suppressor in human leukemia cells by down regulating miR-182 expression.

BACKGROUND: LncRNAs and miRNAs are found to play crucial roles in the tumorigenesis of acute myeloid leukemia (AML). We aimed to investigate the functions and mechanisms of lncRNA-CAT104 and miR-182 in AML. METHODS: Expression of CAT104, miR-182, and ZEB1 in K562 and HL60 cell lines was respectively or synchronously altered by transfection. Expressions of CAT104, miR-182 and ZEB1 in cell were then analyzed by qRT-PCR. Cell viability, migration, invasion and apoptosis were evaluated by MTT, transwell assays and flow cytometry, respectively. Protein expressions of ZEB1 and factors related with apoptosis and two signal pathways (Wnt/ß-catenin and JNK) were detected by western blot. RESULTS: CAT104 expressed highly in K562 and HL60 cells compared to embryonic kidney cell line HEK293 (P < 0.001). Knockdown of CAT104 inhibited cell viability, migration and invasion, but increased cell apoptosis of K562 and HL60 cells through inhibitionof miR-182 (P < 0.05). miR-182 promoted cell survival, migration and invasion through upregulatingthe expression of ZEB1 (P < 0.05). miR-182 silence deactivated Wnt/ß-catenin and JNK signal pathways by downregulating the expression of ZEB1 in K562 and HL60 cells. CONCLUSION: LncRNA-CAT104 expressed highly in leukemia cells and its silence inhibited cell survival, migration and invasion by downregulating miR-182 expression. miR-182 functioned as an oncogene by upregulating ZEB1 via which miR-182 silence deactivated Wnt/ß-catenin and JNK signal pathways in leukemia cells.