The macrophage-associated prognostic gene ANXA5 promotes immunotherapy resistance in gastric cancer through angiogenesis.

Gastric cancer (GC) remains a predominant form of malignant tumor globally, necessitating innovative non-surgical therapeutic approaches. This investigation aimed to delineate the expression landscape of macrophage-associated genes in GC and to evaluate their prognostic significance and influence on immunotherapeutic responsiveness. Utilizing the CellMarker2.0 database, we identified 69 immune cell markers with prognostic relevance in GC, including 12 macrophage-specific genes. A Weighted Gene Co-Expression Network Analysis (WGCNA) isolated 3,181 genes correlated with these macrophage markers. The Cancer Genome Atlas (TCGA-STAD) dataset was employed as the training set, while data from the GSE62254 served as the validation cohort. 13 genes were shortlisted through LASSO-Cox regression to formulate a prognostic model. Multivariable Cox regression substantiated that the calculated risk score serves as an imperative independent predictor of overall survival (OS). Distinct macrophage infiltration profiles, pathway associations, treatment susceptibilities, and drug sensitivities were observed between high- and low-risk groups. The preliminary validation of ANXA5 in predicting the survival rates of GC patients at 1 year, 3 years, and 5 years, as well as its expression levels were higher and role in promoting tumor angiogenesis in GC through immunohistochemistry and angiogenesis experiments. In summary, macrophage-related genes were potentially a novel crosstalk mechanism between macrophages and endothelial cells in the tumor microenvironment, and the interplay between inflammation and angiogenesis might have also offered new therapeutic targets, providing a new avenue for personalized treatment interventions.

Construction of stemness gene score by bulk and single-cell transcriptome to characterize the prognosis of breast cancer.

Breast cancer (BC) is a heterogeneous disease characterized by significant differences in prognosis and therapy response. Numerous prognostic tools have been developed for breast cancer. Usually these tools are based on bulk RNA-sequencing (RNA-Seq) and ignore tumor heterogeneity. Consequently, the goal of this study was to construct a single-cell level tool for predicting the prognosis of BC patients. In this study, we constructed a stemness-risk gene score (SGS) model based on single-sample gene set enrichment analysis (ssGSEA). Patients were divided into two groups based on the median SGS. Patients with a high SGS scores had a significantly worse prognosis than those with a low SGS, and these groups exhibited differences in several tumor characteristics, such as immune infiltration, gene mutations, and copy number variants. Our results indicate that the SGS is a reliable tool for predicting prognosis and response to immunotherapy in BC patients.

Crosstalk between Cancer Cells and Cancer-Associated Fibroblasts Mediated by TGF-ß1-IGFBP7 Signaling Promotes the Progression of Infiltrative Gastric Cancer.

Patients with infiltrative-type gastric cancer (GC) (Ming's classification) have a poor prognosis due to more metastasis and recurrence. Cancer-associated fibroblasts (CAFs) in infiltrative-type extracellular matrix (ECM) have specific characteristics compared with those of expansive types with respect to metastasis, but the mechanism is still unclear. Based on our proteomics data, TCGA data analysis, and immunohistochemical staining results, significantly higher expression of IGFBP7 was observed in GC, especially in the infiltrative type, and was associated with a poor prognosis. Combining single-cell transcriptome data from GEO and multiple immunofluorescence staining on tissue showed that the differential expression of IGFBP7 mainly originated from myofibroblastic CAFs, the subgroup with higher expression of PDGFRB and α-SMA. After treating primary normal fibroblasts (NFs) with conditional medium or recombined protein, it was demonstrated that XGC-1-derived TGF-ß1 upregulated the expression of IGFBP7 in the cells and its secretion via the P-Smad2/3 pathway and mediated its activation with higher FAP, PDGFRB, and α-SMA expression. Then, either conditional medium from CAFs with IGFBP7 overexpression or recombined IGFBP7 protein promoted the migration, invasion, colony formation, and sphere growth ability of XGC-1 and MGC-803, respectively. Moreover, IGFBP7 induced EMT in XGC-1. Therefore, our study clarified that in the tumor microenvironment, tumor-cell-derived TGF-ß1 induces the appearance of the IGFBP7+ CAF subgroup, and its higher IGFBP7 extracellular secretion level accelerates the progression of tumors.

Recent developments and emerging trends in dietary vitamin D sources and biological conversion.

This review elaborates on biochemical characteristics, in vivo metabolism, biological conversion through UV irradiation, as well as dietary fortification of vitamin D. Recent innovations in vitamin D utilization, including nanoencapsulation, direct or indirect addition, emulsion, ultrasound, microwave processing, CRISPR-Cas9 genome editing, as well as UV photoconversion, were summarized. Mushrooms, eggs, yeasts, as well as seafood, such as Barramundi and Atlantic salmon, were typical representatives of original natural food materials for vitamin D bioconversion in relevant research. The critical session thereof referred to the 295 nm UV-B irradiation triggering biological fortification of vitamin D2 and vitamin D3, which occurred in ergosterol from mushrooms, and cholesterol from egg yolk, respectively. The schematic biosynthesis of vitamin D precursors in yeasts regulated miscellaneous enzymes were clearly demonstrated. These summarized pathways played a role as a theoretical primer for vitamin D bioconversion when the UV irradiation technique is concerned. Besides, tomatoes had become the latest potential vitamin D sources after genetic modification. The safety consideration for vitamin D fortified functional food was discussed either. Further research is required to fill the gap of investigating optimized factors like types of eggs, meat, and grain, boarder range of wavelength, and dosage in UV irradiation. Vitamin D has a great potential market in the field of functional food development.

Identification of novel tumor microenvironment-associated genes in gastric cancer based on single-cell RNA-sequencing datasets.

Tumor microenvironment and heterogeneity play vital roles in the development and progression of gastric cancer (GC). In the past decade, a considerable amount of single-cell RNA-sequencing (scRNA-seq) studies have been published in the fields of oncology and immunology, which improve our knowledge of the GC immune microenvironment. However, much uncertainty still exists about the relationship between the macroscopic and microscopic data in transcriptomics. In the current study, we made full use of scRNA-seq data from the Gene Expression Omnibus database (GSE134520) to identify 25 cell subsets, including 11 microenvironment-related cell types. The MIF signaling pathway network was obtained upon analysis of receptor-ligand pairs and cell-cell interactions. By comparing the gene expression in a wide variety of cells between intestinal metaplasia and early gastric cancer, we identified 64 differentially expressed genes annotated as immune response and cellular communication. Subsequently, we screened these genes for prognostic clinical value based on the patients' follow-up data from The Cancer Genome Atlas. TMPRSS15, VIM, APOA1, and RNASE1 were then selected for the construction of LASSO risk scores, and a nomogram model incorporating another five clinical risk factors was successfully created. The effectiveness of least absolute shrinkage and selection operator risk scores was validated using gene set enrichment analysis and levels of immune cell infiltration. These findings will drive the development of prognostic evaluations affected by the immune tumor microenvironment in GC.

Multi-Transcriptomic Analysis Reveals the Heterogeneity and Tumor-Promoting Role of SPP1/CD44-Mediated Intratumoral Crosstalk in Gastric Cancer.

GC is a fatal disease with high heterogeneity and invasiveness. Recently, SPP1 has been reported to be involved in the tumor progression of multiple human cancers; however, the role of SPP1 in GC heterogeneity and whether it is associated with the invasiveness and mortality of GC remain unclear. Here, we combined multiple RNA sequencing approaches to evaluate the impact of SPP1 on GC. Through bulk RNA sequencing (bulk RNA-seq) and immunohistochemistry (IHC), we found that SPP1 was highly expressed in GC, and high levels of SPP1 were associated with macrophage infiltration, an advanced tumor stage, and higher mortality for advanced GC patients. Furthermore, through simultaneous single-cell and spatial analysis, we demonstrated that SPP1+ macrophages are tumor-specific macrophages unique to cancer and enriched in the deep layer of GC tissue. Cell-cell communication analysis revealed that SPP1/CD44 interactions between SPP1+ macrophages and their localized tumor epithelial cells could activate downstream target genes in epithelial cells to promote dynamic changes in intratumor heterogeneity. Moreover, these activated genes were found to be closely associated with poor clinical GC outcomes and with cancer-related pathways that promote GC progression, as shown by survival analysis and enrichment analysis, respectively. Collectively, our study reveals that tumor-specific SPP1+ macrophages drive the architecture of intratumor heterogeneity to evolve with tumor progression and that SPP1 may serve as a prognostic marker for advanced GC patients, as well as a potential therapeutic target for GC.

The safety and efficacy of intralesional triamcinolone acetonide for keloids and hypertrophic scars: A systematic review and meta-analysis.

BACKGROUND: Triamcinolone acetonide (TAC) is widely used for hypertrophic scars and keloids; however, TAC has variable efficacy and safety in different individuals. PURPOSE: To evaluate the efficacy and safety of intralesional TAC for treatment of hypertrophic scars and keloids. DATA SOURCES: Searches of PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov prior to 25 March 2020. STUDY SELECTION: Randomized controlled trials in English that compared TAC with a placebo or other medications that are commonly used for intralesional injection in hypertrophic scars and keloids. DATA EXTRACTION: Primary outcomes were reduction in scar height, vascularity, pliability, pigmentation, total scores on the Vancouver Scar Scale (VSS) or patient and observer scar assessment scale (POSAS), telangiectasia, and skin atrophy. Secondary outcomes included overall scar improvement. DATA SYNTHESIS: Fifteen trials met the inclusion criteria. In the short term, TAC was associated with a significant improvement in vascularity (MD: -0.22, 95% CI: -0.42 to -0.02) and pliability (MD: -0.25, 95% CI: -0.44 to -0.06) compared to verapamil. In the medium term, compared to TAC, 5-FU showed a significant improvement in scar height (SMD: 0.95, 95% CI: 0.15-1.75), while TAC led to a significant improvement in vascularity compared to 5-FU (MD: -0.45, 95% CI: -0.76 to -0.14). Compared to TAC, TAC+5-FU showed a significant improvement in pliability (SMD: 0.98, 95% CI: 0.17-1.78) and pigmentation (MD: 0.45, 95% CI: 0.12-0.78). Botulinum toxin type A resulted in significantly better pliability (SMD: 1.99, 95% CI: 0.98-3.00) compared to TAC. In the long term, compared to TAC, 5-FU led to a significant improvement in scar height (MD: 0.55, 95% CI: 0.17-0.93), but significantly less vascularity (MD: -0.35, 95% CI: -0.65 to -0.05). Compared to TAC, TAC+5-FU produced a significant improvement in scar height (MD: 1.50, 95% CI: 1.12-1.88), pliability (MD: 0.45, 95% CI: 0.10-0.80), and pigmentation (MD: 0.55, 95% CI: 0.24-0.86). CONCLUSION: TAC may be beneficial for the short-term treatment of hypertrophic scars and keloids; however, 5-FU, 5-FU+TAC, and verapamil may produce superior results for medium- and long-term treatments. TAC injections at concentrations of 20 mg/ml or 40 mg/ml are more likely to result in skin atrophy compared to 5-FU or verapamil, and are more likely to cause telangiectasia than 5-FU, 5-FU+TAC, or bleomycin.

Elevated N-methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform.

The cross-talk between hepatic stellate cells (HSCs) and hepatic carcinoma cells contributes to hepatocellular carcinoma (HCC) progression, but the underlying mechanism is largely unknown. We report here that activated HSCs induce upregulation of nicotinamide N-methyltransferase (NNMT), which is known to regulate multiple metabolic pathways in hepatoma cells of the liver. High levels of NNMT in HCC tissues were positively correlated with vascular invasion, increased serum HBV-DNA levels, and distant metastasis. In addition, functional assays showed that NNMT promoted HCC cell invasion and metastasis by altering the histone H3 methylation on 27 methylation pattern and transcriptionally activating cluster of differentiation 44 (CD44). NNMT-mediated N6-methyladenosine modification of CD44 mRNA resulted in the formation of a CD44v3 splice variant, while its product 1-methyl-nicotinamide stabilized CD44 protein by preventing ubiquitin-mediated degradation. Finally, NNMT was also shown to be a target of statins that inhibited metastasis of hepatoma cells. Taken together, our study shows for the first time that the NNMT/CD44v3 axis regulates HCC metastasis and presents NNMT as a promising prognostic biomarker and therapeutic target for HCC.