No abstract

Secreted signaling proteins of the Wnt family are known to regulate a diverse range of developmental processes, and their signaling pathway through b-catenin is frequently activated in cancer. The identification of both Frizzled and LRP5/6 (LRP: low-density lipoprotein receptor-related protein) proteins as components of cellsurface receptors for Wnt proteins has raised questions about their individual functions. We have investigated this issue through a structure-function analysis of Frizzled and LRP proteins that have been implicated in Wnt1 signaling. Consistent with other reports, we find that LRP6/Arrow proteins deleted for their extracellular domain are able to activate the Wnt/b-catenin signaling pathway. Importantly, our results demonstrate that this signaling from LRP6/Arrow derivatives can occur in a Frizzled-and ligand-independent manner. Furthermore, we show that the PPSP motifs within the intracellular domain of LRP6 are required for signaling. In contrast to results with LRP6, overexpression of Frizzled proteins did not activate the pathway. Based on evidence of ligand binding to both Frizzled and LRP6, current models suggest that both proteins are components of a Wnt receptor complex that signals to b-catenin. In light of these models, our data imply that LRP5/6/Arrow proteins constitute the distal signal-initiating component of these receptors. The results also support the notion that LRP5/ 6 are candidate oncogenes.

IMPORTANCE Advances in smartphone photography (both quality and image transmission) may improve access to care via direct parent-to-clinician telemedicine. However, the accuracy of diagnoses that are reliant on parent-provided photographs has not been formally compared with diagnoses made in person.OBJECTIVE To assess whether smartphone photographs of pediatric skin conditions taken by parents are of sufficient quality to permit accurate diagnosis. DESIGN, SETTING, AND PARTICIPANTSA prospective study was conducted among 40 patient-parent dyads at a pediatric dermatology clinic at the Children's Hospital of Philadelphia from March 1 to September 30, 2016, to assess concordance between diagnoses made by an independent pediatric dermatologist based on in-person examination and those based on parental photographs. Half of the patient-parent dyads were randomized for a secondary analysis to receive instructions on how best to take photographs with smartphones. Clinicians were blinded to whether parents had received photography instructions.EXPOSURES Half of the patient-parent dyads received a simple, 3-step instruction sheet on how best to take photographs using a smartphone (intervention group); the other half did not (control group). MAIN OUTCOMES AND MEASURES Concordance between photograph-based vs in-persondiagnosis in the intervention vs control groups, as quantified using Cohen κ, a measure of interrater agreement that takes into account the possibility of agreement occurring by chance.RESULTS Among the 40 patient-parent dyads (22 female children and 18 male children; mean [SD] age, 6.96 [5.23] years), overall concordance between photograph-based vs in-person diagnosis was 83% (95% CI, 71%-94%; κ = 0.81). Diagnostic concordance was 89% (95% CI, 75%-97%; κ = 0.88) in a subgroup of 37 participants with photographs considered of high enough quality to make a diagnosis. No statistically significant effect of photography instructions on concordance was detected (group that received instructions, 85%; group that did not receive instructions, 80%; P = .68). In cases of diagnostic disagreement, appropriate follow-up was suggested.CONCLUSIONS AND RELEVANCE Parent-operated smartphone photography can accurately be used as a method to provide pediatric dermatologic care. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT03246945