BackgroundThe therapeutic efficacy of arsenic trioxide (As2O3) in acute myeloid leukemia (AML) is modest, which is partly related to its limited intracellular uptake into the leukemic cells. As2O3 enters cells via the transmembrane protein aquaglyceroporin 9 (AQP9). Azacytidine, a demethylating agent that is approved for the treatment of AML, has been shown to have synergistic effect with As2O3. We tested the hypothesis that azacytidine might up-regulate AQP9 and enhances As2O3-mediated cytotoxicity in AML.MethodsArsenic-induced cytotoxicity, the expression of AQP9, and the intracellular uptake of As2O3 were determined in AML cell lines and primary AML cells with or without azacytidine pre-treatment. The mechanism of AQP9 up-regulation was then investigated by examining the expression of transcription factors for AQP9 gene and the methylation status of their gene promoters.ResultsAs2O3-induced cytotoxicity in AML cell lines was significantly enhanced after azacytidine pre-treatment as a result of AQP9 up-regulation, leading to increased arsenic uptake and hence intracellular concentration. Blocking AQP9-mediated As2O3 uptake with mercury chloride abrogated the sensitization effect of azacytidine. AQP9 promoter does not contain CpG islands. Instead, azacytidine pre-treatment led to increased expression of HNF1A, a transcription activator of AQP9, through demethylation of HNF1A promoter. HNF1 knockdown abrogated azacytidine-induced AQP9 up-regulation and almost completely blocked intracellular As2O3 entry, confirming that azacytidine enhanced As2O3-mediated cell death via up-regulation of HNF1A and hence increased AQP9 and As2O3 intracellular concentration. Azacytidine sensitization to As2O3 treatment was re-capitulated also in primary AML samples. Finally, azacytidine did not enhance arsenic toxicity in a liver cell line, where HNF1A was largely unmethylated.ConclusionsAzacytidine sensitizes AML cells to As2O3 treatment, and our results provide proof-of-principle evidence that pharmacological up-regulation of AQP9 potentially expands the therapeutic spectrum of As2O3. Further clinical trial should evaluate the efficacy of azacytidine in combination with As2O3 in the treatment of AML.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0143-3) contains supplementary material, which is available to authorized users.

BackgroundPatients with developmental spinal stenosis (DSS) are susceptible to developing symptomatic stenosis due to pre-existing narrowed spinal canals. DSS has been previously defined by MRI via the axial anteroposterior (AP) bony spinal canal diameter. However, MRI is hardly a cost-efficient tool for screening patients. X-rays are superior due to its availability and cost, but currently, there is no definition of DSS based on plain radiographs. Thus, the aim of this study is to develop radiographic indices for diagnosing DSS.MethodsThis was a prospective cohort of 148 subjects consisting of patients undergoing surgery for lumbar spinal stenosis (patient group) and asymptomatic subjects recruited openly from the general population (control group). Ethics approval was obtained from the local institutional review board. All subjects underwent MRI for diagnosing DSS and radiographs for measuring parameters used for creating the indices. All measurements were performed by two independent investigators, blinded to patient details. Intra- and interobserver reliability analyses were conducted, and only parameters with near perfect intraclass correlation underwent receiver operating characteristic (ROC) analysis to determine the cutoff values for diagnosing DSS using radiographs.ResultsImaging parameters from a total of 66 subjects from the patient group and 82 asymptomatic subjects in the control group were used for analysis. ROC analysis suggested sagittal vertebral body width to pedicle width ratio (SBW:PW) as having the strongest sensitivity and specificity for diagnosing DSS. Cutoff indices for SBW:PW were level-specific: L1 (2.0), L2 (2.0), L3 (2.2), L4 (2.2), L5 (2.5), and S1 (2.8).ConclusionsThis is the first study to define DSS on plain radiographs based on comparisons between a clinically relevant patient group and a control group. Individuals with DSS can be identified by a simple radiograph using a screening tool allowing for better cost-saving means for clinical diagnosis or research purposes.

This systematic review suggests that MIS reduces operating time, duration of hospital stay and CPK-MM levels. However, the evidence for these parameters is weak. Moreover, there is no conclusive evidence that MIS reduces reoperation or has better improvement in pain and outcome scores like VAS, SF-36 and JOA scores. The evidence is limited due to poor standardization of MIS definition, methodology and details of surgeon experience. MIS techniques should not be studied as a group, as each procedure is vastly different from each other.