The Journal of investigative dermatology最新文献

Altered epidermal lipid metabolism along with keratinocyte dysfunction is a characteristic feature of psoriasis. CD36, a key fatty acid translocase, has been implicated in various inflammatory diseases through its regulation of lipid metabolism, but its role in the keratinocytes of psoriasis remains unclear. In this study, we found that CD36 was significantly elevated in the lesional epidermis of patients with psoriasis and positively correlated with the disease severity. Mice with keratinocyte-specific CD36 knockout or sulfosuccinimidyl oleate (the blocker of CD36) ointment topical treatment exhibited relieved imiquimod-induced psoriasis-like inflammation visually and histologically. Furthermore, gas chromatography tandem mass spectrometry analysis revealed significant increase of CD36 ligands, particularly long-chain fatty acids, in lesional skin from both patients with psoriasis and mice with imiquimod-induced psoriasis. In vitro, CD36 facilitated long-chain fatty acids transport into keratinocytes, leading to lipid accumulation and elevated expression of chemokines, notably CXCL2 and CCL20, which recruit neutrophils and CCR6⁺ T cells, respectively. Mechanistically, CD36-mediated long-chain fatty acids uptake impaired mitochondrial function and induced mitochondrial ROS generation, thereby activating the NF-κB signaling pathway and promoting chemokine production. These findings demonstrate an essential role of CD36 in lipid metabolic‒inflammatory crosstalk in keratinocytes, suggesting that it could be a potentially effective therapeutic target in inflammatory skin diseases.

To address the need for rapid reduction of atopic dermatitis (AD) clinical manifestations, this study investigated the time course of the effects of ruxolitinib (selective JAK1/JAK2 inhibitor) cream on itch and associated changes in skin and serum biomarkers in adults with AD. In the open-label SCRATCH-AD study (NCT04839380), patients with AD, an Investigator's Global Assessment score ≥2, and a Peak Pruritus Numerical Rating Scale score ≥4 applied 1.5% ruxolitinib cream to all affected areas (except palms, soles, scalp, genitals, and folds; ≤20% body surface area) twice daily for 28 days. Among 46 patients, the mean change from baseline in Peak Pruritus Numerical Rating Scale was -3.4 on day 2 (worst itch, 24-hour recall; primary endpoint) and -5.7 on day 29. Mean change from baseline in modified Peak Pruritus Numerical Rating Scale (current itch) was -2.3 by 15 minutes. Skin (sampled with tape strips) and serum biomarkers associated with AD, such as CCL17 and matrix metalloproteinase 12, were downregulated with ruxolitinib cream and correlated with improvements in disease and symptom severity. There were no serious treatment-emergent adverse events. In summary, patients with AD who applied 1.5% ruxolitinib cream experienced rapid and sustained improvement in itch and clinical improvements that correlated with changes in AD biomarkers.

Patients with atypical mole syndrome may benefit from screening methods that enable early melanoma detection and prevent unnecessary biopsies. Electrical impedance spectroscopy (EIS)'s utility in this patient population has not previously been reported. Therefore, we conducted a cross-sectional study of nevi in patients with atypical mole syndrome to characterize the EIS scores of clinically stable nevi in this patient population and to evaluate the test-retest reliability of EIS. EIS scores of selected clinically stable nevi were taken at an initial visit and 2-6-week follow-up visit. Patients invited for participation were aged ≥30 years, had ≥100 nevi, had at least 3 large acquired nevi >5 mm in diameter, and had baseline total body photographs obtained ≥3 years prior to initial visit. A total of 89.2% of large, 88.3% of atypical-appearing, and 65.0% of small nevi had false-positive EIS scores ≥4. Modest agreement was observed in test-retest reliability at 2-6-week follow-up with Bland-Altman 95% confidence interval of ±2.85. EIS and CASH (color, architecture, symmetry, and homogeneity) dermoscopy scores were positively associated (95% confidence interval = 0.11-0.25, P < .001). We conclude that EIS cannot indiscriminately be used in the screening evaluation of stable nevi in patients with atypical mole syndrome ; changes in EIS score <3 may not represent clinically significant change during short-term follow-up of stable nevi.

Basal cell carcinoma (BCC) is driven in nearly all cases by mutations that constitutively activate upstream Hedgehog (HH) signaling, either through loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO. Unlike other skin cancers such as squamous cell carcinoma, a clinically apparent precursor lesion for BCC has not been identified. Recent genomic analyses of both human and mouse tumors suggest that BCC formation requires not only PTCH1 or SMO mutations but also additional genetic changes. These findings imply that some BCCs may follow a stepwise tumor progression model, whereby the accumulation of multiple mutational "hits" is needed to convert an indolent precursor lesion into malignant disease. On the basis of studies in patients with Gorlin syndrome who harbor germline PTCH1 mutations and are genetically predisposed to forming BCC, we speculate that at least a subset of BCCs arises from a subclinical basaloid follicular hamartoma or similar precursor lesion. Altogether, convergent evidence suggests that activating upstream HH signaling is necessary but not sufficient for BCC formation. This evolving view of BCC has important implications for our basic understanding of these tumors, for our interpretation of findings from BCC mouse models, and for guiding treatment.