Recent studies suggest that peroxisome proliferator‐activated receptor gamma (PPARγ) agonists may have cancer chemopreventive activity. Other studies have shown that loss of epidermal PPARγ results in enhanced chemical carcinogenesis in mice via unknown mechanisms. However, ultraviolet B (UVB) exposure represents the primary etiological agent for skin cancer formation and the role of PPARγ in photobiology and photocarcinogenesis is unknown. In previous studies, we demonstrated that UVB irradiation of cells results in the formation of oxidized glycerophosphocholines that exhibit PPARγ ligand activity. We therefore hypothesized that PPARγ would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPARγ agonist species in vivo. We then generated SKH‐1 hairless, albino mice deficient in epidermal Pparg (Pparg−/−^epi) using a cytokeratin 14 driven Cre‐LoxP strategy. Using a chronic model of UVB photocarcinogenesis, we next showed that Pparg−/−^epi mice exhibit an earlier onset of tumor formation, increased tumor burden and tumor progression. Increased tumor burden in Pparg−/−^epi mice was accompanied by a significant increase in epidermal hyperplasia and p53 positive epidermal cells in surrounding skin lacking tumors. After acute UVB irradiation, Pparg−/−^epi mice exhibited an augmentation of both UVB‐induced Caspase 3/7 activity and inflammation. Increased apoptosis and inflammation was also observed after treatment with the PPARγ antagonist GW9662. With chronic UVB irradiation, Pparg−/−^epi mice exhibited a sustained increase in erythema and transepidermal water loss relative to wildtype littermates. This suggests that PPARγ agonists could have possible chemopreventive activity in non‐melanoma skin cancer.

Peroxisome proliferator-activated receptor gamma (PPARγ) is thought to play a role in sebaceous gland cell function. We previously demonstrated in human epidermoid carcinoma KB cells that UVB irradiation activates PPARγ via the generation of multiple oxidized glycerophosphocholine species with PPARγ ligand activity. UVB-induced cyclooxygenase 2 (COX-2) expression was also shown to be PPARγ-dependent. We therefore reasoned that PPARγ activation and PPARγ-dependent COX-2 expression may occur as a general consequence of oxidative stress. The present studies were designed to examine the effects of the oxidant tert-butylhydroperoxide (TBH) on PPARγ activation and COX-2 expression in SZ95 sebocytes. We first verified that functional PPARγ is expressed and activated by UVB irradiation in these cells. We next demonstrated that TBH increased PPARγ reporter activity in SZ95 sebocytes. Increased COX-2 protein, mRNA expression, and prostaglandin E₂ (PGE₂) production was observed after TBH or PPARγ agonist treatment. The ability of PPARγ agonists and TBH to induce COX-2 expression and PGE₂ production was blocked by pretreatment with the specific PPARγ antagonist GW9662. Finally, TBH and PPARγ agonists failed to elicit a PGE₂ response in SZ95 sebocytes stably expressing a dominant-negative PPARγ. This study illustrates the importance of the PPARγ system in regulating cellular responses to oxidative stress.

Objectives: To implement an electronic laboratory utilization management system (laboratory expert system [LES]) to provide safe and effective reductions in unnecessary clinical laboratory testing. Methods: The LES is a set of frequency filter subroutines within the Veterans Affairs hospital and laboratory information system that was formulated by an interdisciplinary medical team.Results: Since implementing the LES, total test volume has decreased by a mean of 11.18% per year compared with our pre-LES test volume. This change was not attributable to fluctuations in outpatient visits or inpatient days of care. Laboratory cost savings were estimated at $151,184 and $163,751 for 2012 and 2013, respectively. A significant portion of these cost savings was attributable to reductions in high-volume, large panel testing. No adverse effects on patient care were reported, and mean length of stay for patients remained unchanged. Conclusions: Electronic laboratory utilization systems can effectively reduce unnecessary laboratory testing without compromising patient care.

Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-^epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-^epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-^epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.