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Objective: Cerebral circulation time (CCT) and collateral score (CS) are associated with functional outcomes in acute ischemic stroke (AIS) patients after endovascular treatment (EVT), and may be related to each other. We aim to determine the relationship between CS and CCT on functional outcomes. Methods: We retrospectively enrolled consecutive patients with anterior circulation large vessel occlusion (LVO) AIS who received EVT. CS and CCT were measured based on digital subtraction angiography (DSA). We defined CS 0–2 and 3–4 as poor and good collateral status, respectively, and used change of CCT (cCCT), which was defined as the change of stroke side CCT (sCCT) versus healthy side CCT (hCCT). Mediating analysis was used to evaluate the influence of cCCT on the association between CS and functional outcomes, and ROC curves were further used to explore the predictive ability of the interaction between cCCT and CS for functional outcomes. Results: A total of 100 patients were enrolled in the final analysis. A higher cCCT (r = −0.239; p = 0.017) was associated with lower CS, and cCCT mediated the association of CS with functional outcome. Logistic regression analysis found that CS, cCCT and cCCT‐CS interactions were independently associated with functional outcome, and cCCT‐CS interaction has better predictive performance, with a higher area under curve value than CS or cCCT alone (0.79 vs. 0.75 or 0.75). Interpretation: To our knowledge, this study provides the first report of the association of collateral status with cCCT, and their interaction effect on functional outcome in AIS‐LVO patients receiving EVT. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemias (T-ALLs) are clonal lymphoid malignancies with a poor prognosis, and still a lack of effective treatment. Here we examined the interactions between the mammalian target of rapamycin (mTOR) inhibitor rapamycin and idarubicin (IDA) in a series of human T-ALL cell lines Molt-4, Jurkat, CCRF-CEM and CEM/C1. Co-exposure of cells to rapamycin and IDA synergistically induced T-ALL cell growth inhibition and apoptosis mediated by caspase activation via the intrinsic mitochondrial pathway and extrinsic pathway. Combined treatment with rapamycin and IDA down-regulated Bcl-2 and Mcl-1, and inhibited the activation of phosphoinositide 3-kinase (PI3K)/mTOR and extracellular signal-related kinase (ERK). They also played synergistic pro-apoptotic roles in the drug-resistant microenvironment simulated by mesenchymal stem cells (MSCs) as a feeder layer. In addition, MSCs protected T-ALL cells from IDA cytotoxicity by up-regulating ERK phosphorylation, while rapamycin efficiently reversed this protective effect. Taken together, we confirm the synergistic antitumor effects of rapamycin and IDA, and provide an insight into the potential future clinical applications of combined rapamycin-IDA regimens for treating T-cell malignancies. [ABSTRACT FROM AUTHOR]

Objective: To investigate the cytotoxic effects of mTOR inhibitor rapamycin (Rapa) and idarubicin (IDA) on human T-cell acute lymphoblastic leukemia Jurkat cell line., Methods: The proliferation of Jurkat cells was observed by CCK-8 assay. The combined index was analyzed by Isobologram method. Apoptosis was detected by electron microscopy and flow cytometry with Annexin V/PI staining. Protein expressions of Caspase 3, PARP, Caspase 8, Caspase 9, Akt, p-Akt, P85S6K, p-P85S6K, P70S6K, p-P70S6K, ERK1/2 and p-ERK1/2 were determined by Western blotting., Results: The IC(50) of IDA for Jurkat cells was significantly reduced when combined with 10 nmol/L rapamycin. The combined index was <1. Both electron microscopy and Annexin V/PI staining flow cytometry revealed that rapamycin significantly increased apoptotic sensitivity to IDA. The combination of IDA with rapamycin enhanced the expressions of Caspase 3, PARP, Caspase 8 and Caspase 9. Rapamycin significantly inhibited mTOR signaling upstream Akt and downstream S6K activation triggered by IDA, and the combination of the two agents led to synergistic inhibition of ERK phosphorylation., Conclusion: Combination of IDA with rapamycin exerted a synergistic anti-proliferative effect and promoted apoptosis by both extrinsic and intrinsic apoptotic pathways in Jurkat cells. Inhibition of ERK phosphorylation and mTOR signaling by rapamycin may play a certain role in this synergistic effect.