Exploring and clinical validation of prognostic significance and therapeutic implications of copper homeostasis-related gene dysregulation in acute myeloid leukemia.

The patterns and biological functions of copper homeostasis-related genes (CHRGs) in acute myeloid leukemia (AML) remain unclear. We explored the patterns and biological functions of CHRGs in AML. Using independent cohorts, including TCGA-GTEx, GSE114868, GSE37642, and clinical samples, we identified 826 common differentially expressed genes. Specifically, 12 cuproptosis-related genes (e.g., ATP7A, ATP7B) were upregulated, while 17 cuproplasia-associated genes (e.g., ATOX1, ATP7A) were downregulated in AML. We used LASSO-Cox, Kaplan-Meier, and Nomogram analyses to establish prognostic risk models, effectively stratifying patients with AML into high- and low-risk groups. Subgroup analysis revealed that high-risk patients exhibited poorer overall survival and involvement in fatty acid metabolism, apoptosis, and glycolysis. Immune infiltration analysis indicated differences in immune cell composition, with notable increases in B cells, cytotoxic T cells, and memory T cells in the low-risk group, and increased monocytes and neutrophils in the high-risk group. Single-cell sequencing analysis corroborated the expression characteristics of critical CHRGs, such as MAPK1 and ATOX1, associated with the function of T, B, and NK cells. Drug sensitivity analysis suggested potential therapeutic agents targeting copper homeostasis, including Bicalutamide and Sorafenib. PCR validation confirmed the differential expression of 4 cuproptosis-related genes (LIPT1, SLC31A1, GCSH, and PDHA1) and 9 cuproplasia-associated genes (ATOX1, CCS, CP, MAPK1, SOD1, COA6, PDK1, DBH, and PDE3B) in AML cell line. Importantly, these genes serve as potential biomarkers for patient stratification and treatment. In conclusion, we shed light on the expression patterns and biological functions of CHRGs in AML. The developed risk models provided prognostic implications for patient survival, offering valuable information on the regulatory characteristics of CHRGs and potential avenues for personalized treatment in AML.

Identification of Potential Novel Prognosis-Related Genes Through Transcriptome Sequencing, Bioinformatics Analysis, and Clinical Validation in Acute Myeloid Leukemia.

Background: Acute Myeloid Leukemia (AML) is a complex and heterogeneous hematologic malignancy. However, the function of prognosis-related signature genes in AML remains unclear. Methods: In the current study, transcriptome sequencing was performed on 15 clinical samples, differentially expressed RNAs were identified using R software. The potential interactions network was constructed by using the common genes between target genes of differentially expressed miRNAs with transcriptome sequencing results. Functional and pathway enrichment analysis was performed to identify candidate gene-mediated aberrant signaling pathways. Hub genes were identified by the cytohubba plugin in Cytoscape software, which then expanded the potential interactions regulatory module for hub genes. TCGA-LAML clinical data were used for the prognostic analysis of the hub genes in the regulatory network, and GVSA analysis was used to identify the immune signature of prognosis-related hub genes. qRT-PCR was used to verify the expression of hub genes in independent clinical samples. Results: We obtained 1,610 differentially expressed lncRNAs, 233 differentially expressed miRNAs, and 2,217 differentially expressed mRNAs from transcriptome sequencing. The potential interactions network is constructed by 12 lncRNAs, 25 miRNAs, and 692 mRNAs. Subsequently, a sub-network including 15 miRNAs as well as 12 lncRNAs was created based on the expanded regulatory modules of 25 key genes. The prognostic analysis results show that CCL5 and lncRNA UCA1 was a significant impact on the prognosis of AML. Besides, we found three potential interactions networks such as lncRNA UCA1/hsa-miR-16-5p/COL4A5, lncRNA UCA1/hsa-miR-16-5p/SPARC, and lncRNA SNORA27/hsa-miR-17-5p/CCL5 may play an important role in AML. Furthermore, the evaluation of the immune infiltration shows that CCL5 is positively correlated with various immune signatures, and lncRNA UCA1 is negatively correlated with the immune signatures. Finally, the result of qRT-PCR showed that CCL5 is down-regulated and lncRNA UCA1 is up-regulated in AML samples separately. Conclusions: In conclusion, we propose that CCL5 and lncRNA UCA1 could be recognized biomarkers for predicting survival prognosis based on constructing competing endogenous RNAs in AML, which will provide us novel insight into developing novel prognostic, diagnostic, and therapeutic for AML.

Identification and validation of inferior prognostic genes associated with immune signatures and chemotherapy outcome in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a group of heterogeneous hematological malignancies. We identified key genes as ITGAM and lncRNA ITGB2-AS1 through different bioinformatics tools. Furthermore, qPCR was performed to verify the expression level of essential genes in clinical samples. Retrospective research on 179 AML cases was used to investigate the relationship between the expression of ITGAM and the characteristics of AML. The critical gene relationship with immune infiltration in AML was estimated. The clinical validation and prognostic investigation showed that ITGAM, PPBP, and ITGB2-AS1 are highly expressed in AML (P < 0.001) and significantly associated with the overall survival in AML. Moreover, the retrospective research on 179 clinical cases showed that positive expression of ITGAM is substantially related to AML classification (P < 0.001), higher count of white blood cells (P < 0.01), and poor chemotherapy outcome (P < 0.05). Furthermore, based on grouping ITGAM as the high and low expression in TCGA-LAML profile, we found that genes in the highly expressed ITGAM group are mainly involved in immune infiltration and inflammation-related signaling pathways. Finally, we discovered that the expression level of ITGAM and lncRNA ITGB2-AS1 are not just closely related to the immune score and stromal score (P < 0.001) but also significantly positively correlated with various Immune signatures in AML (P < 0.001), indicating the association of these genes with immunosuppression in AML. The prediction of candidate drugs indicated that certain immunosuppressive drugs have potential therapeutic effects for AML. The critical genes could be used as potential biomarkers to evaluate the survival and prognosis of AML.

Identification of MiR-93-5p Targeted Pathogenic Markers in Acute Myeloid Leukemia through Integrative Bioinformatics Analysis and Clinical Validation.

Acute myeloid leukemia (AML) is a type of hematological malignancy with diverse genetic pathogenesis. Identification of the miR-93-5p targeted pathogenic markers could be useful for AML diagnosis and potential therapy. We collected 751 miR-93-5p targeted and AML-related genes by integrating the results of multiple databases and then used the expression profile of TCGA-LAML to construct a coexpression function network of AML WGCNA. Based on the clinical phenotype and module trait relationship, we identified two modules (brown and yellow) as interesting dysfunction modules, which have a significant association with cytogenetics risk and FAB classification systems. GO enrichment and KEGG analysis showed that these modules are mainly involved with cancer-associated pathways, including MAPK signal pathway, p53 signal pathway, JAK-STAT signal pathway, TGF-beta signaling pathway, mTOR signaling pathway, VEGF signaling pathway, both associated with the occurrence of AML. Besides, using the STRING database, we discovered the top 10 hub genes in each module, including MAPK1, ACTB, RAC1, GRB2, MDM2, ACTR2, IGF1R, CDKN1A, YWHAZ, and YWHAB in the brown module and VEGFA, FGF2, CCND1, FOXO3, IGFBP3, GSF1, IGF2, SLC2A4, PDGFBM, and PIK3R2 in the yellow module. The prognosis analysis result showed that six key pathogens have significantly affected the overall survival and prognosis in AML. Interestingly, VEGF with the most significant regulatory relationship in the yellow modules significantly positively correlated with the clinical phenotype of AML. We used qPCR and ELISA to verify miR-93-5p and VEGF expression in our clinical samples. The results exhibited that miR-93-5p and VEGF were both highly expressed in AML.

[Clinical features of invasive candidiasis and risk factors for Candida bloodstream infection in children: a multicenter study in Urumqi, China].

OBJECTIVE: To investigate the clinical features of invasive candidiasis in children and the risk factors for Candida bloodstream infection. METHODS: A retrospective study was performed on 134 children with invasive candidiasis and hospitalized in 5 tertiary hospitals in Urumqi, China, between January 2010 and December 2015. The Candida species distribution was investigated. The clinical data were compared between the patients with and without Candida bloodstream infection. The risk factors for Candida bloodstream infection were investigated using multivariate logistic regression analysis. RESULTS: A total of 134 Candida strains were isolated from 134 children with invasive candidiasis, and non-albicans Candida (NAC) accounted for 53.0%. The incidence of invasive candidiasis in the PICU and other pediatric wards were 41.8% and 48.5% respectively. Sixty-eight patients (50.7%) had Candida bloodstream infection, and 45 patients (33.6%) had Candida urinary tract infection. There were significant differences in age, rate of use of broad-spectrum antibiotics, and incidence rates of chronic renal insufficiency, heart failure, urinary catheterization, and NAC infection between the patients with and without Candida bloodstream infection (P<0.05). The multivariate logistic regression analysis showed that younger age (1-24 months) (OR=6.027) and NAC infection (OR=1.020) were the independent risk factors for Candida bloodstream infection. CONCLUSIONS: The incidence of invasive candidiasis is similar between the PICU and other pediatric wards. NAC is the most common species of invasive candidiasis. Candida bloodstream infection is the most common invasive infection. Younger age (1-24 months) and NAC infection are the risk factors for Candida bloodstream infection.