etherton syndrome (NS) is a rare autosomal recessive skin disorder caused by mutations in SPINK5 (OMIM 605010), leading to severely impaired skin barrier function. Patients are at risk for complications such as hypernatremic dehydration, impaired thermoregulation, failure to thrive, and sepsis. Skin infections are common, as are allergies, asthma, and increased levels of circulating eosinophils and total IgE. 1,2 Affected individuals have lifelong ichthyosis lineariz circumflexa, associated with erythroderma, and pruritus. 3 Treatment of NS is difficult, with the mainstay being bland emollients. Topical corticosteroids and calcineurin in-hibitors may provide short-term benefit, but the former have a high risk of increased transcutaneous absorption and the latter have a high risk of resultant Cushing syndrome and immune suppression. As for systemic agents, low-dose retinoids, infliximab, and intravenous immunoglobulins have been tried with variable success. [4][5][6][7] Recent studies showed that NS shares an immune profile similar to psoriasis with helper T cell (T H ) 17/interleukin 23 (IL-23) and IL-17/tumor necrosis factor (TNF) synergistic activation. 8-10 Herein we report our experience using the IL-17A antagonist secukinumab in patients with NS. IMPORTANCENetherton syndrome (NS) is a rare, severe genetic disorder of cornification with high morbidity. Treatment for NS has been notoriously difficult. Recent studies showed an upregulated helper T cell (T H ) 17/interleukin 23 (IL-23) pathway in NS, suggesting the possibility of treatment strategies that target IL-17. OBJECTIVE To evaluate the clinical response of NS to treatment with the IL-17 antagonist secukinumab.

The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-kB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-kB activity by upregulating expression of IkBa by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IkBa gene expression restored NF-kB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting. Cancer Res; 73(16); 5040-52. Ó2013 AACR.