Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing1–3. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence4,5, a form of terminal cell cycle arrest associated with pro-inflammatory responses6. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA sensing cGAS-STING pathway, leading to both short-term inflammation to restrain activated oncogene and chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Cellular senescence, a state of stable cell cycle arrest in response to cellular stress, is an indispensable mechanism to counter tumorigenesis by halting the proliferation of damaged cells. However, through the secretion of an array of diverse cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP), senescent cells can paradoxically promote carcinogenesis. Consistent with this, removal of senescent cells delays the onset of cancer and prolongs lifespan in vivo, potentially in part through SASP reduction. In this review, we consider the evidence for the SASP and “SASP-like” inflammation in driving skin carcinogenesis, emphasizing how further understanding of both the roles and mechanisms of SASP expression may offer new targets for skin cancer prevention and therapy.

Purpose Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment, are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein, whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment could be an effective strategy for the treatment of melanoma. Experimental Design PPARγ increases klotho levels, and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/ Wnt5A crosstalk, in vitro and in vivo, and the implications of that for targeted therapy in young vs. aged animals. Results We show that rosiglitazone increases klotho and decreases Wnt5A in tumor cells, reducing the burden of both BRAF-inhibitor sensitive, and BRAF inhibitor-resistant tumors in aged, but not young mice. However, when used in combination with PLX4720, tumor burden was reduced in both young and aged mice, even in resistant tumors. Conclusions Using glitazones as adjuvant therapy for melanoma may provide a new treatment strategy for older melanoma patients who have developed resistance to vemurafenib. As klotho has been shown to play a role in other cancers too, our results may have wide relevance for multiple tumor types.

By regulating the accessibility of the genome, epigenetic regulators such as histone proteins and the chromatin-modifying enzymes that act upon them control gene expression. Proper regulation of this "histone code" allows for the precise control of transcriptional networks that are essential for establishing and maintaining cell fate and identity, disruption of which may drive carcinogenesis. How these dynamic epigenetic regulators contribute to both skin homeostasis and disease is only beginning to be understood. Here we provide an update of the current understanding of histone modifiers in the skin. Indeed, as one of the most innovative and rapidly expanding areas in all of medicine, it is clear that epigenome-targeting therapies hold great promise for the treatment of dermatological diseases in the coming years.

Background Many surgeons are reluctant to discontinue prophylactic antibiotics after 24 hours in tissue expander breast reconstruction (TEBR) because of fear of increased risk of surgical site infection (SSI). Currently, there is no consensus regarding antibiotic prophylaxis duration in TEBR. In addition, there remains a lack of research investigating microorganisms involved in SSI across various perioperative antibiotic protocols. The purpose of this study was to examine how 2 different prophylactic antibiotic regimens impacted the bacterial profiles of SSI and rate of implant loss after TEBR. Methods A single-institution retrospective review of immediate TEBRs between 2001 and 2018 was performed. Surgical site infections requiring hospitalization before stage 2 were included. Highly virulent organisms were defined as ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species). Implant loss was defined as removal of tissue expander without immediate replacement. Results Of 660 TEBRs, 85 (12.9%) developed an SSI requiring hospitalization before stage 2. Fifty-six (65.9%) received less than 24 hours of perioperative intravenous antibiotics and oral antibiotics after discharge (group 1), and 29 (34.1%) received less than 24 hours of intravenous antibiotics only (group 2). There was no significant difference in demographics, preoperative chemotherapy/radiation, acellular dermal matrix usage, or treatment of SSI between groups. In group 1, 64% (n = 36) developed culture positive SSIs, compared with 83% (n = 24) in group 2 (P = 0.076). Staphylococcus aureus was the most common bacteria in both groups. Group 2 demonstrated a significantly increased incidence of gram-positive organisms (46.4% vs 72.4%, P = 0.022) and S. aureus (21.4% vs 55.2%, P = 0.002). However, there was no significant difference in overall highly virulent (P = 0.168), gram-negative (P = 0.416), or total isolated organisms (P = 0.192). Implant loss between groups 1 and 2 (62.5% vs 62.1%, P = 0.969) respectively, was nearly identical. Conclusions Our study demonstrates that, despite differences in bacterial profiles between 2 antibiotic protocols, prolonged postoperative antibiotic use did not protect against overall highly virulent infections or implant loss. Antibiotic stewardship guidelines against the overuse of prolonged prophylactic regimens should be considered. Further analysis regarding timing of SSIs and antibiotic treatment is warranted.