CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

Non‐melanoma skin cancer frequently results from chronic exposure to ultraviolet (UV) irradiation. UV‐induced DNA damage activates cell cycle arrest checkpoints through degradation of the cyclin‐dependent kinase activators, the cell division cycle 25 (CDC25) phosphatases. We previously reported increased CDC25A in nonmelanoma skin cancer, but CDC25B and CDC25C had not been previously examined. Consequently, we hypothesized that increased expression of CDC25B and CDC25C increases tumor cell proliferation and skin tumor growth. We found that CDC25B and CDC25C were increased in mouse and human skin cancers. CDC25B was primarily cytoplasmic in skin and skin tumors and was significantly increased in the squamous cell carcinoma (SCC), while CDC25C was mostly nuclear in the skin, with an increased cytoplasmic signal in the premalignant and malignant tumors. Surprisingly, forced expression of CDC25B or CDC25C in cultured SCC cells did not affect proliferation, but instead suppressed apoptosis, while CDC25C silencing increased apoptosis without impacting proliferation. Targeting CDC25C to the nucleus via mutation of its nuclear export sequence, however, increased proliferation in SCC cells. Overexpression of CDC25C in the nuclear compartment did not hinder the ability of CDC25C to suppress apoptosis, neither did mutation of sites necessary for its interaction with 14‐3‐3 proteins. Analysis of apoptotic signaling pathways revealed that CDC25C increased activating phosphorylation of Akt on Ser⁴⁷³, increased inhibitory phosphorylation of proapoptotic BAD on Ser¹³⁶, and increased the survival protein Survivin. Silencing of CDC25C significantly reduced Survivin levels. Taken together, these data suggest that increased expression of CDC25B or CDC25C are mechanisms by which skin cancers evade apoptotic cell death.     

An open-label,prospective, randomized,controlled, multicenter,phase 1b study of StrataGraft skin tissue versus autografting in patients with deep partial-thickness thermal burns

ObjectiveThis open-label, controlled, randomized study assessed the safety, tolerability, and efficacy of StrataGraft tissue compared to autograft in the treatment of deep partial-thickness (DPT) burns.MethodsThirty subjects with DPT thermal burns (3%–43% total body surface area) were treated with StrataGraft tissue as follows: cohort 1, ≤220 cm² refrigerated tissue; cohort 2, ≤440 cm² refrigerated tissue; and cohort 3, ≤440 cm² cryopreserved tissue. On each subject, two comparable areas of DPT burn were randomized to receive StrataGraft tissue or autograft. Coprimary end points were the percent area of the StrataGraft tissue treatment site undergoing salvage autografting by Day 28 and wound closure of treatment sites by 3 months.ResultsBy Day 28, no StrataGraft tissue treatment sites underwent autografting. By 3 months, 93% and 100% of the StrataGraft tissue and autograft treatment sites achieved complete wound closure, respectively. No significant differences in observer total and overall opinion POSAS scores between StrataGraft tissue and autograft treatment sites were observed at any timepoint. The most common adverse event was pruritus (17%).ConclusionsStrataGraft tissue treatment of DPT thermal burns reduced the need for autograft, resulted in wound closure and treatment-site cosmesis comparable to that of autograft, and was well tolerated.     

Chronic Stress Remodels Synapses in an Amygdala Circuit–Specific Manner

Background

Chronic stress exposure increases the risk of developing various neuropsychiatric illnesses. The behavioral sequelae of stress correlate with dendritic hypertrophy and glutamate-related synaptic remodeling at basolateral amygdala projection neurons (BLA PNs). Yet, though BLA PNs are functionally heterogeneous with diverse corticolimbic targets, it remains unclear whether stress differentially impacts specific output circuits.