Publications

Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). We developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis. Bioinformatics and microscale thermophoresis demonstrated that oxidation of Cys in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro. This effect was reproduced by ALDO-induced oxidant stress in cultured human pulmonary artery endothelial cells (HPAECs), resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with Nk2 homeobox 5 (NKX2-5), and increased NKX2-5 binding to Up-regulation of NEDD9-dependent collagen III expression corresponded to changes in cell stiffness measured by atomic force microscopy. HPAEC-derived exosomal signaling targeted NEDD9 to increase collagen I/III expression in human pulmonary artery smooth muscle cells, identifying a second endothelial mechanism regulating vascular fibrosis. ALDO-NEDD9 signaling was not affected by treatment with a TGF-β ligand trap and, thus, was not contingent on TGF-β signaling. Colocalization of NEDD9 with collagen III in HPAECs was observed in fibrotic pulmonary arterioles from PAH patients. Furthermore, ablation or inhibition prevented fibrotic vascular remodeling and pulmonary hypertension in animal models of PAH in vivo. These data identify a critical TGF-β-independent posttranslational modification that impairs SMAD3-NEDD9 binding in HPAECs to modulate vascular fibrosis and promote PAH.

BACKGROUND & AIMS

Adenoma detection rate (ADR) and serrated polyp detection rate (SDR) vary significantly among colonoscopists. Colonoscopy inspection quality (CIQ) is the quality with which a colonoscopist inspects for polyps and may explain some of this variation. We aimed to determine the relationship between CIQ and historical ADRs and SDRs in a cohort of colonoscopists and assess whether there is variation in CIQ components (fold examination, cleaning, and luminal distension) among colonoscopists with similar ADRs and SDRs.

METHODS

We conducted a prospective observational study to assess CIQ among 17 high-volume colonoscopists at an academic medical center. Over 6 weeks, we video-recorded >28 colonoscopies per colonoscopist and randomly selected 7 colonoscopies per colonoscopist for evaluation. Six raters graded CIQ using an established scale, with a maximum whole colon score of 75.

RESULTS

We evaluated 119 colonoscopies. The median whole-colon CIQ score was 50.1/75. Whole-colon CIQ score (r=0.71; P<.01) and component scores (fold examination r=0.74; cleaning r=0.67; distension r=0.77; all P<.01) correlated with ADR. Proximal colon CIQ score (r=0.67; P<.01) and component scores (fold examination r=0.71; cleaning r=0.62; distension r=0.65; all P<.05) correlated with SDR. CIQ component scores differed significantly between colonoscopists with similar ADRs and SDRs for most of the CIQ skills.

CONCLUSION

In a prospective observational study, we found CIQ and CIQ components to correlate with ADR and SDR. Colonoscopists with similar ADRs and SDRs differ in their performance of the 3 CIQ components-specific, actionable feedback might improve colonoscopy technique.