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Embryonic craniofacial development depends on the coordinated outgrowth and fusion of multiple facial primordia, which are populated with cranial neural crest cells and covered by the facial ectoderm. Any disturbance in these developmental events, their progenitor tissues, or signaling pathways can result in craniofacial deformities such as orofacial clefts, which are among the most common birth defects in humans. In the present study, we show that Rdh10 loss of function leads to a substantial reduction in retinoic acid (RA) signaling in the developing frontonasal process during early embryogenesis, which results in a variety of craniofacial anomalies, including midfacial cleft and ectopic chondrogenic nodules. Elevated apoptosis and perturbed cell proliferation in postmigratory cranial neural crest cells and a substantial reduction in Alx1 and Alx3 transcription in the developing frontonasal process were associated with midfacial cleft in Rdh10-deficient mice. More important, expanded Shh signaling in the ventral forebrain, as well as partial abrogation of midfacial defects in Rdh10 mutants via inhibition of Hh signaling, indicates that misregulation of Shh signaling underlies the pathogenesis of reduced RA signaling-associated midfacial defects. Taken together, these data illustrate the precise spatiotemporal function of Rdh10 and RA signaling during early embryogenesis and their importance in orchestrating molecular and cellular events essential for normal midfacial development.

Developmental defects of primitive choanae, an anatomical path to connect the embryonic nasal and oral cavity, result in disorders called choanal atresia, which are associated with many congenital diseases and require immediate clinical intervention after birth. Previous studies revealed that reduced retinoid signaling underlies the etiology of choanal atresia. In the present study, by using multiple mouse models which conditionally deleted Rdh10 and Gata3 during embryogenesis, we showed that Gata3 expression is regulated by retinoid signaling during embryonic craniofacial development and plays crucial roles for development of the primitive choanae. Interestingly, Gata3 loss of function is known to cause hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, which exhibits choanal atresia as one of the phenotypes in humans. Our model partially phenocopies HDR syndrome with choanal atresia, and is thus a useful tool for investigating the molecular and cellular mechanisms of HDR syndrome. We further uncovered critical synergy of Gata3 and retinoid signaling during embryonic development, which will shed light on novel molecular and cellular etiology of congenital defects in primitive choanae formation.

Background Esophageal carcinoma is an invasive malignancy with a poor prognosis. Inflammatory cells are related to the prognosis in many malignancies; however, the prognostic values of preoperative neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR) and platelet-lymphocyte ratio (PLR) in esophageal squamous cell carcinomas (ESCCs) are contentious. Methods We performed a retrospective study on 178 patients who had proven ESCC and underwent R0 resection. A complete peripheral blood cell count on all patients 1 week before surgery was used to calculate NLR, LMR and PLR. All patients were grouped by the median count of NLR, LMR and PLR respectively. Kaplan-Meier curves were adopted to test the difference of overall survival (OS) and disease-free survival (DFS) between the high group of NLR, LMR and PLR and the low group. All data analysis was performed by SPSS. P<0.05 was assigned to admit statistical significance. Results The median follow-up after the surgery was 39 months. The preoperative LMR showed no significant association with the OS [hazard ratio (HR) =0.733, 95% confidence interval (CI): 0.397–1.353, P=0.321] and DFS (HR =0.850, 95% CI: 0.491–1.473, P=0.562). Neither NLR nor PLR exhibited a significant correlation with OS or DFS. Conclusions NLR, LMR, and PLR could not take the roles of prognostic biomarkers for patients with operable ESCCs.