Age-induced and photoinduced changes in gene expression profiles in facial skin of Caucasian females across 6 decades of age.

BACKGROUND: Intrinsic and extrinsic factors, including ultraviolet irradiation, lead to visible signs of skin aging. OBJECTIVE: We evaluated molecular changes occurring in photoexposed and photoprotected skin of white women 20 to 74 years of age, some of whom appeared substantially younger than their chronologic age. METHODS: Histologic and transcriptomics profiling were conducted on skin biopsy samples of photoexposed (face and dorsal forearm) or photoprotected (buttocks) body sites from 158 women. 23andMe genotyping determined genetic ancestry. RESULTS: Gene expression and ontologic analysis revealed progressive changes from the 20s to the 70s in pathways related to oxidative stress, energy metabolism, senescence, and epidermal barrier; these changes were accelerated in the 60s and 70s. The gene expression patterns from the subset of women who were younger-appearing were similar to those in women who were actually younger. LIMITATIONS: Broader application of these findings (eg, across races and Fitzpatrick skin types) will require further studies. CONCLUSIONS: This study demonstrates a wide range of molecular processes in skin affected by aging, providing relevant targets for improving the condition of aging skin at different life stages and defining a molecular pattern of epidermal gene expression in women who appear younger than their chronologic age.

Melanocytic nevi excised during B-Raf proto-oncogene (BRAF) inhibitor therapy: A study of 19 lesions from 10 patients.

BACKGROUND: There are limited descriptions of histopathology and immune profiles of new or changing melanocytic nevi in the setting of B-Raf proto-oncogene (BRAF) inhibitor therapy. OBJECTIVE: We sought to identify their distinctive features. METHODS: Clinical charts and histologic review, neuroblastoma RAS viral (v-ras) oncogene homolog genotyping, and immunohistochemistry for HMB-45, BRAFV600E, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated protein kinase B, CD4, and CD8 were performed on 19 melanocytic nevi from 10 patients and 23 control nevi. RESULTS: BRAF inhibitors were administered for metastatic melanoma (7), colonic adenocarcinoma (2), and papillary thyroid carcinoma (1). The average duration of BRAF inhibition before lesion excision was 8 months. Frequently associated histologic features included pigmentation of the stratum corneum, hyperpigmented keratinocytes, dermal melanophages, and deep HMB-45 expression. The lesions were BRAFV600E and neuroblastoma RAS viral (v-ras) oncogene homolog wild-type, expressed diffuse weak-moderate pERK, and possessed a predominance of CD8(+) in comparison with CD4(+) T lymphocytes within the dermal infiltrates. LIMITATION: This is a retrospective study of a small and heterogeneous group. CONCLUSION: The nevi associated with BRAF inhibitor therapy invariably lack BRAFV600E mutation. BRAF inhibition appears to cause an increased cytotoxic T-cell response and increased mitogen-activated protein kinase activity in BRAF wild-type lesions, supported by pERK expression, possibly resulting in an activated phenotype characterized by increased melanin pigmentation and deep HMB-45 expression.

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with altered cornification and specific T cell expansion in atopic dermatitis.

In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells spanning 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from four studies into a comprehensive human skin cell atlas in health and disease. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD. This disrupted epithelial differentiation was associated with signals from a unique immune and stromal multicellular community comprised of MMP12 + dendritic cells (DCs), mature migratory DCs, cycling ILCs, NK cells, inflammatory CCL19 + IL4I1 + fibroblasts, and clonally expanded IL13 + IL22 + IL26 + T cells with overlapping type 2 and type 17 characteristics. Cell subsets within this immune and stromal multicellular community were connected by multiple inter-cellular positive feedback loops predicted to impact community assembly and maintenance. AD GWAS gene expression was enriched both in disrupted cornified keratinocytes and in cell subsets from the lesional immune and stromal multicellular community including IL13 + IL22 + IL26 + T cells and ILCs, suggesting that epithelial or immune dysfunction in the context of the observed cellular communication network can initiate and then converge towards AD. Our work highlights specific, disease-associated cell subsets and interactions as potential targets in progression and resolution of chronic inflammation.

Efficacy and tolerability of a cosmetically acceptable coal tar solution in the treatment of moderate plaque psoriasis: a controlled comparison with calcipotriene (calcipotriol) cream.

BACKGROUND: Topical coal tar is a well known and effective treatment for psoriasis, but the messiness, staining, odor, and inconvenience associated with its use make patient satisfaction and compliance a challenge. OBJECTIVE: To determine the efficacy, patient tolerability, and cosmetic acceptability of a new topical liquor carbonis distillate (LCD) 15% solution compared with calcipotriene (calcipotriol) cream in patients with moderate, chronic plaque psoriasis. STUDY DESIGN: A randomized, single-blind, active-controlled, parallel-group, clinical trial consisting of a 12-week treatment phase and a 6-week post-treatment follow-up phase. SETTING: Outpatient dermatology research unit in an academic hospital. PATIENTS: Sixty adults with moderate, chronic plaque psoriasis (3-15% body surface area affected) not receiving other psoriasis therapies. INTERVENTION: Patients were randomized to apply either an LCD 15% solution (Psorent) or a commercially available calcipotriene 0.005% cream (Dovonex) to their psoriasis areas (excluding the head) twice daily at home for 12 weeks. ASSESSMENTS: A blinded investigator evaluated the patients' psoriasis using a modified Psoriasis Area and Severity Index (PASI) that excluded the head, and a Physician's Global Assessment (PGA) scale at weeks 0 (baseline), 2, 4, 8, and 12 (end of treatment), and 18 (6 weeks after treatment was withdrawn). Patients assessed their psoriasis symptoms and quality of life and completed a cosmetic acceptability survey about their medication. OUTCOME MEASURES: The changes in the baseline PASI scores after 12 weeks of treatment were compared between LCD and calcipotriene groups. Additional comparisons were performed for success rates during treatment (PASI 75 and PASI 50), changes in PGA scores, patient-reported psoriasis symptom scores, patients' quality-of-life scores, and recurrence rates during post-treatment follow-up. RESULTS: Both treatment groups showed improvement in psoriasis severity and quality of life. However, the LCD group had greater mean reductions in PASI scores: 58% vs 37% in the calcipotriene group (p < 0.05) at week 12. Additionally, the LCD group had more patients (14/27) with absent or minimal psoriasis on the PGA scale than the calcipotriene group (6/28) by the end of treatment (p < 0.05). LCD-treated patients also maintained their improvement better than calcipotriene-treated patients through week 18 after treatment was withdrawn for 6 weeks. Both treatments were well tolerated and cosmetically acceptable to patients. CONCLUSION: The newly formulated LCD solution, applied twice daily at home for 12 weeks, was more effective and as well tolerated and cosmetically acceptable as the calcipotriene cream over 12 weeks of treatment and 6 weeks of follow-up. The LCD solution is a patient-accepted and effective corticosteroid-sparing treatment alternative for psoriasis patients.