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Abstract Background Our previous works have demonstrated that 8-bromo-7-methoxychrysin suppressed stemness of human hepatocellular carcinoma (HCC) cell line SMMC-7721 induced by condition medium from hepatic stellate cell line LX-2 that was activated by liver cancer stem-like cells (LCSCs). However, whether and whereby BrMC inhibits the stemness induced by co-culture of LCSCs and LX-2 cells remains to be investigated. Methods The second-generation spheres by sphere culture were identified and used as SMMC-7721-and MHCC97H-derived LCSLCs. SMMC-7721-and MHCC97-derived LCSCs/LX-2 cells transwell co-culture system was treated with BrMC and its lead compound chrysin. The concentrations of IL-6, IL-8, HGF and PDGF in condition medium from co-culture were measured by enzyme-linked immunosorbent assay (ELISA). The stemness of SMMC-7721 cells was evaluated by sphere formation assay and western blot analysis for expression levels of cancer stem cell markers (CD133 and CD44).The expression levels of cancer-associated fibroblast markers (FAP-α and α-SMA) were employed to evaluate pathologic activation of LX-2 cells. Addition of IL-6 and/or HGF or deletion of IL-6 and/or HGF was conducted to investigate the mechanisms for BrMC and chrysin treatment in SMMC-7721-derived LCSLCs co-cultured with LX-2cells. Results The co-culture of LCSLCs with LX-2 cells increased sphere formation capability as well as expression of CD133 and CD44 in SMMC-7721 cells, meanwhile, upregulated expression of FAP-α in LX-2 cells. ELISA indicated that the concentrations of IL-6 and HGF were significantly elevated in Co-CM than that of condition media from co-cultured SMMC-7721 cells/LX-2 cells. Treatment of BrMC and chrysin with co-cultures of SMMC-7721- and MHCC97H-derived LCSLCs and LX-2 cells effectively inhibited the above responses. Moreover, addition of IL-6 and/or HGF induced stemness of SMMC-7721 cells and activation of LX-2 cells, conversely, deletion of IL-6 and/or HGF suppressed those. Furthermore, the inhibitory effects of BrMC and chrysin on stemness of SMMC-7721 cells and activation of LX-2 cells were attenuated by addition of IL-6 or HGF, and enhanced by deletion of IL-6 or HGF. Conclusions Our results suggest IL-6 and HGF may be the key communication molecules for the interaction between LCSLCs and HSCs, and BrMC and chrysin could block these effects and be the novel therapeutic candidates for HCC management.

Introduction: Echocardiographic assessment of diastolic function during atrial fibrillation (AF) remains challenging due to the irregular cardiac cycle length. We sought to assess whether the index-beat method, the beat following two preceding cardiac cycles of equal duration, could provide a more reliable measurement of E/e′ (mitral E wave/diastolic tissue Doppler velocity) than the conventional averaging of consecutive beats and hence facilitate the noninvasive estimation of elevated left atrial pressure (LAP) in patients with AF. Methods: We prospectively studied 35 patients with persistent AF who had preserved left ventricular ejection fraction and underwent radiofrequency ablation. LAP was measured in conjunction with transseptal puncture during catheter ablation. Echocardiography was performed 24 h before ablation and E/e′ was determined using the recommended averaging of 10 beats and the index-beat method, with the observers blinded to the clinical details and LAP measurements. Results: Correlation analysis showed a strong positive correlation between two methods in terms of both septal E/e′ (r = 0.841, p < 0.001) and lateral E/e′ (r = 0.930, p < 0.001). Bland-Altman analysis also showed a good agreement between the two measurement methods in terms of E/e′. E/e′ determined using both conventional averaging and the index-beat method was significantly correlated with LAP (p < 0.05). After Fisher Z transformation, we found that the index-beat septal E/e′ had a better correlation with LAP than did the conventional averaging E/e′ (r = 0.736 vs. r = 0.392, Zr = −2.110, p = 0.035). Furthermore, the index-beat method took significantly less time to measure E/e′ (mean 33.6 s; 95% confidence intervals [CIs]: 32.1 s–36.2 s) than did conventional averaging method (mean 96.2 s; 95% CI: 90.2 s–102.3 s; p < 0.001). Receiver operating characteristic curve analysis revealed that the optimal cut-off for predicting mean LAP >12 mm Hg was 11 (sensitivity 100%; specificity 77.3%) for index-beat septal E/e′ and 16 (sensitivity 61.5%; specificity 95.5%) for index-beat lateral E/e′. Conclusions: Good correlations were found between E/e′ and LAP in patients with AF, particularly with the index-beat method. Moreover, the index-beat method can easily measure E/e′ at an accuracy similar to that for the conventional averaging of consecutive beats, which can therefore be applied to assess the diastolic dysfunction and potentially improve the diagnosis of heart failure in patients with AF. [ABSTRACT FROM AUTHOR]

As an epitranscriptomic modulation manner, N6‐methyladenosine (m6A) modification plays important roles in various diseases, including hepatocellular carcinoma (HCC). m6A modification affects the fate of RNAs. The potential contributions of m6A to the functions of RNA still need further investigation. In this study, we identified long noncoding RNA FAM111A‐DT as an m6A‐modified RNA and confirmed three m6A sites on FAM111A‐DT. The m6A modification level of FAM111A‐DT was increased in HCC tissues and cell lines, and increased m6A level was correlated with poor survival of HCC patients. m6A modification increased the stability of FAM111A‐DT transcript, whose expression level showed similar clinical relevance to that of the m6A level of FAM111A‐DT. Functional assays found that only m6A‐modified FAM111A‐DT promoted HCC cellular proliferation, DNA replication, and HCC tumor growth. Mutation of m6A sites on FAM111A‐DT abolished the roles of FAM111A‐DT. Mechanistic investigations found that m6A‐modified FAM111A‐DT bound to FAM111A promoter and also interacted with m6A reader YTHDC1, which further bound and recruited histone demethylase KDM3B to FAM111A promoter, leading to the reduction of the repressive histone mark H3K9me2 and transcriptional activation of FAM111A. The expression of FAM111A was positively correlated with the m6A level of FAM111A‐DT, and the expression of methyltransferase complex, YTHDC1, and KDM3B in HCC tissues. Depletion of FAM111A largely attenuated the roles of m6A‐modified FAM111A‐DT in HCC. In summary, the m6A‐modified FAM111A‐DT/YTHDC1/KDM3B/FAM111A regulatory axis promoted HCC growth and represented a candidate therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

Let X and Y be two pointed metric spaces. In this article, we give a generalization of the Cheng–Dong–Zhang theorem for coarse Lipschitz embeddings as follows: If f:X → Y is a standard coarse Lipschitz embedding, then for each x* ∈ Lip0(X) there exist α, γ > 0 depending only on f and Qx* ∈ Lip0(Y) with ‖ Q x * ‖ L i p ≤ α ‖ x * ‖ L i p such that | Q x * f (x) − x * (x) | ≤ γ ‖ x * ‖ L i p , f o r a l l x ∈ X. Coarse stability for a pair of metric spaces is studied. This can be considered as a coarse version of Qian Problem. As an application, we give candidate negative answers to a 58-year old problem by Lindenstrauss asking whether every Banach space is a Lipschitz retract of its bidual. Indeed, we show that X is not a Lipschitz retract of its bidual if X is a universally left-coarsely stable space but not an absolute cardinality-Lipschitz retract. If there exists a universally right-coarsely stable Banach space with the RNP but not isomorphic to any Hilbert space, then the problem also has a negative answer for a separable space. [ABSTRACT FROM AUTHOR]