Person:

Liao, Eric

Background: Sensation is decreased or absent after breast reconstruction. This leaves reconstructed breasts vulnerable to injury from common household thermal sources such as heating pads and hot water bottles. We sought to categorize these injuries, provide a treatment plan, and prevent these injuries in the future. Methods: A retrospective review of patients who had sustained burns to reconstructed breasts with household devices was performed at a single institution. A PubMed search was performed to identify and summarize articles cataloguing patients who had suffered burns to breast reconstructions. Results: Five patients in our practice were affected. Fifteen articles were identified in the literature search. A total of 40 patients had sustained thermal injury to reconstructed breasts, with the majority being full thickness burns (67.5%). Patients who sustained full thickness burns to reconstructed breasts were more likely to require an operative procedure compared with patients who sustained partial thickness burns (P = 0.0076). Conclusions: Reconstructed breasts are at risk for injury from commonly used household warming devices and ambient heat from the sun. As a result, patients should be counseled about these risks accordingly, to avoid injury or loss of reconstruction. These injuries require immediate vigilant treatment.

Summary: There is renewed interest in sparing the pectoralis major muscle in implant breast reconstruction, placing the implant in the subcutaneous position. This advance is made reliable by improvements in mastectomy skin flap quality, evolution of technique, and increased awareness of breast animation deformity. This retrospective review presents 13 patients (23 breasts) reconstructed immediately with placing the definitive implant in the subcutaneous space without disruption of the underlying chest muscles. None of the 13 patients had breast animation deformity postoperatively. One patient experienced an early hematoma, and 3 patients had small seromas that resolved uneventfully. One morbidly obese patient undergoing chemotherapy using a nearby chest port experienced infection requiring implant removal. This study describes an early experience, demonstrates feasibility, and discusses patient selection considerations that are important because we continue to evolve breast reconstruction approaches.

Cranial neural crest cells (CNCCs) delaminate from embryonic neural folds and migrate to pharyngeal arches, which give rise to most mid-facial structures. CNCC dysfunction plays a prominent role in the etiology of orofacial clefts, a frequent birth malformation. Heterozygous mutations in SPECC1L have been identified in patients with atypical and syndromic clefts. Here, we report that in SPECC1L-knockdown cultured cells, staining of canonical adherens junction (AJ) components, β-catenin and E-cadherin, was increased, and electron micrographs revealed an apico-basal diffusion of AJs. To understand the role of SPECC1L in craniofacial morphogenesis, we generated a mouse model of Specc1l deficiency. Homozygous mutants were embryonic lethal and showed impaired neural tube closure and CNCC delamination. Staining of AJ proteins was increased in the mutant neural folds. This AJ defect is consistent with impaired CNCC delamination, which requires AJ dissolution. Further, PI3K-AKT signaling was reduced and apoptosis was increased in Specc1l mutants. In vitro, moderate inhibition of PI3K-AKT signaling in wildtype cells was sufficient to cause AJ alterations. Importantly, AJ changes induced by SPECC1L-knockdown were rescued by activating the PI3K-AKT pathway. Together, these data indicate SPECC1L as a novel modulator of PI3K-AKT signaling and AJ biology, required for neural tube closure and CNCC delamination.

Large-scale sequencing efforts have captured a rapidly growing catalogue of genetic variations. However, the accurate establishment of gene variant pathogenicity remains a central challenge in translating personal genomics information to clinical decisions. Interferon Regulatory Factor 6 (IRF6) gene variants are significant genetic contributors to orofacial clefts. Although approximately three hundred IRF6 gene variants have been documented, their effects on protein functions remain difficult to interpret. Here, we demonstrate the protein functions of human IRF6 missense gene variants could be rapidly assessed in detail by their abilities to rescue the irf6 -/- phenotype in zebrafish through variant mRNA microinjections at the one-cell stage. The results revealed many missense variants previously predicted by traditional statistical and computational tools to be loss-of-function and pathogenic retained partial or full protein function and rescued the zebrafish irf6 -/- periderm rupture phenotype. Through mRNA dosage titration and analysis of the Exome Aggregation Consortium (ExAC) database, IRF6 missense variants were grouped by their abilities to rescue at various dosages into three functional categories: wild type function, reduced function, and complete loss-of-function. This sensitive and specific biological assay was able to address the nuanced functional significances of IRF6 missense gene variants and overcome many limitations faced by current statistical and computational tools in assigning variant protein function and pathogenicity. Furthermore, it unlocked the possibility for characterizing yet undiscovered human IRF6 missense gene variants from orofacial cleft patients, and illustrated a generalizable functional genomics paradigm in personalized medicine.

The neural crest is a dynamic progenitor cell population that arises at the border of neural and non-neural ectoderm. The inductive roles of FGF, Wnt, and BMP at the neural plate border are well established, but the signals required for subsequent neural crest development remain poorly characterized. Here, we conducted a screen in primary zebrafish embryo cultures for chemicals that disrupt neural crest development, as read out by crestin:EGFP expression. We found that the natural product caffeic acid phenethyl ester (CAPE) disrupts neural crest gene expression, migration, and melanocytic differentiation by reducing Sox10 activity. CAPE inhibits FGF-stimulated PI3K/Akt signaling, and neural crest defects in CAPE-treated embryos are suppressed by constitutively active Akt1. Inhibition of Akt activity by constitutively active PTEN similarly decreases crestin expression and Sox10 activity. Our study has identified Akt as a novel intracellular pathway required for neural crest differentiation.

Background: Craniofacial malformations are among the most common congenital anomalies. Cranial neural crest cells (CNCCs) form craniofacial structures involving multiple cellular processes, perturbations of which contribute to craniofacial malformations. Adhesion of cells to the extracellular matrix mediates bidirectional interactions of the cells with their extracellular environment that plays an important role in craniofacial morphogenesis. Talin (tln) is crucial in cell-matrix adhesion between cells, but its role in craniofacial morphogenesis is poorly understood. Methods: Talin gene expression was determined by whole mount in situ hybridization. Craniofacial cartilage and muscles were analyzed by Alcian blue in Tg(mylz2:mCherry) and by transmission electron microscopy. Pulse-chase photoconversion, 5-ethynyl-2’-deoxyuridine proliferation, migration, and apoptosis assays were performed for functional analysis. Results: Expression of tln1 was observed in the craniofacial cartilage structures, including the palate. The Meckel’s cartilage was hypoplastic, the palate was shortened, and the craniofacial muscles were malformed in tln1 mutants. Pulse-chase and EdU assays during palate morphogenesis revealed defects in CNCC proliferation in mutants. No defects were observed in CNCC migration and apoptosis. Conclusions: The work shows that tln1 is critical for craniofacial morphogenesis in zebrafish. Loss of tln1 leads to a shortened palate and Meckel’s cartilage along with disorganized skeletal muscles. Investigations into the cellular processes show that tln1 is required for CNCC proliferation during palate morphogenesis. The work will lead to a better understanding of the involvement of cytoskeletal proteins in craniofacial morphogenesis.

Summary: Direct-to-implant reconstruction after mastectomy is routinely performed with excellent oncologic and aesthetic outcomes. Several different techniques for placement of the prosthesis including total and partial subpectoral coverage have been described. Prepectoral implant placement is increasingly reported as a safe method, while patient selection and techniques are areas of further work. Most prepectoral prosthesis placement techniques describe complete acellular dermal matrix (ADM) coverage of the implant, often requiring multiple or larger ADM sheets than a comparable subpectoral implant procedure, resulting in high cost per reconstructed breast. This article describes the use of a vicryl mesh pocket and ADM support in prepectoral breast reconstruction achieving predicable and safe results at a lower cost.