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BackgroudActivation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL.MethodsA cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells.ResultsALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK.ConclusionsOverexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.

The t(5;17)/NPM-RARalpha is the second variant chromosomal translocation in acute promyelocytic leukemia (APL) to be characterized and also the second most plentiful variant translocation. So far, there is a lack of information on the effectiveness of arsenic trioxide (ATO) in relapsed APL with variant RARalpha chimera including t(5;17)/NPM-RARalpha. We report here a long-term survived APL patient with variant NPM-RARalpha fusion who relapsed four times and each time responded well to ATO or ATO-based re-induction therapy. The patient had received a total of more than 3,500 mg of ATO, but showed no obvious arsenic-related toxicities. This case illustrates the long-term efficiency and safety of ATO-based therapy not only in newly diagnosed APL, but also in relapsed APL including those with variant translocations.

The requirements for high energy and green primary explosives are more and more stringent because of the rising demand in the application of micro initiation explosive devices. Four new energetic compounds with powerful initiation ability are reported and their performances are experimentally proven as designed, including non‐perovskites ([H2DABCO](H4IO6)2·2H2O, named TDPI‐0) and perovskitoid energetic materials (PEMs) ([H2DABCO][M(IO4)3]; DABCO=1,4‐Diazabicyclo[2.2.2]octane, M=Na+, K+, and NH4+ for TDPI‐1, ‐2, and ‐4, respectively). The tolerance factor is first introduced to guide the design of perovskitoid energetic materials (PEMs). In conjunction with [H2DABCO](ClO4)2·H2O (DAP‐0) and [H2DABCO][M(ClO4)3] (M=Na+, K+, and NH4+ for DAP‐1, ‐2, and ‐4), the physiochemical properties of the two series are investigated between PEMs and non‐perovskites (TDPI‐0 and DAP‐0). The experimental results show that PEMs have great advantages in improving the thermal stability, detonation performance, initiation capability, and regulating sensitivity. The influence of X‐site replacement is illustrated by hard–soft‐acid–base (HSAB) theory. Especially, TDPIs possess much stronger initiation capability than DAPs, which indicates that periodate salts are in favor of deflagration‐to‐detonation transition. Therefore, PEMs provide a simple and feasible method for designing advanced high energy materials with adjustable properties.