Bin Qu

Due to the high mortality and hospitalization rate in chronic heart failure (HF), it is of great significance to study myocardial nutrition conditions. Amino acids (AAs) are essential nutrient metabolites for cell development and survival. This study aims to investigate the associations and prognostic value of plasma branched-chain amino acid/aromatic amino acid ratio (Fischer’s ratio, FR) in patients with left ventricular ejection fraction (LVEF) ≤ 50%. The value of serum AAs was obtained from 441 cardiovascular patients by liquid chromatography-tandem, including 213 HF patients [all LVEF ≤ 50%, E/e’>14 (n = 101) and E/e’≤14 (n = 112)], and 228 controls without HF [(excluding HF with preserved ejection fraction (EF)]. Two-dimensional echocardiography and Doppler flow imaging determined LVEF and the ratio of early diastolic mitral inflow to mitral annular tissue velocities (E/e’). The abnormal LVEF (≤ 50%) refers to the definition of HF with reduced, mildly reduced, or improved EF. The logistic regression analysis was conducted to measure the FR index and the risk of cardiac dysfunction, and further confirmed by receiver-operating characteristic curves (ROC curve) analysis. In the prospective study, the 188 HF patients were followed up for a mean year (11.74 ± 1.44 months). The event-free HF endpoint or HF readmission was determined by Kaplan–Meier curves, and differences were assessed using log‐rank tests, respectively. Cox regression analysis was used to further assess the prognostic value of FR in HF. FR index decreased gradually along with the control group, HF with E/e’≤14 group, and HF with E/e’>14 group (3.73 ± 1.20 vs. 3.45 ± 0.94 vs. 3.18 ± 0.83, respectively, P < 0.001). Low FR index was associated with HF after full adjustment in all patients [odds ratio (OR): 2.072; 95% confidence interval (CI): 1.546–2.776; P < 0.001]. Meanwhile, low FR index was the independent risk factor for E/e’>14 in HF patients (OR:1.659; 95% CI:1.125–2.446; P = 0.011). The area under the ROC curve for predicting abnormal E/e’ was 0.762 (sensitivity 75.51%, specificity 65.05%) by multivariate logistic regression. Furthermore, the decreased FR values indicated poor HF endpoint or HF readmission in HF patients (all Log-rank P < 0.01). The Cox regression analysis showed that low FR tertiles remained correlated to the risk of HF endpoint [hazard ratio (HR): 1.949; 95% CI: 1.006–3.778; P = 0.048]. In all patients, low FR confers an increased risk for predicting HF. Decreased FR levels could also indicate increased left ventricular (LV) filling pressure in HF. In addition, a lower FR value was associated with higher HF endpoint events. Thus, FR can be a valuable indicator of heart function.

MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated. MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function. As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies.

Background: Previous studies suggest S100A9 is a promising biomarker for prognosis in cancer, including hepatocellular carcinoma (HCC). We examined the utility of serum S100A9 in predicting prognosis in HCC after curative resection.

MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis. As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.