Zinc-finger protein transcription factors (ZFP TFs)D efects in transcriptional regulation underlie numerous disease states, most notably cancer (1). A major goal of current strategies for correcting such defects is to achieve sufficient specificity of action (2). Designed zinc-finger protein transcription factors (ZFP TFs) emulate natural transcriptional control mechanisms and therefore provide an attractive tool for precisely regulating gene expression. Accurate control of gene expression is important for understanding gene function (target validation) and for developing therapeutics to treat disease (3). We and others have used engineered ZFP TFs to either activate or repress a variety of endogenous gene targets (4-11). For these proteins, or any other gene-regulation technology, to succeed as tools in drug discovery or direct agents in the clinic, their specificity of action within the genome must be precise, a challenging criterion to meet given the size and complexity of the human genome. Recent studies with small interfering RNA (12, 13) and antisense DNA͞RNA (14) have illuminated the magnitude of the task of achieving single-gene specificity in regulating the human genome.We focus here on the use of ZFP TFs in the area of oncology and specifically on the emerging role of checkpoint kinase 2 (CHK2). CHK2 acts as a key integrator of DNA-damage signals regulating cell-cycle progression, DNA repair, and cell death by phosphorylating a variety of substrates, including the p53 tumor suppressor protein (15, 16). Here we show that a designed ZFP TF targeted to a unique 18-bp recognition sequence in the promoter of the CHK2 gene binds the intended site within chromatin and represses CHK2 transcription in vivo. Moreover, repression of CHK2 by this engineered ZFP TF occurs with remarkable specificity, while simultaneously reducing CHK2 protein to levels that functionally ablate the action of this kinase. Finally, we show that constitutive expression of the ZFP TF in telomerase-immortalized, untransformed human fibroblasts provides stable repression of the CHK2 gene and results in loss of DNA-damage-induced CHK2-dependent phosphorylation of p53 on Ser-20. These data demonstrate that ZFP TFs can be exquisitely specific, yet potent repressors of gene expression and, therefore, are potentially powerful reagents for target validation and therapeutic interventions in vivo.

Background. High-flow nasal cannula (HFNC) can be used in stable chronic obstructive pulmonary disease (COPD) patients, but the effect of HFNC on clinical outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is still uncertain. Methods. We searched electronic literature databases for randomized controlled trials (RCTs) comparing HFNC with noninvasive ventilation (NIV) in hypercapnic patients with AECOPD. The primary endpoint of this meta-analysis was PaCO2, PaO2, and SpO2. The secondary outcomes were the respiratory rate, mortality, complications, and intubation rate. Results. We included 7 RCTs with a total of 481 patients. There were no significant differences on measures of PaCO2 (MD = −0.42, 95%CI −3.60 to 2.75, Z = 0.26, and P  = 0.79), PaO2 (MD = −1.36, 95%CI −4.69 to 1.97, Z = 0.80, and P  = 0.42), and SpO2 (MD = −0.78, 95%CI −1.67 to 0.11, Z = 1.72, P  = 0.08) between the HFNC group and the NIV group. There was no significant difference in measures of the mortality and intubation rate between the HFNC group (OR = 0.72, 95%CI 0.30 to 1.69, Z = 0.76, and P  = 0.44) and the NIV group (OR = 2.38, 95%CI 0.49 to 11.50, Z = 1.08, and P  = 0.28), respectively. But the respiratory rate in the HFNC group was lower than that in the NIV group (MD = −1.13, 95%CI −2.13 to −0.14, Z = 2.23, and P  = 0.03), and fewer complications were found in the HFNC group (OR = 0.26, 95%CI 0.14 to 0.47, Z = 4.46, and P  < 0.00001). Conclusion. NIV was noninferior to HFNC in decreasing PaCO2 and increasing PaO2 and SpO2. Similarly, the mortality and intubation rate was similar among the two groups. The respiratory rate and complications were inferior in the AECOPD group treated with HFNC.

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