ABSTRACT Vitiligo is an autoimmune disease characterized by progressive depigmentation of the skin due to T cell‐mediated destruction of melanocytes. Disease onset varies but usually initiates during adolescence. Sex differences in disease development and therapeutic outcomes have not been explored. We previously associated stress induced HSP70i with immune activation in depigmentation and showed that HSP70i Q435A can tolerize dendritic cells (DCs) to prevent cutaneous recruitment and activation of T cells. Among male and female vitiligo‐prone mice, we investigated the long‐term efficacy of HSP70i Q435A plasmid DNA treatment introduced by biolistic administration at varying stages of vitiligo development. Mice were followed up to 46 weeks of age. Female mice exhibited 1.89‐fold greater depigmentation than males overall, while both responded proportionally to treatment with effects lasting throughout. This sex difference was associated with significantly elevated IFN‐γ secretion by melanocyte‐reactive T cells among female mice. Humoral responses to the protein remained readily detectable at end point regardless of treatment interval. These findings also suggest greater benefit from earlier intervention.
ABSTRACT Melanoma is a high‐tumor‐mutational‐burden (TMB) cancer, largely driven by ultraviolet‐induced DNA damage. Although TMB predicts response to immune checkpoint inhibitors (ICIs), the genomic factors underlying its variability remain unclear. In addition to canonical DNA‐repair defects such as mismatch repair (MMR) and POLE/POLD1 mutations, alterations in chromatin regulators (CRs) may influence genome stability and mutational load. We analyzed melanoma cohorts from the MSK‐ICI, TCGA, MSK‐Met, DFCI, and UCLA datasets. TMB was compared between CR‐mutant and CR–wild‐type tumors and overall cohorts, along with gene‐level analyses of individual CRs. Associations between the number of CR mutations and TMB were assessed. Overall survival (OS) in ICI‐treated patients was evaluated using Kaplan–Meier and Cox models, with TCGA as a non–ICI‐treated comparator. Across datasets, CR‐mutant melanomas consistently exhibited significantly higher TMB than CR–wild‐type tumors. Several CRs were linked to elevated TMB, comparable to MMR‐ or POLE/POLD1‐mutant tumors. Multiple CR alterations showed a positive linear relationship with TMB. In ICI‐treated cohorts, CR‐mutant tumors had significantly longer OS, while this link was not observed in non–ICI‐treated cases. These findings suggest that CR mutations define a subset of melanomas with high TMB and improved response to ICIs, warranting prospective validation as predictive biomarkers.
ABSTRACT Vitiligo and melasma frequently coexist, creating a treatment dilemma, since agents effective for one condition can destabilize the other, and no consensus currently exists on safe management. We conducted a scoping literature review (through June 2023) on treatment of patients with concomitant vitiligo and melasma, followed by a two‐round international e‐Delphi survey (22 experts from 14 countries; consensus defined as ≥ 70% agreement) and a final online consensus meeting. Only one study supported the safe use of oral tranexamic acid for melasma in vitiligo patients. Expert consensus favored prioritizing vitiligo treatment, particularly when active, while incorporating patient's preferences. Targeted phototherapy is suitable for localized facial lesions of vitiligo, and non‐facial vitiligo can be treated alongside melasma after covering the face. Topical calcineurin inhibitors, ruxolitinib, tretinoin, corticosteroids, and oral tranexamic acid can be used. Lasers and chemical peels were recommended only with caution by experienced pigment specialists. Until there is enough scientific evidence, hydroquinone would be replaced by other safer cosmetic lightening agents (e.g., niacinamide, ascorbic acid, thiamidol, melasyl), which show comparable efficacy with less theoretical risk. This first international consensus offers practical, patient‐centered guidance for managing coexisting vitiligo and melasma, emphasizing individualized, disease‐activity‐based treatment sequencing. Trial Registration: PROSPERO reference number: RD42023395586 Significance . Depigmenting agents used for melasma inhibit melanogenesis, a mechanism that can further compromise the already‐stressed melanocyte populations characteristic of vitiligo. This consensus gives clinicians an expert‐informed pathway through a common but understudied comorbidity. It also identifies a clear research gap: controlled, mechanistic comparisons of hydroquinone against newer tyrosinase inhibitors specifically in vitiligo‐prone skin are still lacking.
ABSTRACT Melanoma is a highly aggressive skin tumour that poses considerable challenges in treatment and prognostic assessment. Epithelial–mesenchymal transition (EMT) is a critical process in melanoma progression and contributes to tumour invasion and metastasis. This study aimed to identify EMT‐related genes associated with melanoma prognosis and to develop a risk model for patient stratification. Based on previous studies, an EMT‐related gene set comprising 200 genes was compiled. Gene expression data from normal skin and skin cutaneous melanoma tissues were obtained from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression (GTEx) databases. Differential expression analysis was performed to identify differentially expressed genes (DEGs), using an adjusted p value < 0.05 as the significance threshold. Univariable Cox regression analysis was subsequently conducted to identify survival‐related genes among the DEGs ( p < 0.05), resulting in the selection of six genes: LAMC2, IL32, MGP, CAP2, ECM1 and BGN. A risk score model was then constructed based on these genes. The model showed prognostic stratification ability in both the TCGA cohort and the external validation cohort GSE65904. Patients were classified into high‐ and low‐risk groups, and overall survival was significantly shorter in the high‐risk group than in the low‐risk group ( p < 0.0001). Analysis of the immune microenvironment showed higher levels of immune cell infiltration in the low‐risk group. BGN was significantly overexpressed in melanoma tissues and cell lines. In vitro experiments demonstrated that BGN silencing inhibited the proliferation, migration and invasion of A375 cells and reversed EMT‐related changes, whereas BGN overexpression enhanced the malignant phenotype of A2058 cells. In vivo experiments further confirmed that BGN knockdown significantly suppressed xenograft tumour growth and altered the expression of EMT‐related markers. These findings establish an EMT‐related prognostic model for melanoma risk stratification and provide experimental evidence supporting the potential role of BGN in melanoma progression. This study integrates computational analysis with functional validation; however, further validation in independent prospective cohorts is required before clinical application.
ABSTRACT Melanin is the primary pigment found in the skin, hair, wool and feathers of many vertebrates and plays a crucial role in determining the physical appearance and physiological performance of livestock species. Melanin functions in thermoregulation as well as coloration, photoprotection, and adaptation to diverse environmental conditions. This review examines the biosynthesis of melanin and the genetics of melanogenesis in major livestock species such as cattle, sheep, goats, pigs, horses, and poultry, and the roles of melanin‐based pigmentation within different systems of animal production. The genetic loci ( MC1R, ASIP , TYRP1, TYR, PMEL, MITF, KIT, and others) and polygenic modifiers determine the type and intensity of pigment distribution patterns. Melanin also has a variety of ecological roles, or functions, in addition to economically important traits, affecting adaptation to environmental restraints, product quality, and market preferences. Despite major advances in genomic and transcriptomic studies, many questions still remain, especially in the lack of direct experimental evidence, an insufficient understanding of the physiological roles of melanin in livestock, and a lack of functional validation of key pigmentation genes under production conditions. Future research should focus on bridging these gaps and translating this genetic knowledge to breeding strategies.
