Objective:To investigate the anti-leukemic effects and resistance mechanisms of venetoclax in acute myeloid leukemia (AML). Genomic, transcriptomic, and clinical data from AML patients who underwent venetoclax drug sensitivity testing were downloaded from the Beat AML database. Correlation analysis was performed between these data and venetoclax sensitivity outcomes. Differentially expressed genes (DEGs) associated with venetoclax sensitivity were identified from transcriptomic data and subsequently validated using GEO database transcriptomic results and in vitro experiments (including Western blot). Functional enrichment analyses (KEGG and GSEA), transcription factor enrichment analysis (KnockTF), and data from public databases were employed to further investigate key genes and pathways influencing drug sensitivity.Results:After filtering the Beat AML cohort, data from 52 patient samples with available in vitro venetoclax sensitivity results were included for analysis. Patients with FLT3 mutations exhibited greater sensitivity to venetoclax compared to those with FLT3 wild-type. Correlation analysis between clinical information and drug sensitivity data indicated that higher peripheral blood tumor burden was associated with increased sensitivity to venetoclax. Transcriptomic analysis and in vitro experiments confirmed that venetoclax inhibits the FLT3-related signaling pathway, including downregulation of FLT3 expression and reduced phosphorylation of its downstream targets AKT and STAT5. KEGG pathway and KnockTF transcription factor enrichment analyses indicated that venetoclax resistance was associated with increased transcriptional activity of FOXM1 and STAT3. Moreover, high expression of FOXM1 and STAT3 correlated with shorter overall survival in patients.Conclusion:Venetoclax can inhibit the activation of FLT3-related signaling pathways. The activation of STAT3 and FOXM1 transcription factors is a potential key mechanism contributing to venetoclax resistance in AML.

Objective:To investigate the anti-leukemic effects and resistance mechanisms of venetoclax in acute myeloid leukemia (AML). Genomic, transcriptomic, and clinical data from AML patients who underwent venetoclax drug sensitivity testing were downloaded from the Beat AML database. Correlation analysis was performed between these data and venetoclax sensitivity outcomes. Differentially expressed genes (DEGs) associated with venetoclax sensitivity were identified from transcriptomic data and subsequently validated using GEO database transcriptomic results and in vitro experiments (including Western blot). Functional enrichment analyses (KEGG and GSEA), transcription factor enrichment analysis (KnockTF), and data from public databases were employed to further investigate key genes and pathways influencing drug sensitivity.Results:After filtering the Beat AML cohort, data from 52 patient samples with available in vitro venetoclax sensitivity results were included for analysis. Patients with FLT3 mutations exhibited greater sensitivity to venetoclax compared to those with FLT3 wild-type. Correlation analysis between clinical information and drug sensitivity data indicated that higher peripheral blood tumor burden was associated with increased sensitivity to venetoclax. Transcriptomic analysis and in vitro experiments confirmed that venetoclax inhibits the FLT3-related signaling pathway, including downregulation of FLT3 expression and reduced phosphorylation of its downstream targets AKT and STAT5. KEGG pathway and KnockTF transcription factor enrichment analyses indicated that venetoclax resistance was associated with increased transcriptional activity of FOXM1 and STAT3. Moreover, high expression of FOXM1 and STAT3 correlated with shorter overall survival in patients.Conclusion:Venetoclax can inhibit the activation of FLT3-related signaling pathways. The activation of STAT3 and FOXM1 transcription factors is a potential key mechanism contributing to venetoclax resistance in AML.

Among current novel druggable targets, protein–protein interactions (PPIs) are of considerable and growing interest. Diacylglycerol kinase α (DGKα) interacts with focal adhesion kinase (FAK) band 4.1-ezrin-radixin-moesin (FERM) domain to induce the phosphorylation of FAK Tyr397 site and promotes the malignant progression of esophageal squamous cell carcinoma (ESCC) cells. Chrysin is a multi-functional bioactive flavonoid, and possesses potential anticancer activity, whereas little is known about the anticancer activity and exact molecular mechanisms of chrysin in ESCC treatment. In this study, we found that chrysin significantly disrupted the DGKα/FAK signalosome to inhibit FAK-controlled signaling pathways and the malignant progression of ESCC cells both in vitro and in vivo, whereas produced no toxicity to the normal cells. Molecular validation specifically demonstrated that Asp435 site in the catalytic domain of DGKα contributed to chrysin-mediated inhibition of the assembly of DGKα/FAK complex. This study has illustrated DGKα/FAK complex as a target of chrysin for the first time, and provided a direction for the development of natural products-derived PPIs inhibitors in tumor treatment.

Objective To investigate the clinical characteristics and efficacy of acute myeloid leukemia (AML) with NPM1 and FLT3 mutations.Methods NPM1 and FLT3 mutations were detected in 67 patients with newly diagnosed AML by PCR-capillary electrophoresis.The relationship was analyzed between the mutations and efficacy.Results The incidence of NPM1 mutation was 10.4％ (7/67) in total AML patients and 26.1％ (6/23) in normal karyotypes AML patients.The incidence of FLT3-ITD mutation was 10.4％ (7/67) in total AML patients and 17.4％ (4/23) in normal karyotypes AML patients.The characteristics of 60 NPM1 wild type patients vs that of 7 NPMl mutation patients was as follow,platelet count (BPC) (54× 109/L vs.27.5 × 109/L,P ＜ 0.01),proportion of AML-M5 (57.1％ vs.27.3％,P ＜ 0.01),incidence of CD34+ (28.6％ vs.63.3％,P＜0.01),normal karyotypes (85.7％ vs.28.3％,P＜0.01),cases with particular fusion gene (0 vs.48.3％,P ＜ 0.01),incidence of FLt3-1TD-mutations positive (28.6％ vs.8.3％,P ＜ 0.01),and the differences were significant (P＜0.01).No statistic difference was found in white blood cell(WBC) counts,percentage of blasts in bone marrow,sex,median age and complete remission rate between the two groups (P ＞0.05).The WBC counts (26.9 × 109/L vs.8.1 × 109/L,P =0.013),percentage of blastsin in bone marrow (90％ vs.76％,P=0.014) in the FLT3-ITD mutationg positive patients were clearly higher than those in the FLT3-ITD negative patients.If not associated with FLT3-ITD mutations,mutant NPM1 appears to identify patients with improved response toward treatment.Conclusion It is necessary to detect NPM1 mutation and FLT3-ITD mutation in newly diagnosed AML patients,especially in patients with normal karyotype,which might help to molecular classification and treatment.

Objective: To investigate the candidal infection status in puerperas in Lanzhou, and the candidal transmission from mothers to their newborn infants. Methods: Vaginal fluid and saliva samples from 104 puerperas, as well as 104 saliva samples from their newborn infants were collected. The Candida species were cultured, isolated and identified using CHROMagar media. Further identification was done using molecular biological method. Results; In 81 of 312 specimens (104 x2 from mothers and 104 from infants), Candida species were found. 39.42% (41 cases) was observed in the vaginal fluid and 33.65% (35 cases) was in saliva of puerperas respectively, and 21. 15% (22 cases) in both vagina and oral cavity. 4.81% (5 cases) was found in oral cavities of newborn infants. The distribution of Candida species were 53 Candida albicans, 33 Candida glabrata, 2 Candida krusei and 1 Candida tropical. In 2 pairs of mother-infant, the same genotype of Candida ablicans was identified using PCR method. Conclusion; The Candida detection rate of newborn infants and transmission rate from mothers to their neonates in Lanzhou are higher than that reported in other areas. The colonization of Candida in newborn infants is relevant to both horizontal and vertical transmission. It can decrease the possibility of Candidal infection in newborn infants by controlling the Candidal transmission in hospital and preventing the infection in pregnant women.