The prevalence of CHD of live infants in Tianjin was found to be relatively high by using a colour Doppler ultrasonic diagnostic system to screen CHD. Several maternal factors were associated with CHD risk.

Background: To evaluate whether homoharringtonine (HHT) combined with venetoclax could produce a synergistic anti-acute myeloid leukemia (AML) effect and determine the underlying mechanisms. Methods:The effect of HHT and venetoclax combination on cell viability, apoptosis, and mitochondrial membrane potential was investigated in vitro using AML cell lines and primary cells. High-throughput mRNA sequencing was used to analyze mRNA level changes after the application of HHT and venetoclax on OCI-AML3 cells. Western blotting was used to verify the changes in protein expression within the mitogenactivated protein kinases/extracellular signal-regulated kinase (MAPK/ERK), phosphatidylinositiol 3-kinase (PI3K)/AKT and p53 pathway. The efficacy of HHT and venetoclax in vivo and their effects on survival time were evaluated in a xenograft model established in severe immunodeficiency (NOD/SCID) mice. Results: Venetoclax and HHT synergistically inhibited the proliferation of AML cells, decreased the mitochondrial membrane potential, and promoted AML cell apoptosis in a time-and concentrationdependent manner. Venetoclax combined with HHT increased the expression of the caspase-3, Poly (ADPribose) polymerase (PARP), and γH2AX proteins. HHT enhanced the proapoptotic effect of venetoclax by reducing the expression of myeloid cell leukemia sequence 1 (Mcl-1). HHT arrested AML cells in G1 phase of the cell cycle. HHT enhanced the proapoptotic effect of venetoclax by inhibiting the activation of the MAPK/ERK and PI3K/AKT pathways and activating the p53 pathway. In vivo experiments confirmed that the combination of HHT and venetoclax could inhibit the growth of tumors in AML xenotransplanted mice and prolong the survival time of tumor-bearing mice. Conclusions: HHT combined with venetoclax synergistically promoted apoptosis in AML cell lines and primary cells by inhibiting the activation of the MAPK/ERK and PI3K/AKT pathways and activating the p53 pathway.

No abstract

Background: Acute myeloid leukemia (AML) is a hematological malignancy with a low remission rate and high recurrence rate. Overexpression of the antiapoptotic protein Bcl-2 is associated with a lower overall survival rate in AML patients. Venetoclax (ABT199) is a selective inhibitor of Bcl-2 that has a significant effect in AML, but single-drug resistance often occurs due to the high expression of Mcl-1 protein. Studies have confirmed that chidamide can downregulate the expression levels of Bcl-2 and Mcl-1 and induce apoptosis. Methods: This study aimed to use AML cell lines and primary cells to study the effects of venetoclax and chidamide combination therapy on AML cell apoptosis, the cell cycle, and changes in related signaling pathways in vitro; establish an AML mouse model to observe the efficacy and survival time of combination therapy in vivo; and analyze the drug effects with multi-omics sequencing technology. The changes in gene and protein expression before and after treatment were examined to clarify the molecular mechanism driving the synergistic effect of the two drugs. Results: (I) Both venetoclax and chidamide promoted apoptosis in AML cell lines and primary cells in a time-and concentration-dependent manner. The effect was further enhanced when the two drugs were combined, and a synergistic effect was observed (combination index <1). (II) At both the mRNA and protein levels, the expression of Mcl-1 was upregulated by venetoclax and downregulated by chidamide, and the expression of Mcl-1 decreased further after combination treatment. (III) Transcriptome sequencing showed that differentially expressed genes in the combination group compared with the venetoclax monotherapy group were mainly enriched in the PI3K-AKT pathway and JAK2/STAT3 pathway. Moreover, qRT-PCR and Western blot confirmed these results. (IV) The combination therapy group exhibited significantly inhibited disease progression and a prolonged survival time among AML mice. Conclusions: Chidamide combined with venetoclax synergistically promoted apoptosis in AML cell lines and primary cells by inhibiting activation of the PI3K/AKT pathway and JAK2/STAT3 pathway.

Background: Cuproptosis is the recently defined regulatory cell death (RCD) that plays essential roles in tumorigenesis and progression. Long noncoding RNAs (lncRNAs) regulate the gene expression through various means. However, the clinical value of cuproptosis-related lncRNAs in bladder cancer (BLCA) remains poorly described. Methods:We downloaded the transcriptome sequencing data and clinical information from The Cancer Genome Atlas (TCGA) database. Univariate, multivariate, and lasso Cox regression analyses were performed to construct the prognostic risk signature, the predictive accuracy of which was validated in the subsequent independence and stratification analyses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to explore the underlying molecular mechanisms involved in the signature to explore therapeutic vulnerabilities and potential targets in BLCA. Tumor mutational burden (TMB) and tumor immune dysfunction and exclusion (TIDE) were used to estimate the response to immune checkpoint inhibitors (ICIs). We further explored the potential new drug-target candidates based on the half maximal inhibitory concentration for this patient population.Results: Fifteen cuproptosis-related lncRNAs significantly associated with survival were identified to construct the risk signature based on the normalized expression level and regression coefficient of each gene.The patients with BLCA and high-risk scores defined by the signature were associated with worse survival outcomes. The differentially expressed genes (DEGs) between the 2 risk groups had different biological activity. Furthermore, the patients in the low-risk group exhibited a higher TMB index and a lower TIDE score. The sensitivity of multiple antitumor drugs was negatively related to risk score, including AR-42, AS605240, FK866, TAK-715, and tubastatin A, while the sensitivity of some antitumor drugs, such as AMG-706, BX-795, and RO-3306, were positively correlated with risk score.Conclusions: Our study established and verified a novel clinical risk signature with cuproptosis-related lncRNAs that may predict therapy response and prognosis with robust and stable accuracy in patients with BLCA and enhance the personalized management of this patient population.