p63 is a recently identified homolog of p53 that is found in the basal layer of several stratified epithelial tissues such as the epidermis, oral mucosa, prostate, and urogenital tract. Studies with p63 ؊/؊ mice and analysis of several human autosomal-dominant disorders with germ line p63 mutations suggest p63 involvement in maintaining epidermal stem cell populations. The p63 gene encodes six splice variants with reported transactivating or dominant-negative activities. The goals of the current study were to determine the splice variants that are expressed in primary human epidermal keratinocytes (HEKs) and the biochemical activity p63 has in these epithelial cell populations. We found that the predominant splice variant expressed in HEKs was ⌬Np63␣, and it was present as a phosphorylated protein. During HEK differentiation, ⌬Np63␣ and p53 levels decreased, while expression of p53 target genes p21 and 14-3-3 increased. ⌬Np63␣ had transcriptional repressor activity in vitro, and this activity was reduced in ⌬Np63␣ proteins containing point mutations, corresponding to those found in patients with Hay-Wells syndrome. Further, we show that ⌬Np63␣ and p53 can bind the p21 and 14-3-3 promoters in vitro and in vivo, with decreased binding of p63 to these promoters during HEK differentiation. These data suggest that ⌬Np63␣ acts as a transcriptional repressor at select growth regulatory gene promoters in HEKs, and this repression likely plays an important role in the proliferative capacity of basal keratinocytes.

Although all three DeltaNp63 isoforms are present in HNSCC, DeltaNp63alpha protein is the predominant isoform expressed in these malignancies. DeltaNp63alpha is also overexpressed in tumors compared with matched normal tissue specimens and is underexpressed in the pro-apoptotic condition of lichen planus. These findings suggest that DeltaNp63alpha plays an anti-differentiation and anti-apoptotic role in the mucosal epithelium of the head and neck, possibly playing a pivotal role in the formation of HNSCC. Currently, DeltaNp63alpha is an attractive target for mechanistic study aimed at therapeutic intervention.

Our study reveals that in the past decade, in significant malpractice litigations, overall outcomes favored otolaryngologists. The average awards was significantly higher when cases involved malignancy. Our analysis reveals the importance of meticulous surgical techniques and thorough preoperative evaluations. Last, when otolaryngologists are defendants in litigation, our review reiterates the value of the otolaryngologist as the defense's expert witnesses.

Free tissue transfer continues to be the reconstructive modality of choice for head and neck defects.