Studies have established that autophagy constitutes an efficient process to recycle cellular components and certain proteins. The phenomenon was demonstrated primarily in response to nutrient starvation, and there are increasing evidences that it is implied in differentiation. Keratinocyte differentiation was going along an activation of lysosomal enzymes and organelle clearance, and terminal steps are sometimes described as a specialized form of cell death leading to corneocytes. We examined whether initiation of the process in human keratinocyte HaCaT involves autophagy. The KSFM™ culture medium was substituted by M199, which contains a low glucose concentration but a high calcium level (known to induce differentiation). Metabolic stress reduced enhanced cell number in G(1) phase, without apoptotic features (ΔΨmt and membrane integrity are unchanged). Morphological changes were associated with a lower integrin ß1 expression and modifications of protein levels involved in keratinocyte differentiation (involucrin, keratin K10 and ΔNp63α). Whereas autophagic signalling was supported by SIRT1 and pAMPK (T172) increase according to time kinetic, which led to the disappearance of mTOR phosphorylated on S2448 residue. The significant Bcl-X(L) level reduction with stress promoted autophagy, by the release of Beclin-1, whereas ATG5-ATG12 and LC3-II that are involved in autophagosome formation were enhanced significantly. Then, the level of lysosomal protein cathepsin B rose to execute autophagy. Kinetic studies established that autophagy would constitute an early signalling process required for keratinocyte commitment in differentiation pathway.

Short title: Transcriptome analysis of dermal fibroblasts Abbreviations: ECM, extracellular matrix; Fp, papillary fibroblast; Fr, reticular fibroblast; Pn, number of cell passage. COL, collagen; MMP, matrix metalloproteinase Word count: 995 words

The inflammatory context contributes to the morphological, functional and transcriptomic changes observed in AD skin. As a result, this compromised RE model shares some characteristics with those found in AD skin and thus can be used as a relevant tool for screening formulations and drugs for the treatment of AD.

Acne vulgaris is a disease of pilosebaceous units associated with increased follicular stratum corneum (SC) thickness and hyperkeratinization, increased sebum secretion, inflammation and impaired skin barrier. We hypothesized that excess unsaturated free fatty acids (UFFAs) in sebum may contribute to these symptoms seen in Acne. Therefore, skin surface lipids in acne and healthy subjects were investigated. In addition, a human epidermal equivalent (HEE) model treated topically with an UFFA was developed mimicking these symptoms seen in Acne. Gene expression profiling of human skin biopsies with and without acne lesions as well as of UFFA-treated HEEs Vs. controls was also performed. Increased levels of UFFAs were observed in skin lipids of human acne subjects. Topical treatment of HEEs with an UFFA resulted in impaired barrier and increased secretion of interleukin-1a (IL-1a), associated with SC thickening and hyperkeratinization, and with increased SC lipid conformational disorder indicating a decrease in barrier integrity. Furthermore, gene expression analysis showed a similar increase in gene expression of inflammatory cytokines and epidermal differentiation both in acne lesions and UFFA-treated HEEs. These data are in agreement with the hypothesis that excess unsaturated free fatty acids (UFFAs) in sebum may contribute to the increased follicular stratum corneum (SC) thickness and hyperkeratinization, inflammation and impaired skin barrier seen in Acne. Taken together, these results suggest that UFFA-treated epidermal tissue induces a phenotypic in vitro model of acne hyperkeratinization which can be useful for the investigation of treatments that modulate acne.

EB is a group of genetic disorders defined by blistering of the skin, mucosa, and epithelial lining of organs. Currently, there are no approved treatments specific to EB. ESSENCE (NCT02384460) is an ongoing phase 3, global, multicenter, randomized, double-blind, vehicle-controlled study assessing the efficacy and safety of SD-101 in pts diagnosed with EB. While baseline characteristics for all randomized pts will be available at the time of presentation, here we report baseline characteristics of enrolled pts (n¼106) as of Dec. 2, 2016. Pts were randomized 1:1 to receive SD-101 (6.0% allantoin) cream or vehicle (0% allantoin), applied topically once daily to the entire body for 90 days. Eligible pts were aged !1 month and had a target wound (10-50 cm 2 ) present for !21 days. Pts completing ESSENCE were eligible to enter a separate open-label study (NCT02670330) to assess the long-term efficacy and safety of SD-101. Proportions of randomized pts with EB subtype were: 11.3 % simplex; 63.2% recessive dystrophic; and 25.5% junctional non-Herlitz. Demographics were as follows: 56.6% female; 77.4% white; 5.7% African American; and 6.6% Asian. Mean (SD) age was 16.1 (15.0) yrs (range 0-67 yrs) and body mass index was 17.6 (4.4) (range 9.9-31). Randomized pts had a mean (SD) body surface area index for a total body wound burden of 9.4% (8.5%). One hundred pts (94.3%) were taking !1 concomitant medication at baseline. This study is the largest clinical trial of an investigational drug for EB. Results are expected in mid-2017. ABSTRACTS | Pharmacology and Drug Development