Cancer cells show increased glycolysis and take advantage of this metabolic pathway to generate ATP. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits aerobic glycolysis and protects tumor cells from intracellular reactive oxygen species (ROS)-associated apoptosis. However, the function of TIGAR in glycolysis and survival of acute myeloid leukemia cells remains unclear. We analyzed TIGAR expression in cytogenetically normal (CN-) AML patients and the correlations with clinical and biological parameters. In vivo and in vitro, we tested whether glycolysis may induce TIGAR expression and evaluated the combination effect of glycolysis inhibitor and TIGAR knockdown on human leukemia cell proliferation. High TIGAR expression was an independent predictor of poor survival and high incidence of relapse in adult patients with CN-AML. TIGAR also showed high expression in multiple human leukemia cell lines and knockdown of TIGAR activated glycolysis through PFKFB3 upregulation in human leukemia cells. Knockdown of TIGAR inhibited the proliferation of human leukemia cells and sensitized leukemia cells to glycolysis inhibitor both in vitro and in vivo. Furthermore, TIGAR knockdown in combination with glycolysis inhibitor 2-DG led leukemia cells to apoptosis. In addition, the p53 activator Nutlin-3α showed a significant combinational effect with TIGAR knockdown in leukemia cells. However, TIGAR expression and its anti-apoptotic effects were uncoupled from overexpression of exogenous p53 in leukemia cells. TIGAR might be a predictor of poor survival and high incidence of relapse in AML patients, and the combination of TIGAR inhibitors with anti-glycolytic agents may be novel therapies for the future clinical use in AML patients.

Almonertinib is the initial third-generation EGFR-TKI in China, but its resistance mechanism is unknown. Cancer-associated fibroblasts (CAFs) are essential matrix components in the tumor microenvironment, but their impact on almonertinib resistance is unknown. This study aimed to explore the correlation between CAFs and almonertinib resistance in non-small cell lung cancer (NSCLC). The anti-cancer effects of almonertinib on NSCLC cells, as well as the reversal of these effects mediated by CAFs, were validated through phenotypic experiments. Differential gene expression analysis, along with GO and KEGG enrichment analyses, was performed to predict the potential mechanisms underlying resistance to third-generation EGFR-TKIs. Finally, qPCR and Western blot analyses were used to explore the signaling pathways by which CAFs induce resistance to almonertinib in NSCLC cells. Our findings revealed that almonertinib significantly suppressed the invasion, migration, and proliferation of EGFR T790M-mutant NSCLC cells. TGF-β1 successfully induced the differentiation of CAFs and upregulated the expression of CAF markers, including α-SMA and fibroblast activation protein (FAP). Exposure of H1975 cells to almonertinib increased TGF-β1 secretion. Additionally, CAFs enhanced the survival of almonertinib-treated NSCLC cells, whereas normal fibroblasts (NFs) exerted the opposite effect. qPCR analysis demonstrated that the expression of the core molecules of the Hippo pathway, YAP and TAZ, was lower in A549 cells than in H1975 cells, and CAF intervention further reduced YAP/TAZ expression in H1975 cells. Western blot analysis confirmed a significant reduction in YAP/TAZ protein levels in cancer cells treated with CAF-conditioned medium (CAF-CM) compared to those treated with normal control-conditioned medium (NC-CM). Finally, we demonstrated that CAFs induced resistance to almonertinib in NSCLC cells, potentially through a mechanism involving YAP/TAZ. This study demonstrated that H1975 cells stimulated by almonertinib promoted the accumulation of CAFs in NSCLC cells, likely through increased secretion of TGF-β1. The accumulation of CAFs enhanced the survival of NSCLC cells undergoing almonertinib treatment and induced drug resistance. Additionally, the mechanism underlying CAF-induced drug resistance in NSCLC cells was potentially linked to the activation of the YAP/TAZ signaling pathway.

Definite prognostic clinical factors of benefit for decitabine-based induction chemotherapy in elderly patients newly diagnosed with acute myeloid leukaemia (AML) are not identified. This study was designed to explore the potential biomarker, especially regeneration of haematopoiesis, of treatment response and survival in elderly patients with newly diagnosed AML. We analysed the clinical data of 117 elderly AML patients who were treated with a decitabine dose of 15 mg/m2 for 5 days, granulocyte colony-stimulating factor of 300 μg/d for priming, plus cytarabine 10 mg/m2 q12h for 7 days and aclarubicin 10 mg/d for 4 days (D-CAG). After initial induction chemotherapy, the overall response rate and complete remission (CR) were 71.8% and 58.1%, respectively. Patients responding to the D-CAG regimen achieved higher platelet counts on day 14 after initial treatment (p < 0.001). Median counts were 59.5 × 109/L in the CR group, 37 × 109/L in the partial remission group and 28 × 109/L in the non-responsive group. We then classified patients into those who achieved platelet counts≥60 × 109/L or 100 × 109/L on day 14 after D-CAG vs. those who did not. Platelet counts≥60 × 109/L or 100 × 109/L on day 14 were significantly associated with superior CR, overall survival and disease-free survival (80.9% vs. 45.3% p < 0.001,16.5 vs. 9.1 months p = 0.009 and 16.3 vs. 7.4 months p = 0.024; 85.2% vs. 50% p = 0.001, 31 vs. 10.1 months p = 0.003 and 16.9 vs. 8.9 months p = 0.006). Multivariate analysis confirmed that poor cytogenetics (p = 0.010) and FLT3-ITD mutation (p = 0.007) were identified as independent factors of OS, but not platelet count (p = 0.091). However, platelet count≥100 × 109/L on day 14 was an independent prognostic factor of CR and DFS. Platelet count recovery on day 14 after D-CAG induction chemotherapy is associated with response. D-CAG regimen was registered on ChicTR with number 11001700 .

Background Almonertinib is a third-generation EGFR-TKI, and studies on its resistance mechanisms are lacking. Cancer-associated fibroblasts (CAFs) can influence resistance to targeted therapeutics, but their role and mechanism of action in relation to almonertinib resistance are unclear. The study explored relationships among glycolysis, cancer-associated fibroblasts (CAFs), and almonertinib resistance. Methods A dose-escalation method was used to develop the almonertinib-resistant cell line H1975AR. Hexokinase 2 (HK2) effects on almonertinib resistance were evaluated using Cell Counting Kit-8 assays, transcriptome sequencing, western blotting, real-time PCR, siRNA assays, glucose consumption, and lactate production assays. Differential gene expression analysis and siRNA assays in H1975 cells cultured with CAF-conditioned medium (H1975/CAF-CM) revealed S-phase kinase-associated protein 2 (SKP2) as a target driving the effects of HK2. The impact of almonertinib and HK2 inhibitors on H1975/CAF-CM cells was assessed using colony formation, wound healing, transwell, and flow cytometry apoptosis assays. Results H1975AR cells displayed elevated glycolysis and HK2. Subsequently, we showed that knockdown reduced almonertinib resistance in cells. H1975/CAF-CM induced almonertinib resistance and upregulation of HK2, which was reversed by knockdown of SKP2. CAFs regulate HK2-mediated glycolysis through SKP2, promoting almonertinib resistance in NSCLC. Conclusions CAFs regulate HK2-mediated glycolysis through SKP2, which promotes almonertinib resistance in NSCLC.

This retrospective study was designed to describe the clinical characteristics and prognosis of human immunodeficiency virus (HIV)-infected diffuse large B-cell lymphoma (DLBCL) patients. We retrospectively enrolled 31 patients newly diagnosed with HIV-infected DLBCL from 2009 to 2019 in our institution. The median age of patients was 47 years, and most patients were male ( n = 27, 87.1%). Baseline mean CD4⁺ count was 150.72 ± 146.57/μl. Eighteen (58.1%) patients had B symptoms. Categorized by international prognostic index (IPI) score, 7 cases (22.6%) were in low-risk group (IPI 0-1) and 24 cases (77.4%) were in medium-high risk group (IPI 2-5). Twenty-five (80.6%) patients received highly active antiretroviral therapy (HAART) and 16 (51.6%) underwent standard chemotherapy. The mortality rate was 58.1% (18/31). Univariate survival analysis revealed that HCV infection ( p = 0.032), standard chemotherapy treatments ( p = 0.038) were associated with overall survival (OS). Our results showed that HIV-infected DLBCL patients had high-risk stratification and high mortality. HCV-coinfection might be associated with poor OS. Early diagnosis and standardized treatments might be beneficial for promoting the survival of HIV-infected DLBCL patients.

Background Circular RNAs (circRNAs) play critical roles in tumorigenesis. However, their function in cisplatin (CDDP) resistance of non-small cell lung cancer (NSCLC) remains incompletely understood. We aimed to investigate the expression pattern of hsa_circ_0135681 in NSCLC and its role in regulating cisplatin resistance. Method RNA sequencing was performed on serum samples to identify differentially expressed circRNAs (DEcircRNAs) using thresholds of |log2FC| >1 and p < 0.05. We validated candidate DEcircRNAs via quantitative real-time PCR (qRT-PCR) in NSCLC tissues. We conducted functional assays, including CCK-8 proliferation, wound healing assay, and flow cytometry apoptosis analysis. Finally, nude mouse xenograft models were used to investigate the role of circRNA in vivo. In mechanistic investigations, lactate and glucose detection kits were used, with subsequent validation conducted via Western blot (WB) and qRT-PCR. Results A total of 411 DEcircRNAs were identified in serum samples, and the 9 selected candidate DEcircRNAs were further validated in NSCLC tissues. Among these, hsa_circ_0135681 was significantly downregulated in NSCLC tissues compared to adjacent non-cancerous tissues. Overexpression of hsa_circ_0135681 could inhibit the proliferation and migration of A549/DDP cells, induce apoptosis in vitro, and similarly suppress tumorigenesis in vivo. Mechanistically, hsa_circ_0135681 overexpression reduced glycolytic activity and reversed EMT in A549/DDP cells. Additionally, bioinformatics analysis predicted two potential regulatory axes: hsa_circ_0135681/hsa-miR-4299/RNF180 and hsa_circ_0135681/hsa-miR-4299/SOCS5. Conclusion Collectively, hsa_circ_0135681 is a tumor-suppressive circRNA that modulates glycolysis and EMT. These findings may provide a potential therapeutic target for cisplatin-resistant NSCLC.