Publications

Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7). In normal fibroblasts, the efficiency of iPSC generation was enhanced by transducing mutant ACVR1 (617G > A) or SMAD1 or adding BMP4 protein at early times during the reprogramming. In contrast, adding BMP4 at later times decreased iPSC generation. ID genes, transcriptional targets of BMP-SMAD signaling, were critical for iPSC generation. The BMP-SMAD-ID signaling axis suppressed p16/INK4A-mediated cell senescence, a major barrier to reprogramming. These results using patient cells carrying the ACVR1 R206H mutation reveal how cellular signaling and gene expression change during the reprogramming processes.

BACKGROUND/AIMS

We compared the 6-Point Scale, a screening tool to identify low-income women for referral to genetic counseling, with genetic counselors' (GCs') recommendation and the Referral Screening Tool (RST).

METHODS

RST and 6-Point Scale scores were computed for 2 samples: (1) S1, public hospital mammography clinic patients in 2006-2010 (n = 744), classified by GCs as high risk (meriting referral to counseling) or not high risk, and (2) S2, primary care patients enrolled in an education intervention study in 2011-2012 (n = 1,425). Sensitivity, specificity, and area under the ROC curve (AUROC) were computed for the 6-Point Scale score versus GC and RST classification as high risk.

RESULTS

The 6-Point Scale had low sensitivity (0.27, 95% confidence interval [CI] 0.21-0.34) but high specificity (0.97, 95% CI 0.95-0.99) and AUROC (0.85, 95% CI 0.81-0.90) versus GC classification, and high sensitivity (S1: 0.90, 95% CI 0.79-1.00; S2: 0.94, 95% CI 0.87-0.97), specificity (S1: 0.95, 95% CI 0.93-0.97; S2: 0.94, 95% CI 0.93-0.96), and AUROC (S1: 0.98, 95% CI 0.96-0.99; S2: 0.98, 95% CI 0.98-0.99) versus the RST.

CONCLUSION

The 6-Point Scale compared favorably with the RST, a validated instrument, and is potentially useful as a simple tool for administration in a safety net setting, requiring minimal time investment by primary care physicians and their staff and no financial investment in tablet computers or software.

Immune tolerance between the fetus and mother represents an active process by which the developing fetus must not mount immune responses to noninherited Ags on chimeric maternal cells that reside in fetal tissue. This is, in part, mediated by the suppressive influence of CD4FOXP3CD25 regulatory T cells (Tregs). Fetal secondary lymphoid organs have an increased frequency of Tregs and, as compared with adult T cells, fetal naive CD4 T cells exhibit a strong predisposition to differentiate into Tregs when stimulated. This effect is mediated by the TCR and TGF-β pathways, and fetal T cells show significantly increased Treg differentiation in response to anti-CD3 and TGF-β stimulation. Naive fetal T cells also exhibit increased signaling through the TGF-β pathway, with these cells demonstrating increased expression of the signaling mediators TGF-βRI, TGF-βRIII, and SMAD2, and higher levels of SMAD2/SMAD3 phosphorylation. Increased fetal Treg differentiation is mediated by the RNA-binding protein Lin28b, which is overexpressed in fetal T cells as compared with adult cells. When Lin28b expression is decreased in naive fetal T cells, they exhibit decreased Treg differentiation that is associated with decreased TGF-β signaling and lowered expression of TGF-βRI, TGF-βRIII, and SMAD2. Lin28b regulates the maturation of let-7 microRNAs, and these TGF-β signaling mediators are let-7 targets. We hypothesize that loss of Lin28b expression in fetal T cells leads to increased mature let-7, which causes decreased expression of TGF-βRI, TGF-βRIII, and SMAD2 proteins. A reduction in TGF-β signaling leads to reduced Treg numbers.