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Objective·To identify key genes that may be regulated by fatty acid alteration in pancreatic cancer through tumor transcriptome screening, and to explore the expression of zinc finger protein 143 (ZNF143) in pancreatic cancer and its effect on the migration and invasion of pancreatic cancer cells.Methods·The R language was utilized to integrate transcriptome data, including the GSE164760 dataset from the Gene Expression Omnibus (GEO) database, 179 pancreatic cancer tissue samples and 4 adjacent non-cancerous tissue samples from The Cancer Genome Atlas (TCGA) database, as well as 167 normal pancreatic tissue samples from the Genotype-Tissue Expression (GTEx) database. We conducted screening and analysis of potential differential genes that may be induced by dysregulation of fatty acid metabolism in pancreatic cancer. After treating pancreatic cancer cells with palmitic acid (PA) and oleic acid (OA) for 24 hours, the mRNA levels of candidate genes were detected by qRT-PCR. According to the median expression level of the screened gene, pancreatic cancer patients in the TCGA database were divided into two groups with high and low expression of ZNF143. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were performed for the differential genes of the two groups. siRNA was used to knock down the expression of ZNF143 in pancreatic cancer cells, and the effects on cell migration and invasion were examined by wound healing assay and invasion assay. Western blotting was used to explore the impact of ZNF143 on epithelial mesenchymal transition (EMT)-related proteins and the Wnt/β-catenin pathway.Results·The bioinformatics database was processed to analyze key genes associated with the up-regulation of genes in lipid metabolism disorders in pancreatic cancer and liver cancer. Among them, ZNF143 was a potential gene associated with fatty acid accumulation in pancreatic cancer. In vitro experiments confirmed that the mRNA level of ZNF143 was significantly up-regulated after treating pancreatic cancer cells with palmitic acid or oleic acid. Both KEGG and GO enrichment analyses demonstrated that the differentially expressed genes associated with ZNF143 were predominantly enriched in adhesion pathways. In functional experiments, the migration and invasion abilities of pancreatic cancer cells transfected with ZNF143 siRNA were reduced, and the expression of EMT-related proteins was also decreased, potentially related to the activation of the Wnt/β- catenin pathway.Conclusion·Fatty acid accumulation up-regulates the mRNA expression of ZNF143 in pancreatic cancer cells, and ZNF143 may enhance the migration and invasion of these cells by facilitating EMT through activation of the Wnt/β-catenin pathway.

Objective·To examine the expression level of protein arginine methyltransferase 6 (PRMT6) in breast carcinoma tissues and to assess its impact on the proliferative and migratory behaviors of breast cancer cells. Methods·The PRMT6 transcriptome sequencing data between 33 tumor tissues and normal tissues from The Cancer Genome Atlas (TCGA) database was analyzed through the R language. The gene expression profile interactive analysis (GEPIA2) online database was used to analyze the difference of PRMT6 expression in normal breast tissues and breast cancer tissues. By using the immunohistochemistry (IHC) data of human normal breast tissues and breast cancer tissues from Human Protein Atlas (HPA) database to analyze the protein expression of PRMT6. IHC was used to detect the expression of PRMT6 in breast cancer tissues and paired para-tumor tissues from 27 clinical samples. After PRMT6 was knocked down with small interfering RNA (siRNA) in MDA-MB-231 and MCF-7 cells, the expression of PRMT6 was detected by qRT-PCR and Western blotting. The proliferation ability of breast cancer cells was measured with cell counting kit-8 (CCK-8) assay and colony formation assay. The effect of PRMT6 on the migration ability of breast cancer cells was detected by wound healing assay and Transwell assay. By using the RNA-sequence data from GSE210948 of Gene Expression Omnibus (GEO) database, differentially expressed genes were analyzed in control and low expression groups of PRMT6. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to reveal the signaling pathways associated with PRMT6. Cell cycle analysis was detected by flow cytometry. The expressions of cyclin D1 and EMT-related proteins (E-cadherin, N-cadherin and Vimentin) were detected by Western blotting after knocking down PRMT6. Results·Bioinformatics analysis and IHC results showed that PRMT6 was highly expressed in breast cancer tissues compared with normal tissues (P=0.000) and para-tumor tissues (P=0.001). qRT-PCR and Western blotting results verified that the siRNA significantly reduced the expression level of PRMT6 in MDA-MB-231 and MCF-7 cell lines compared with the control group (mRNA: P=0.006, P=0.004; P=0.001, P=0.043. Protein: P=0.035, P=0.001; P=0.003, P=0.002). After knocking down PRMT6, the proliferation (P=0.014, P=0.000; P=0.003, P=0.003) and migration (P=0.000, P=0.000; P=0.000, P=0.002) ability of breast cancer cells were inhibited significantly. The KEGG pathway enrichment analysis showed that the expression of PRMT6 affected the cell cycle pathway. After knocking down PRMT6, the expression of cyclin D1 decreased in protein level (P=0.021, P=0.000; P=0.034, P=0.014) and transcription level (P=0.036, P=0.001; P=0.044, P=0.000). Knock down of PRMT6 increased the number of cells in G0/G1 phase (P=0.000; P=0.003) and decreased the number of cells in G2/M phase of the cell cycle. The expression level of E-cadherin increased (P=0.002, P=0.012; P=0.043, P=0.003), while the expression levels of N-cadherin (P=0.004, P=0.041; P=0.032, P=0.034) and Vimentin (P=0.028, P=0.005; P=0.024, P=0.001) decreased in PRMT6 knockdown cells. Conclusion·PRMT6 is highly expressed in breast cancer, which can promote the proliferation and migration of breast cancer cells.

Osteosarcoma is a common primary malignant bone tumor in adolescents and children, characterized by a high recurrence rate and metastasis, making its treatment extremely challenging. Traditional treatment modalities, including surgery, radiation therapy, and chemotherapy, can alleviate symptoms to some extent, but improving long-term survival rates remains a pressing issue. With the continuous development of immunotherapy, breakthroughs have been made in the research of tumor immune microenvironment and the application of immunotherapy in recent years, providing new perspectives and strategies for osteosarcoma treatment. Currently, immunotherapy strategies include tumor vaccines, targeted cytokines, immune checkpoint inhibition, adoptive cell therapy, combination therapy, etc., significantly enhancing patient immune responses from the aspects of boosting immunity, overcoming immune tolerance, and preventing immune evasion, thereby effectively improving the patients′ survival rates and prognosis. This review aims to systematically introduce the immune microenvironment of osteosarcoma and discuss the latest advances in immunotherapy in clinical translational research of osteosarcoma. By deeply understanding the immune characteristics of osteosarcoma and corresponding treatment methods, it is hopeful to provide more effective strategies for personalized treatment, contributing to the improvement of the patients′ survival rates and prognosis.

Objective·To explore the effect of C-X-C motif chemokine ligand 9 (CXCL9) expression on the prognosis of breast cancer patients and its correlation with tumor-infiltrating immune cells (TIICs).Methods·Transcriptome data of 1 100 breast tumor tissues and 112 adjacent tissues were obtained from The Cancer Genome Atlas (TCGA) database. CIBERSORT deconvolution algorithm was used to analyze the proportion of TIIC subgroups in breast cancer immune microenvironment and its effect on the prognosis of patients. Differentially expressed genes, immune-related genes and breast cancer prognostic-related genes were downloaded from TCGA database, ImmPort database and GEPIA2 data platform, respectively. The intersection relationships of the three gene sets were analyzed by using R language, and the target genes were screened. Based on the downloaded transcriptome data, CXCL9 positive-related genes, the difference of CXCL9 mRNA expression in breast cancer tissues and adjacent tissues and its effect on the prognosis of patients were analyzed. STRING data platform was used to analyze the protein-protein interaction (PPI) network of CXCL9. Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis were performed on CXCL9 positive correlation genes and the genes corresponding to the interacting proteins obtained from the PPI network by using R language. Spearman correlation coefficient was used to analyze the correlation between CXCL9 mRNA expression and TIIC subgroups and immune checkpoint-related genes. Paraffin tissue samples of 60 clinical breast cancer patients were collected and made into tissue chips. The correlation between CXCL9 expression and CD8+ T cells infiltration in the tissue chips was detected by immunohistochemical staining (IHC). The types of CXCL9+ cells in breast cancer interstitium were analyzed by multiplex immunohistochemistry staining (mIHC). Kaplan-Meier (KM) survival curve was used to analyze the effect of CXCL9 mRNA expression and CD8+ T cell infiltration on the prognosis of breast cancer patients.Results·CIBERSORT algorithm analysis showed that the distribution proportion of TIIC subgroups in breast cancer immune microenvironment varied greatly, and their effect on patients′ prognosis was also different. The Venn diagram of three types of gene sets was drawn, and CXCL9 was screened out. The top 150 positive correlation genes with CXCL9 were obtained. CXCL9 mRNA expression levels in four molecular types of breast cancer were higher than those in adjacent tissues (all P=0.000), and their high expressions were significantly associated with good prognosis of patients (P=0.013). A total of 41 interacting proteins were obtained through PPI network analysis. GO and KEGG analysis showed that CXCL9 and its related genes were mainly enriched in biological functions and pathways related to immune regulation. Spearman correlation coefficient analysis showed that the expression level of CXCL9 mRNA was positively correlated with CD8+ T cells infiltration ratio, negatively correlated with M2-type macrophages infiltration ratio, and positively correlated with most immune checkpoint genes expression (all P

The biochar (BC) pyrolyzed from corn straw (CS), spent mushroom substrate (SMS) and hardwood sawdust (HS), which are activated by K2CO3, were utilized for lead (Pb) and cadmium (Cd) sorption in solution. The effects of different pyrolysis factors on the Pb and Cd sorption capacities of three types of K2CO3-activated biochar (ABC) were analyzed. A series of characterization analyses were applied to compare the differences between various ABCs and to explore the Pb and Cd removal mechanisms. The results showed that the pyrolysis temperature, residence time and K2CO3 concentration obviously affect the sorption capacity of all ABCs. According to characterization, SMS had a loosely porous structure, which might be more favorable for K2CO3 activation. Furthermore, SMS possessed a rich elemental composition. Therefore, the pyrolysis product derived from SMS exhibited a larger specific surface area and higher polar functional group content, which might be the reason why ABCs synthesized from SMS exhibited better Pb and Cd sorption capacities than did ABCs synthesized from CS or HS. Moreover, the contributions of different Pb or Cd sorption mechanisms by different ABCs decreased as follows: mineral precipitation > cation exchange > complexation of oxygen-containing functional groups > π-bonding or physical sorption. Overall, the ABC synthesized from SMS was more suitable for Pb or Cd removal in solution, which also provided a new approach for the comprehensive utilization of SMS. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)–related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance. Editor's summary: Cancer-associated fibroblasts (CAFs) are stromal cells that make up most of the tumor microenvironment (TME) and have been implicated in cancer progression and relapse, including in breast cancer (BC). Here, Fan et al. have identified a subset of TSPAN8+ myofibroblastic CAFs (myCAFs) that correlated to chemoresistance and poor survival in patients with BC. They found that these myCAFs potentiated stemness of BC cells through down-regulation of SIRT6. They next treated xenograft mice with the SIRT6 activator MDL-800 and anti-TSPAN8 antibody, which increased sensitivity to chemotherapy, suggesting a potential target that requires further investigation. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m6A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore– elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC. Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy. [ABSTRACT FROM AUTHOR]

The pollution of lead (Pb (II)) to water resources is becoming more and more serious. It is always a difficult problem to find efficient and low‐cost adsorbents. Chicken manure (CM) and Chinese medicine residue (CMR) were modified with potassium dihydrogen phosphate (KH2PO4) and pyrolyzed to obtain a modified material (PBC) for the treatment of Pb(II) in an aqueous solution. A variety of characterization analysis results could prove that KH2PO4 was successfully introduced to PBC. By adjusting the initial pH, the zeta potential of PBC varies from −3.2 to −43.1 mV, it could be seen that PBC had excellent applicability in the broad range pH value (1.0–6.0). Experimental and model results showed that R2 of the pseudo‐first order kinetic model and the pseudo‐second order kinetic model are greater than 0.99, indicating that that physical and chemical adsorption played a significant role in Pb(II) removal by PBC. An adsorption isotherm analysis showed that the adsorption capacity n in this study is greater than 1, confirming that PBC has a good adsorption effect on Pb (II). R2 of the Langmuir model of PBC is 0.981, and its maximum adsorption capacity of Pb(II) could reach 599.4 mg/g. Environmentally friendly PBC could be used as an effective adsorbent to remove Pb(II) from aqueous systems. Research highlights: Chicken manure and Chinese medicine residue were converted into biochar to improve utilization.The modified biochar exhibited extraordinary Pb(II) adsorption capacity.Adsorption mechanisms: Surface complexation, ions exchange, coprecipitation, and so on.Remained great Pb(II) removal efficiency at different pH and Pb(II) concentration. [ABSTRACT FROM AUTHOR]

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2 K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Periodontitis is a chronic inflammatory disease characterized by plaque accumulation, resulting in immune microenvironment disorders and resorption of alveolar bone. To promote bone healing under inflammatory environments, a functional biomaterial based on disease pathophysiology is designed. A novel fatty acid C10-modified polypeptide, C 10 -KR8, is discovered to have excellent abilities in modulating macrophage repolarization and promoting bone regeneration in periodontitis. To build a multifunctional material localized drug delivery system, C 10 -KR8@ZIF-8 (C 10 -KR8-loaded zeolitic imidazolate framework-8) nanoparticles are constructed to sustainedly release the C 10 -KR8 peptide and Zn elements. By synergistic effects of providing a dynamic immuno-modulatory environment and promoting osteogenesis under pathological conditions, the obtained pH-responsive nanoparticles display excellent bone regeneration capability. Furthermore, coimmunoprecipitation/liquid chromatography-tandem mass spectrometry analysis and proteomics analysis revealed that the C 10 -KR8 peptide directly interacts with the high-temperature requirement protein A1 (Htra1), and C 10 -KR8@ZIF-8 nanoparticles promote the osteogenic differentiation of bone mesenchymal stem cells by activating the focal adhesion kinase (FAK)/phosphatidylinositide 3-kinase (PI3K)/AKT pathway and enhancing the nuclear localization of Yes-associated protein (YAP). Taken together, this study demonstrates C 10 -KR8 peptide regulate osteoimmunology and bone regeneration by Htra1/FAK/YAP pathway and that ZIF-8-based peptide loading platform is a promising strategy for periodontitis., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Xuechun Wang et al.)

Cardiac fibrosis is a primary phenotype of cardiac remodeling that contributes to cardiac dysfunction and heart failure. The expansion and activation of CD4 + T cells in the heart has been identified to facilitate pathological cardiac remodeling and dysfunction; however, the underlying mechanisms remained not well clarified. Herein, we found that exosomes derived from activated CD4 + T cells (CD4-activated Exos) evoked pro-fibrotic effects of cardiac fibroblasts, and their delivery into the heart aggravated cardiac fibrosis and dysfunction post-infarction. Mechanistically, miR-142-3p that was enriched in CD4-activated Exos recapitulated the pro-fibrotic effects of CD4-activated Exos in cardiac fibroblasts, and vice versa. Furthermore, miR-142-3p directly targeted and inhibited the expression of Adenomatous Polyposis Coli (APC), a negative WNT signaling pathway regulator, contributing to the activation of WNT signaling pathway and cardiac fibroblast activation. Thus, CD4-activated Exos promote post-ischemic cardiac fibrosis through exosomal miR-142-3p-WNT signaling cascade-mediated activation of myofibroblasts. Targeting miR-142-3p in CD4-activated Exos may hold promise for treating cardiac remodeling post-MI.