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We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformation-specific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD). Off-targets of NKX2-5 mutants, but not those of an NKX2-5 YRD mutant, showed overrepresentation of ETS binding sites and were occupied by ETS proteins, as determined by DamID. Analysis of kernel transcription factor and ETS targets show that ETS proteins are highly embedded within the cardiac gene regulatory network. Our study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.DOI: http://dx.doi.org/10.7554/eLife.06942.001

Tumor puncture and spillage were the only variables that have an independent effect on recurrence, 26.9% of punctured tumors and 80% of cases of spillage recurred (P = .043 and P = .035, respectively). Although tumor size, safety margin, and adherence to facial nerve are related to recurrence, logistic regression suggests that these are confounding variables influencing recurrence through effect on puncture and spillage rates.

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Background. We aimed to report our experience with bronchial artery embolization (BAE) in the management of moderate recurrent and/or life-threatening hemoptysis. Methods. We evaluated the demographics, clinical presentation, radiographic studies, short- and long-term efficacy, and complications in patients Who underwent BAE, at a tertiary university hospital, from 2003 to 2012. Results. Three hundred forty-one patients underwent BAE for the management of moderate recurrent or life-threatening hemoptysis. Pulmonary TB and bronchiectasis were the most common etiologies for hemoptysis in our locality. The most common angiographic signs for hemoptysis were hypervascularity and systemic-pulmonary artery shunt. BAE was successful in controlling hemoptysis immediately in 95% of patients and at 1 month in 90% of patients. Recurrence of hemoptysis was observed in 9.6% of patients, and reembolization was indicated in 85% of those cases. Complications of BAE were self-limited acute and subacute complications, while chronic complications were not recorded during this study. Conclusions. TB and bronchiectasis are the commonest etiologies for moderate recurrent or life-threatening hemoptysis in our locality. Hypervascular lesions from the bronchial arteries and nonbronchial systemic arteries represented the major vascular abnormalities. Bronchial and nonbronchial systemic artery embolizations were effective to control both acute and chronic hemoptyses, with no serious complications.

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Abstract.Chemokines play an important role in the pathogenesis of non-small cell lung cancer (NSCLC). However, aberrant methylation of CXCL12 has not been examined in NSCLC. CXCL12 mRNA expression and methylation were examined in 17 NSCLC cell lines by RT-PCR and methylationspecific PCR (MSP). MSP was performed on 236 tumor specimens from NSCLC patients who received curative intent surgery. CXCL12 and CXCR4 protein expression was examined in 90 of the 236 NSCLC specimens by immunohistochemistry. Down-regulation of CXCL12 expression was found in 10 of 17 (59%) NSCLC cell lines compared with normal bronchial cells. Treatment of 8 expression-negative cell lines with a demethylating agent restored expression in all cases. Twelve cell lines (71%) showed aberrant methylation, and good concordance between methylation and expression was present. Aberrant methylation occurred in 85 out of 236 (36%) primary NSCLCs in a tumor-specific manner. In multivariate analysis, CXCL12 methylation correlated strongly and independently with prognosis both in all patients with NSCLCs and in those with stage I NSCLCs (hazard ratio=1.68, P=0.015 and hazard ratio=3.58, P=0.017). Secreted protein CXCL12 and its receptor CXCR4 were abundant in NSCLC cells (72 out of 90, 80%; 57 out of 90, 63%) and correlated with the progression of NSCLCs. In conclusion, epigenetic silencing of CXCL12 is a frequent event in NSCLCs, and could be an independent and powerful prognostic marker in patients with NSCLCs and those with stage I disease. Analysis for CXCL12 may provide novel opportunities for prognosis and therapy of resected NSCLCs.

In patients with paroxysmal AF-related tachycardia-bradycardia syndrome, AF ablation seems to be superior to a strategy of pacing plus AAD. Pacemaker implantation can be waived in the majority of patients after a successful ablation.