Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by proteins involved in skin barrier maintenance and vitamin D metabolism. Using an intra-patient design, this study compared protein expression in intra-lesional (IL) and peri-lesional (PL) skin biopsies from AD patients and examined associations between protein levels, vitamin D status, and clinical features. Forty-four biopsies from twenty-two AD patients were analyzed using antibody microarrays targeting twelve proteins. IL samples had significantly higher total protein levels than PL samples, with a mean difference of 77.7% (p < 0.001). Several proteins, including cathelicidin, cingulin, occludin, filaggrin, and the vitamin D receptor, were upregulated in IL samples. Patients with vitamin D levels below 30 ng/mL showed higher expression of CYP24A (p = 0.054), alpha-catenin (p = 0.043), and haptoglobin (p = 0.033). Increased EASI scores (≥16) were associated with elevated expression of CYP24A (p = 0.024), CYP27B (p = 0.044), filaggrin (p = 0.027), occludin (p = 0.049), and claudin-1 (p = 0.052). Multivariate regression analysis identified significant correlations between protein expression, skin prick test positivity, and low vitamin D levels. These findings suggest that proteins related to epithelial barrier function and vitamin D metabolism are highly upregulated in IL skin regions, offering potential therapeutic targets for improving both skin barrier function and overall disease severity in AD patients.

Vitamin D is increasingly recognized as a key regulator of epithelial barrier integrity and mucosal immune homeostasis, with implications extending far beyond skeletal health. Through the vitamin D receptor (VDR), vitamin D regulates epithelial cohesion, innate immune responses, and tight-junction gene expression. This review explores the multifactorial role of vitamin D in modulating inflammation and preserving tissue barriers, with particular emphasis on its effects on tight junction (TJ) regulation and disease states characterized by barrier dysfunction, namely atopic dermatitis, psoriasis, inflammatory bowel disease (IBD), and celiac disease. In these settings, vitamin D/VDR signaling exerts protective actions by enhancing barrier structure, suppressing Th1/Th17-driven inflammation, modulating the gut and skin microbiome, and promoting epithelial repair. Animal studies and clinical data suggest that vitamin D supplementation can restore TJ expression, reduce disease activity, and improve clinical outcomes in both intestinal and dermatologic diseases. In the cardiovascular system, the role of vitamin D remains complex. While vitamin D influences endothelial function, insulin sensitivity, and systemic inflammation, supplementation trials yield mixed results, indicating a need for individualized approaches. Overall, this review synthesizes mechanistic, translational, and clinical data supporting vitamin D as a crucial modulator of barrier integrity and inflammation. These findings highlight its therapeutic relevance in chronic diseases characterized by immune dysregulation and epithelial disruption.

Atopic dermatitis (AD) is a chronic inflammatory skin disease marked by impaired barrier function and immune dysregulation. This study explores transcriptomic differences between lesional (IL) and perilesional (PL) skin in patients with AD, focusing on barrier-related and vitamin D-associated pathways. RNA sequencing was performed on matched IL and PL biopsies from 21 adults with moderate-to-severe AD. Differential gene expression, pathway enrichment, and correlation analysis with clinical variables were assessed. A total of 8817 genes were differentially expressed in IL versus PL skin (padj < 0.05). Among genes with the highest level of dysregulation, strong upregulation was observed for inflammatory mediators (IL-19, IL-8, CXCL6), and epidermal remodeling and barrier-disrupting genes (MMP1, GJB2). The vitamin D pathway genes CYP27B1 and CYP24A1 were also significantly upregulated. In contrast, key barrier-related genes such as FLG2 and CGNL1 were markedly downregulated. While some patterns in gene expression showed subgroup-specific trends, no independent clinical predictors emerged in multivariate models. Reactome pathway analysis revealed the enrichment of pathways involved in keratinization, cornified envelope formation, IL-4/IL-13 signaling, chemokine activity, and antimicrobial responses, highlighting coordinated structural and immunologic dysregulation in lesional skin. Lesional skin in AD displays a distinct transcriptomic profile marked by barrier impairment, heightened inflammatory signaling, and activation of vitamin D-related pathways. These findings provide the first RNA-seq-based comparison of IL and adjacent PL skin in AD. We identify subclinical activation in PL skin and vitamin D pathway upregulation with disrupted gene coordination in lesions. These findings enhance our understanding of the molecular mechanisms underlying inflammation in AD.

Abstract Background Primitive location of melanoma could be a relevant prognostic factor. As regards the scalp, some studies indicate a particularly aggressive biological behaviour for this anatomical localisation. Objectives In this multicentric study, data regarding head–neck melanoma (HNM) have been revised. Methods The design of the study included two main phases. In this retrospective study, data regarding HNM have been collected and analysed. Results In summary, our data suggest that the posterior neck is the area most affected by thicker melanomas. Cheeks and neck melanoma are associated with reduced disease‐free years of life and overall survival compared with all other sites of HNM. Conclusions This study provides useful information in defining the clinical features of HNM, thus improving diagnosis and treatment strategies.

Background: Few studies have explored the intricate connections between vitamin D receptor (VDR) gene polymorphisms, VDR, tight junction (TJ) protein expression and clinical features of atopic dermatitis (AD). Methods: From 43 adult AD patients, VDR polymorphisms were genotyped from peripheral blood samples using polymerase chain reaction-restriction fragment length polymorphism. VDR, occludin, claudin-1 and ZO-1 protein expression from skin lesion biopsies were assessed by immunohistochemistry. Results: The A1012G heterozygous VDR polymorphism exhibited a lower odds ratio (OR) for juvenile AD onset (OR: 0.046, 95% CI 0.004-0.51, p=0.012). In contrast, the presence of ≥2 homozygous VDR polymorphisms were significantly associated with positive skin prick test (SPT) (10/20, 50%) vs. negative SPT (1/23, 4.3%; p=0.0003). The most highly expressed TJ proteins in lesions of AD patients were claudin-1 and ZO-1, while VDR and occludin were less prevalent. A significant correlation was observed between ZO-1 expression and a body mass index ≥30 kg/m2 (OR: 12.1, 95% CI 1.06-137.9, p=0.045). Claudin-1 expression was associated with a positive SPT (OR: 8.23, 95% CI 1.04-65.5, p=0.046) and serum 25(OH)D levels were negatively correlated with ZO-1 expression (rho= -0.43, p=0.0058). Conclusion: This study provides novel insights into the relationship between VDR gene polymorphisms, VDR, TJ protein expression, and clinical features in adult AD patients, highlighting a significant role of vitamin D in the pathophysiology of this disease.

BACKGROUND: Second primary melanomas (SPMs) are new developed primary melanomas occurring in a subset of patients affected by BRAF-mutated metastatic melanoma during treatment with BRAF-inhibitors. A drug-induced paradoxical activation of mitogen-activated protein kinase (MAPK) signaling pathway in BRAF-wild type/RAS-mutated cells have been proposed as a possible molecular mechanism but data on the mutational status of SPMs are lacking. In order to better understand genetic alterations affecting the biological mechanism of SPMs, we performed a personalized and targeted next-generation sequencing analysis of a patient affected by metastatic melanoma who developed multiple SPMs during treatment with encorafenib (LGX818). METHODS: Using a cancer panel of 50 genes for solid tumors enriched with a custom panel of 10 genes specifically involved in melanoma pathogenesis, we analyzed the primary melanoma, two SPMs, one benign compound nevus and the normal DNA extracted from blood lymphocytes of the patient. RESULTS: We identified HRAS Q61 somatic mutation in one SPM developed in a pre-existing nevus. In the primary melanoma, besides the BRAF mutation, we identified the clinically actionable IDH1 R132C somatic mutation. Both SPMs were BRAF wild type. The patient harbors the recently recognized pathogenetic germline variant KDR Q472. We observed that mutations detected in tumor samples involving genes related to melanoma pathogenesis (TP53, PIK3CA, FGFR3, ATF1, KIT, HRAS and MAP2K2) were present in heterozygosis in the germline status of the patient. CONCLUSIONS: Our results support the paradoxical mechanism of MAPK pathway for SPMs under BRAF inhibitors. Moreover, they suggest that targeted mutational assessment based on matching somatic and germline analysis represent a promising approach to detect the neoplastic landscape of the tumor and to identify most accurate treatment in metastatic melanoma patient.

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The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is fundamental to increasing survival and therapeutic adjustment. In stages II–IV especially, additional indications for adjuvant therapy purposes after resection and for treatment of metastatic patients are urgently needed. We investigated whether the fatty acid (FA) and protein compositions of small extracellular vesicles (sEV) derived from the plasma of stage 0–I, II and III–IV melanoma patients (n = 38) could reflect disease stage. The subpopulation of sEV expressing CD81 EV marker (CD81sEV) was captured by an ad hoc immune affinity technique from plasma depleted of large EV. Biological macromolecules were investigated by gas chromatography and mass spectrometry in CD81sEV. A higher content of FA was detectable in patients with respect to healthy donors (HD). Moreover, a higher C18:0/C18:1 ratio, as a marker of cell membrane fluidity, distinguished early (stage 0–I) from late (III–IV) stages’ CD81sEV. Proteomics detected increases in CD14, PON1, PON3 and APOA5 exclusively in stage II CD81sEV, and RAP1B was decreased in stage III–IV CD81sEV, in comparison to HD. Our results suggest that stage dependent alterations in CD81sEV’ FA and protein composition may occur early after disease onset, strengthening the potential of circulating sEV as a source of discriminatory information for early diagnosis, prediction of metastatic behavior and following up of melanoma patients.

The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is key to increase survival and therapeutic adjustment. Especially in stages II-IV biomarkers are urgently needed for adjuvant therapy purposes after resection and for treatment of metastatic patients. We here investigated if fatty acid (FA) and protein composition of small extracellular vesicles (sEV) deriving from plasma of 0-I, II, and III-IV stage melanoma patients (n=38) could reflect disease stage and thus function as biomarker. The subpopulation of sEV expressing CD81 (CD81sEV) was isolated by an ad hoc immune affinity technique from microvesicle-depleted plasma. Biological macromolecules were investigated by gas chromatography and mass spectrometry in CD81sEV. A higher content of FA and a decrease in Saturation Index (C18:0/C18:1), already detectable in early stages, distinguished patients’ from healthy donor CD81sEV. Proteomics (identifier PXD024434) detected an exclusive and significant increase of CD14, PON1, PON3 and APOA5 in stage II and a significant decrease of Rap1b in stage III-IV CD81sEV. The FA and proteomic stage dependent CD81sEV signature strengthens the potential of circulating sEV studies in providing discriminatory information for early diagnosis, prediction of metastatic behavior and follow up of melanoma patients.

staining showed positive immunoreactivities for LC3 and Beclin-1 within the cytoplasm of histiocytes and multinucleated giant cells in the skin of most granulomatous diseases (Fig. 1b,c and Fig. S1). These positive immunoreactivities were observed as having a multiple dot-like appearance by immunofluorescence staining (Fig. 1d–g). Among rheumatoid nodule cases, there was neither LC3 expression in one case nor Beclin-1 expression in the other. Giant cells did not show positive immunoreactivity for either LC3 or Beclin-1 in rheumatoid nodules. In sporotrichosis, histiocytes showed positive immunoreactivity for both LC3 and Beclin-1, but giant cells did not show positive immunoreactivity for them, implying the different roles of autophagy in infectious granulomas from other granulomas. The results are summarized in Figure 1(h). To the best of our knowledge, the expressions of LC3 and Beclin-1 proteins in granulomatous skin diseases have not yet been examined, and their pathophysiological roles in histiocytes and giant cells infiltrating cutaneous granulomatous foci are unknown at present. However, histiocytes are a subtype of tissue macrophage, and autophagy can be observed in macrophages under specific stimulus conditions such as innate immune response. In general, granulomatous reaction accompanies innate immune reaction. Therefore, innate immune reaction may induce ATG-related protein expression and autophagy in histiocytes and giant cells in the cutaneous granulomatous foci. Although autophagy is implicated in the pathogenesis of rheumatoid arthritis, we could not detect enough ATG-related protein expression in rheumatoid nodules. This may be due to the disease severity, stage or duration, but further studies are required to clarify the reason. In summary, we demonstrated for the first time that LC3 and Beclin-1 proteins are expressed in several granulomatous skin diseases, suggesting that the autophagy is involved in their pathogenesis. CONFLICT OF INTEREST: None declared.

BACKGROUND:Head and neck melanoma is a clinical challenge. Indeed, cutaneous head and neck melanoma shows a worse prognosis in comparison to melanomas of other body sites. Although the emphasis on facial cosmetic preservation plays a pivotal role in comparison to other body areas, specific Facial Aesthetic Units (FAU) could also play a key role in the prognostic evaluation of the malignancy.METHODS:The aim of the current study was to evaluate the general outcome and clinicopathological features of head and neck melanoma and to detect prognostic differences according to each FAU. The Kaplan-Meier product was used to calculate survival curves, while Cox proportional-hazard regression was performed to evaluate the predictive value of each FAU.RESULTS:A total of 221 head and neck melanoma patients was included in our analysis. In the nasal FAU, we found a high rate of local recurrence, which affected significantly disease-free survival. The worse prognosis was observed in melanoma of the scalp, which showed a greater tendency to skip metastases in internal organs. Moreover, we found that scalp showed a low incidence of non-melanoma skin cancers, if compared to other FAU, highlighting that the scalp local milieu might play a more prominent role in melanoma biology than chronic UV exposition.CONCLUSIONS:Although FAUs have an aesthetic function, they could also play a role in the evaluation and follow-up of melanoma.

The ultraviolet (UV) component of solar radiation is the driving force of life on earth, but it can cause photoaging and skin cancer. In this study, we investigated the effects of the glucosamine‐derivative 2‐(N‐Acetyl)‐L‐phenylalanylamido‐2‐deoxy‐β‐D‐glucose (NAPA) on human primary fibroblasts (FBs) stimulated in vitro with environmental levels of UVB radiation. FBs were irradiated with 0.04 J cm −2 UVB dose, which resulted a mild dosage as shown by the cell viability and ROS production measurement. This environmental UVB dose induced activation of MAP kinase ERK 1/2, the stimulation of c‐fos and at lower extent of c‐jun, and in turn AP‐1‐dependent up‐regulation of pro‐inflammatory factors IL‐6 and IL‐8 and suppression of collagen type I expression. On the contrary, 0.04 J cm −2 UVB dose was not able to stimulate metalloprotease production. NAPA treatment was able to suppress the up‐regulation of IL‐6 and IL‐8 via the inhibition of MAP kinase ERK phosphorylation and the following AP‐1 activation, and was able to attenuate the collagen type I down‐regulation induced by the UVBs. Taken together, our results show that NAPA, considering its dual action on suppression of inflammation and stimulation of collagen type I production, represents an interesting candidate as a new photoprotective and photorepairing agents.

INTRODUCTION:In Italy, the real-world evidence on the extent of adherence to guidelines and the benefits of recommended therapeutic medications and their impact on the quality of life (QoL) of H1-antihistamines (H1-AH) refractory chronic urticaria (CU) patients is limited. METHODS:AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) was a global prospective, non-interventional study of CU in real-world setting which included patients aged ≥18 years with a medically confirmed diagnosed of CU present for more than 2 months. In this study, the disease characteristics, pharmacological treatments and patient-reported outcomes (PROs) are reported. RESULTS:In total, 159 patients from 24 study centres in Italy completed the study. At baseline, 221 (89.5%) and 8 (3.2%) patients had chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), respectively, while 18 (7.3%) patients had concomitant CSU and CIndU. For CSU patients, mean dermatology life quality index and CU quality of life questionnaire scores reduced to 3.0 ± 4.9 and 14.6 ± 18.6 at Month 24 from baseline scores of 7.5 ± 6.6 and 33.2 ± 19.5, respectively, indicating an improvement in QoL. This was reflected in their work-life as work productivity impairment reduced considerably after 2 years. Only 71.9% CSU patients had a prior treatment, while during the study, 96.8% of the patients were treated with a medication. At baseline, only 52.9% CSU patients reported nonsedating H1-antihistamines as first-line of treatment in prior medication, this increased to 89.6% during current medication. CONCLUSION:This study shows that CSU has a considerable socio-economic burden and an improvement in QoL can be achieved in CSU patients if an appropriate therapeutic path is followed.