JID innovations : skin science from molecules to population health最新文献

Intralesional therapies are used for recalcitrant warts, but no Food and Drug Administration–approved treatment exists nor is there consensus regarding the most efficacious therapy. Therefore, this systematic review aims to summarize efficacy and adverse events reported in 62 randomized controlled trials (RCTs) of intralesional therapies for cutaneous warts. The most studied intralesional therapies included measles, mumps, rubella (MMR) vaccine (n = 24 studies), purified protein derivative (PPD) (n = 19 studies), vitamin D3 (n = 15 studies), and Candida antigen (n = 14 studies). Most studies included adult and pediatric patients or adults alone, with only 4 studies on pediatric patients alone. MMR vaccine was the most studied treatment (n = 853 patients). MMR had a complete response rate of 27–90%. The next most common treatment, PPD, had a complete response rate of 45–87%. Other treatments included Candida antigen and vitamin D3, with complete response rates of 25–84% and 40–96%, respectively. The most frequent side effects were injection-site reactions and flu-like symptoms. This systematic review represents a useful summary of intralesional therapy RCTs for clinician reference. This study also highlights the lack of large multi-institutional RCTs, despite many patients being treated for this widespread problem.

Advancements in pathology have given rise to software applications intended to minimize human error and improve efficacy of image analysis. Still, the subjectivity of image quantification performed manually and the limitations of the most ubiquitous tissue stain analysis software requiring parameters tuned by the observer, reveal the need for a highly accurate, automated nuclear quantification software specific to immunohistochemistry, with improved precision and efficiency compared with the methods currently in use. We present a method for the quantification of immunohistochemical biomarkers in keratinocyte nuclei proposed to overcome these limitations, contributing sensitive shape-focused segmentation, accurate nuclear detection, and automated device-independent color assessment, without observer-dependent analysis parameters.

Outdoor workers have increased risk of developing keratinocyte cancer due to accumulated skin damage resulting from chronic and excessive exposure to UVR. This study aims to identify potential noninvasive biomarkers to assess chronic UVR exposure. We analyzed stratum corneum biomarkers collected from 2 skin locations and 2 occupational groups with contrasting solar UVR exposure: the forehead and retroauricular skin among outdoor workers and indoor workers. Using a linear mixed model adjusting for age and skin phototype, we compared biomarkers between both skin sites in indoor and outdoor workers. We measured markers of the immune response and skin barrier, including cytokines, GFs, 15-hydroxyeicosatetraenoic acid, cis- and trans-urocanic acid, and corneocyte topography, indicated by circular nano objects. Differences between the 2 skin sites were found for cis-urocanic acid, total urocanic acid, IL-1α, IL-1RA, IL-1RA/IL-1α, IL-18, 15-hydroxyeicosatetraenoic acid, CCL4, and circular nano objects. The levels of cis-urocanic acid and CCL4 also differed between indoor and outdoor workers. These findings underscore changes in both immune response and skin barrier induced by UVR. They indicate the potential utility of stratum corneum biomarkers in detecting both chronic UVR exposure in occupational setting and aiding in the development of preventive measures.

Acral and mucosal melanomas are often driven by sequence variants in the KIT receptor tyrosine kinase, with nearly 40% harboring alterations in the KIT locus. Despite advances in the knowledge of KIT-mutated melanomas, little is known about the molecular reprogramming that occurs during KIT-mediated melanoma progression owing to the rarity of acral and mucosal melanomas and the lack of comprehensive biological tools and models. To this end, we used a murine model that allows us to ascertain the molecular underpinnings of the stages of cancer progression—transformation, tumorigenesis, immune engagement, and tumor escalation. We found dramatic increases in biosynthetic demands associated with the transformation stage, including DNA and RNA metabolism, leading to replication stress. Tumorigenesis was closely linked to neuronal and axonal development, likely necessary for invasion into the host. Immune engagement highlighted early immune excitation and rejection pathways, possibly triggered by abrupt neoantigen exposure. Finally, tumor escalation pathways proved consistent with immune evasion, with immune-related pathways becoming significantly downregulated. To our knowledge, it is previously unreported that these critical milestones needed for KIT-driven melanoma tumor formation have been studied at the molecular level using isogenically matched and phenotypically defined cells.

Some antihypertensive medications are photosensitizing. The implications for skin cancer risk remain unclear because results from prior studies are inconsistent and as new evidence is published. We performed a systematic review and meta-analysis to evaluate the association between antihypertensives and common skin cancers (cutaneous squamous cell carcinoma, basal cell carcinoma, and melanoma) and to evaluate dose–response relationships. Forty-four articles met inclusion criteria, and 42 could be meta analyzed. Increased risks were seen for basal cell carcinoma with calcium channel blockers (relative risk [RR] = 1.17, 95% confidence interval [CI] = 1.11–1.22), diuretics (RR = 1.06, 95% CI = 1.03–1.10), and thiazides (RR = 1.10, 95% CI = 1.04–1.16); for squamous cell carcinoma with calcium channel blockers (RR = 1.08, 95% CI = 1.01–1.14), diuretics (RR = 1.29, 95% CI = 1.17–1.43), and thiazides (RR = 1.36, 95% CI = 1.15–1.61); and for melanoma in angiotensin-converting enzyme inhibitors (RR = 1.09, 95% CI = 1.03–1.14), calcium channel blockers (RR = 1.08, 95% CI = 1.03–1.12), and thiazides (RR = 1.09, 95% CI = 1.02–1.17). The quality of evidence was low or very low. We observed evidence for dose–response for thiazides with basal cell carcinoma; angiotensin-converting enzyme inhibitors, diuretics, and thiazides with squamous cell carcinoma; and angiotensin-converting enzyme inhibitors, diuretics, and thiazides with melanoma. Our meta-analysis supports a potential causal association between some antihypertensives, particularly diuretics, and skin cancer risk.

Proteomic profiling on other primary cicatricial alopecias, such as frontal fibrosing alopecia and lichen planopilaris, have suggested a T helper 1–mediated inflammatory pathway, but in central centrifugal cicatricial alopecia (CCCA), the protein expression patterns are unknown. In this study, we sought to characterize protein expression patterns in CCCA to identify biomarkers of disease activity that will identify potential therapeutic avenues for treatment. Scalp protein quantification was performed to understand protein expression patterns in affected versus unaffected scalps in CCCA. A total of 5444 proteins were identified, of which 148 proteins were found to be differentially expressed in CCCA-affected scalp, with upregulation of adaptive immune pathways (IGHG3, P = .034; IGHG4, P = .01; IGG1, P = .026) and markers of fibrosis (ITGA1, P = .016; SFRP2, P = .045; TPM2, P = .029; SLMAP, P = .016) and downregulation of metabolic proteins (ALOX15B, P = .003; FADS2, P = .006; ELOVL5, P = .007; FA2H, P = .017; FAR2, P = .011; SC5D, P < .001). Our analysis revealed, to our knowledge, previously unknown humoral immune canonical pathways, notably IgG, implicated in CCCA and additionally confirmed aberrant lipid metabolism pathways implicated in diabetes mellitus, suggesting unique mechanisms of disease in patients with CCCA.

Loss-of-function variants in the FLG gene have been identified as the strongest cause of susceptibility to atopic dermatitis (AD) in Europeans and Asians. However, very little is known about the genetic etiology behind AD in African populations, where the prevalence of AD is notably high. We sought to investigate the genetic origins of AD by performing whole-genome sequencing in an Ethiopian family with 12 individuals and several affected in different generations. We identified 2 variants within FLG2 (p.D13Y) and NOD2 (p.A918S) genes cosegregating with AD in the affected individuals. Further genotyping analyses in both Ethiopian and Swedish AD cases and controls revealed a significant association with the FLG2 variant (p.D13Y, P < .0013) only in the Ethiopian cohort. However, the NOD2 variant (p.A918S) did not show any association in our Ethiopian cohort. Instead, 2 previously recognized NOD2 variants (p.A849V, P < .0085 and p.G908R, P < .0036) were significantly associated with AD in our Ethiopian cohort. Our study indicates that the FLG2 and NOD2 genes might be important in the etiology of AD in Ethiopians. Additional genetic and functional studies are needed to confirm the role of these genes and the associated variants into the development of AD.

The skin is a multifunctional organ, forming a barrier between the external and internal environment, thereby functioning as a safeguard against extrinsic factors. Autophagy has been implicated in epidermal differentiation and in preserving skin homeostasis. LC3-associated phagocytosis (LAP) uses some but not all components of autophagy. The Atg16l1 ($\Delta$ WD) mouse model lacks the WD40 domain required for LAP and has been widely used to study the effects of LAP deficiency and autophagy on tissue homeostasis and response to infection.

In this study, the $\Delta$ WD model was used to study the relationship between LAP and skin homeostasis by determining whether LAP-deficient mice display a cutaneous phenotype. Skin histology of wild-type and $\Delta$ WD mice aged 1 year revealed minor morphological differences in the tail skin dermal layer. RT-qPCR and western blot analysis showed no differences in key keratin expression between genotypes. Skin barrier formation, assessed by dye permeation assays, demonstrated full and proper formation of the skin barrier at embryonic day 18.5 in both genotypes. Biomechanical analysis of the skin showed decreased skin elasticity in aged $\Delta$ WD but not wild-type mice. In summary, the LAP-deficient $\Delta$ WD mice displayed subtle alterations in dermal histology and age-related biomechanical changes.

ROS are involved in the pathogenesis of bullous pemphigoid (BP), but this involvement has not been fully elucidated. In this study, to further elucidate the pathogenic role of ROS in BP, we examined the results of the diacron-reactive oxygen metabolite test and the biological antioxidant potential test for 16 patients with BP who visited our hospital before being treated with systemic corticosteroids. In the patients with BP, the average diacron-reactive oxygen metabolite levels, expressed in Carratelli units, were significantly reduced at 1 month of treatment (from 335.6 ± 40.3 Carratelli units to 224.7 ± 61.6 Carratelli units, P < .001). Bullous Pemphigoid Disease Area Index (erosions/blisters) scores correlated with diacron-reactive oxygen metabolite levels (r = 0.51), suggesting that those levels reflect the disease severity. We also performed staining of 3,5-dibromotyrosine in skin tissues. The 3,5-dibromotyrosine is expected to be a marker of tissue damage related to inflammation and allergies. The 3,5-dibromotyrosine was stained in infiltrated cells around the dermis, throughout the blister fluid, and at the basement membrane within the blister. It is considered that tissue destruction caused by the myeloperoxidase released from neutrophils and by eosinophil peroxidase released from eosinophils is involved in blister formation. The results suggest that ROS play a role in BP.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intense pruritus and skin nodules. Beyond the skin, PN involves circulating blood inflammation that may contribute to systemic disease comorbidities. Dupilumab was recently approved for treatment of PN, but its effects on systemic inflammation are unknown. Thus, we aimed to characterize changes in plasma concentrations of inflammatory proteins after dupilumab treatment. In this exploratory study, plasma samples were collected from 3 patients with moderate-to-severe PN before and after ≥6 months of dupilumab treatment. All patients exhibited clinically significant improvements after treatment. Of the 2569 proteins tested, 186 were differentially expressed after treatment (q < 0.1, fold change > 1.3). Downregulated proteins included cytokines associated with T helper (Th) 1 (IFN-γ, TNF-α), Th2 (IL-4, IL-13), and Th17/Th22 (IL-6, IL-22) signaling. Markers of innate immunity (IL-19, toll-like receptor 1, nitric oxide synthase 2), immune cell migration (CCL20, CD177), and fibrosis (IL-11, IL-22) were also decreased (q < 0.1). Gene set variation analysis of Th2, Th17, and epithelial–mesenchymal transition gene sets showed reduced pathway expression in the post-treatment cohort (P < .05). Plasma cytokine levels of IL-11, nitric oxide synthase 2, IL-13, IL-4, and IFNG (R² > 0.75, q < 0.10) showed the strongest correlations with pruritus severity. Dupilumab may reduce systemic inflammatory proteins associated with multiple immune and fibrosis pathways in patients with PN, potentially modulating the development of systemic disease comorbidities.