RESUMO
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RESUMO
Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 and K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation. We therefore tested the combination of these two agents in AML models. The combination treatment resulted in synergistic growth inhibition of AML cells, accompanied by enhanced transdifferentiation of an erythroid leukemia lineage into granulomonocytic-like lineage cells. In addition, pevonedistat-induced rereplication stress during the S phase was greatly augmented by concomitant treatment with T-3775440, as reflected by the increased induction of apoptosis. We further demonstrated that the combination treatment was markedly effective in subcutaneous tumor xenograft models as well as in a disseminated model of AML, leading to tumor eradication or prolonged survival in T-3775440/pevonedistat cotreated mice. Our findings indicate the therapeutic potential of the combination of LSD1 inhibitors and pevonedistat for the treatment of AML.
RESUMO
We examined the outcomes and levels of patient satisfaction in 202 consecutive cases of ultrasound-guided supraclavicular brachial plexus block (SBPB) in upper limb surgery performed between September 2007 and March 2010. All blocks were performed by orthopaedic surgeons using ultrasound visualisation with a high-frequency linear probe. The probe was placed in the coronal-oblique plane in the supraclavicular fossa, and the puncture was 'in-plane' from lateral to medial. Most of the blocks were performed with 0.75% ropivacaine/1% lidocaine (1:1), with or without adrenaline in 1:200 000 dilution. In 201 patients (99.5%) the brachial plexus block permitted surgery without conversion to general anaesthesia. The mean procedure time for block was 3.9 min (2 to 12), the mean waiting time for surgery was 34.1 min (10 to 64), the mean surgical time was 75.2 min (6 to 232), and the mean duration of post-anaesthetic analgesia was 437 min (171 to 992). A total of 20 patients (10%) developed a transient Horner's syndrome. No nerve injury, pneumothorax, arterial puncture or systemic anaesthetic toxicity were recorded. Most patients (96.7%) were satisfied with ultrasound-guided SBPB. This study demonstrates the efficacy and safety of ultrasound-guided SBPB for orthopaedic surgery on the upper limb.