Experimental Dermatology

The time of day of UV exposure impacts both erythema and cancer development. To investigate whether UV-relevant clock-controlled gene expression can be modulated pharmacologically, we treated human skin explants with a combination of a cryptochoursome inhibitor and REV-ERB antagonist and then examined changes in gene expression of a limited number of core clock and clock-regulated genes. mRNA levels of both the DNA repair factor XPA and cell cycle checkpoint kinase WEE1 were found to be significantly increased by treatment. This pilot study suggests that clock-controlled gene expression can be altered pharmacologically to possibly alter skin responses to UV radiation.

The aim of this study was to explore the scalp bacterial flora structure and functional characteristics in androgenetic alopecia (AGA) patients, analyze its association with disease phenotypes and unhealthy lifestyles, and provide a basis for clarifying AGAs microecological pathogenic mechanism and targeted interventions. A total of 7 AGA patients and 6 healthy controls (HC) were enrolled, with scalp microbial samples collected. High-throughput sequencing of the 16S rRNA V3-V4 region was used to analyze flora alpha/beta diversity, species composition and differential species. LEfSe and KEGG functional prediction screened marker bacteria and differential pathways, and clinical/lifestyle data were collected for inter-group comparisons. No significant difference in Chao index was observed between groups (P>0.05), but Shannon/Simpson indices/Pielou evenness (P<0.01) and intra-group Bray-Curtis distance (P<0.001) were significantly higher in the AGA group, indicating reduced community stability. Staphylococcus dominated healthy scalps; the AGA group had fewer symbiotic bacteria but enriched Acinetobacter, Pseudomonas, andCutibacterium. LEfSe identified Firmicutes/Staphylococcus as HC markers and Proteobacteria/Gammaproteobacteria/Acinetobacter/Pseudomonas as AGA dysbiotic flora. KEGG showed upregulated metabolic, immune and cell motility pathways in AGA (P<0.05), with only infectious diseases pathway enriched in HC. AGA patients had more frequent hair washing and higher rates of staying up late, high-fat diet and insufficient fruits/vegetables (all P<0.05). In conclusion, AGA patients have typical scalp microecological dysbiosis closely related to unhealthy lifestyles, which may accelerate alopecia by inducing follicular inflammation. Scalp flora can be potential biomarkers and targets for AGA assessment and intervention.

Background Lichen Planus (LP) is a chronic inflammatory disorder that can affect the skin, hair, nails, and mucous membranes. Oral lichen planus (OLP), the most common LP subtype, is a disease of the oral mucosa, often diagnosed through clinical examination and histopathological confirmation. Extracellular vesicles (EVs) transfer proteins, lipids, and nucleic acids among cells and have become increasingly studied for their potential as minimally invasive diagnostic biomarkers and therapeutic agents in inflammatory and autoimmune diseases. Methods PUBMED and Embase were searched from inception through June 27th, 2026. Human studies investigating EV-associated miRNA or protein biomarkers in LP and its subtypes were included, with risk of bias assessed using a modified Newcastle-Ottawa Scale. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) and BRMA models when sufficient data were available. Results Ten articles met the inclusion criteria, encompassing biomarker discovery, functional, and mechanistic studies of EVs in OLP. These included studies (n = 10) comprised 298 individuals with LP (weighted mean age 50.7 years; 61.5% female) and 194 controls (weighted mean age 47.8 years; 58.5% female). OLP-specific cohorts (n = 9 studies) included 261 individuals with OLP (weighted mean age 50.7 years; 61.4% female). Although no individual EV-associated miRNAs or proteins overlapped across studies, EV-associated miRNAs demonstrated substantial heterogeneity, while EV-associated protein findings centered on pathways related to antigen presentation, inflammatory signaling, and immune activation. Several candidate biomarkers, including miR-4484, miR-34a-5p, GJA1, PDIA3, and Cx43, showed potential diagnostic or prognostic relevance. ROC analyses demonstrated good diagnostic utility for miR-4484 (AUC = 0.81), and the combination of GJA1 and Cx43 showed the strongest discriminatory ability (AUC = 0.892). The diagnostic accuracy meta-analysis showed good discrimination (pooled AUC = 0.89). Functional and mechanistic studies suggested that EVs may actively contribute to OLP pathogenesis through promoting epithelial injury and activating inflammatory signalling pathways. Conclusions EV-associated miRNAs and proteins are potential biomarker candidates for LP and may provide insight into the inflammatory and immune mechanisms underlying disease pathophysiology. Functional and mechanistic evidence further suggests that EVs may play an active role in disease progression. However, current evidence has limitations such as small sample sizes and methodological heterogeneity. Larger, standardized, and longitudinal studies are needed to v

Keloids are fibroproliferative skin disorders arising following dermal injury that extend beyond the original wound margins. Their pathogenesis remains poorly understood, and current treatments are associated with high recurrence rates. Identifying transcriptomic biomarkers that distinguish keloids from other skin and scar phenotypes may provide insight into disease mechanisms and facilitate the development of targeted therapeutic approaches. However, previous transcriptomic studies have often been limited by small sample sizes, pairwise comparisons between tissue classes, heterogeneous data-integration strategies, and a reliance on conventional differential gene expression (DGE) analysis. Here, we employed a multi-stage machine learning (ML) workflow for robust keloid biomarker discovery using transcriptomic datasets derived from both bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq). We assembled and harmonized, to the best of our knowledge, the largest curated cross-study keloid transcriptomic cohort currently available, comprising 81 samples from 13 independent studies spanning four clinically relevant tissue classes: normal skin, normotrophic scar, hypertrophic scar, and keloid scar. Through study-aware cross-validation, feature selection, partition-stability analysis, and bootstrap validation across multiple ML classifiers, we identified a panel of eight highly consistent biomarkers capable of distinguishing keloid from non-keloid samples. These biomarkers were associated with dysregulation of extracellular matrix homeostasis, fibrosis-resolution pathways, vascular remodelling, and metabolic reprogramming. Comparison with conventional DGE analysis demonstrated substantial agreement while also highlighting important differences between the two approaches. In particular, FASN was consistently identified by the ML workflow as an upregulated discriminatory biomarker despite exhibiting weak, non-significant differential expression in the DGE analysis. Cell-type-specific analysis further supported this finding, revealing significant FASN upregulation in fibroblast and vascular endothelial populations. These results demonstrate that ML and DGE capture complementary aspects of transcriptomic variation. This study provides a robust strategy for cross-study transcriptomic biomarker discovery and identifies candidate genes and pathways for future mechanistic and therapeutic investigation in keloids. 1 Author SummaryKeloids are abnormal scars that continue to grow beyond the original wound and can be difficult to treat because they frequently recur after therapy. Although many studies have investigated the biology of keloids, the molecular mechanisms that distinguish them from other scar types remain incompletely understood. Identifying biomarkers involved in keloid formation may help inform improved treatment strategies. Previous transcriptomic studies have often been limited by small sample sizes and inconsistent analytical approaches. In this study, we combined gene-expression data from multiple independent studies to create, to the best of our knowledge, the largest cross-study transcriptomic collection available for keloid analysis. We then applied several machine learning approaches to identify genes that consistently distinguished keloids from other skin and scar phenotypes. The identified biomarkers were associated with extracellular matrix remodeling, fibrosis, vascular function, and cellular metabolism. One gene involved in fatty-acid synthesis, FASN, was repeatedly identified by the machine learning analyses despite being overlooked by conventional gene-expression methods. Additional single-cell analyses confirmed elevated FASN expression in specific cell populations within keloid tissue. More broadly, this work provides a strategy for discovering robust biomarkers from heterogeneous biological datasets and identifies molecular targets for future studies of keloid disease.

Cooling the skin may increase its tolerance to mechanical loading and decrease the risk of developing pressure ulcers. Yet, the mechanisms of action (e.g. cooling-modulation of cytotoxic, post-occlusive hyperaemia), and their individual variability, remain unclear. We investigated the effects of different cooling levels (24{degrees}C and 16{degrees}C) on microvascular, inflammatory and perceptual responses to mechanical loading of the sacrum in healthy young (N=23) and older adults (N=19), and in spinal cord injury patients (SCI; N=10). Healthy participants underwent 45-min loading (~60 mmHg) and 20-min unloading of the sacrum, using an instrumented indenter probe set at either 38{degrees}C (control condition), 24{degrees}C or 16{degrees}C. SCI participants completed a more conservative protocol (i.e. 25min, ~45mmHg loading, 38{degrees}C and 16{degrees}C conditions). Pre-insult skin structure was characterised with optical coherence tomography; skin blood flow (SkBF) at the loading site was continuously measured, alongside thermal acceptability; and post-insult inflammatory responses were determined via skin-sebum cytokines analyses. Compared to control, 24{degrees}C- and 16{degrees}C-cooling induced a similar ~8-fold decrease in peak post-occlusive reactive hyperaemia in healthy participants, with similar temperature-related differences observed in SCI. Pro-inflammatory cytokines decreased post-insult; yet this occurred similarly across all temperatures and groups. The majority of participants ([&ge;]70%) rated both 24{degrees}C- and 16{degrees}C-cooling as thermally acceptable. We conclude that cooling is a potent modulator of the skin microvascular response to mechanical loading in younger, older, and vulnerable skin (SCI). These findings can inform design parameters for thermal technology aimed at preventing the loss of skin integrity (e.g. integrating 24{degrees}C-cooling in support surfaces and skin wearables).

Fibroproliferative diseases such as systemic sclerosis are complex conditions characterized by chronic skin inflammation and progressive fibrosis, with fibroblast activation as a central feature. While Transforming Growth Factor Beta (TGF-{beta}) signaling is a well-established driver of fibrosis in SSc, inflammatory pathways such as Nuclear Factor Kappa B (NF-{kappa}B) also contribute substantially to disease morbidity. We previously identified CD109 as a TGF-{beta} co-receptor and negative regulator of fibrotic signaling; however, its role in inflammatory signaling remains unknown. Here, we investigate the function of CD109 in regulating inflammatory signaling in skin fibroblasts. We show that, CD109 co-localizes and associates with Toll-like receptors (TLR2, TLR4) and tumor necrosis factor receptors (TNFRI, TNFRII), and that loss of CD109 enhances TNF--induced NF-{kappa}B activation and reprograms cytokine production in human dermal fibroblasts. Furthermore, both global and fibroblast-specific CD109 knockout mice exhibit increased immune cell infiltration and skin inflammation. In parallel, single-cell transcriptomic analyses across a pan-disease fibroblast atlas show that CD109 expression is preferentially maintained in structural and homeostatic fibroblast subtypes, whereas immune-interacting fibroblast subsets consistently display decreased CD109 levels. Pathway-level analyses of fibroblast pseudobulk samples reveal altered activity of canonical inflammatory pathways in SSc compared to healthy skin. Together, these findings identify CD109 as a fibroblast-intrinsic negative regulator of inflammatory signaling and suggest a broader role for CD109 in modulating inflammatory responses in systemic sclerosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/736423v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@be9e08org.highwire.dtl.DTLVardef@794173org.highwire.dtl.DTLVardef@b81eb5org.highwire.dtl.DTLVardef@1e811f5_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: CD109 Restrains Fibroblast-Driven Inflammation by Modulating NF-{kappa}B Signaling. Generated using FigureLabs.ai and edited using Adobe Photoshop. C_FIG

Merkel cell carcinoma (MCC) is a neuroendocrine skin tumor that is frequently driven by integration of Merkel cell polyomavirus (MCPyV). In MCC, the MCPyV genome is truncated, but expression of the viral tumor antigens, truncated large tumor antigen (LTT) and small tumor antigen (sT), is maintained and drives uncontrolled proliferation. We introduced constitutive expression of the MCPyV T antigens (TAs) into primary mouse dermal fibroblasts (MDFs) to determine whether these cells are susceptible to MCPyV-driven transformation. TA expression alone in MDFs induced key MCC markers, cytokeratin-20 (CK20) and Sry-box transcription factor 2 (SOX2), and promoted anchorage-independent growth indicative of cellular transformation. Subcutaneous implantation of TA-transformed fibroblasts produced high-grade MCC-like tumors that grew persistently in immunodeficient NSG mice but not in immunocompetent C57BL/6 mice. Serial in vivo passaging of the tumor cell line enhanced tumor growth, reduced expression of p53-target genes and MHC-1, and was accompanied by a shift in T antigen isoform expression, with decreased LTT and increased sT expression. Our data demonstrate that MCPyV-driven tumors acquire immune-evasive adaptions during tumor progression in vivo and suggest that the anti-tumor immune response exerts selective pressure in MCC that favors expression of sT rather than LTT. The model established in this study provides a unique platform for studying evolution of MCPyV-driven tumors under immune pressure and identifying mechanisms of immune evasion in MCC that could be used to develop new therapeutic strategies. Significance StatementMCPyV tumor antigen expression transforms mouse dermal fibroblasts to generate MCC-like tumors. Serial in vivo passaging reveals tumor evolution under immune pressure, providing a model to study immune evasion mechanisms in MCC.

Background Erythema nodosum leprosum (ENL) is a severe immune-mediated complication of multibacillary leprosy requiring prolonged immunosuppression. Steroid-sparing agents are essential to reduce relapse and treatment-related morbidity. Methods This longitudinal analytical observational study compared outcomes in patients with ENL treated with prednisolone plus thalidomide (Group A; n=30) and prednisolone plus tofacitinib (Group B; n=31). Patients were followed for 6 months. Primary outcomes included relapse rate and ENLIST ENL Severity Score (EESS). Secondary outcomes were neutrophil-lymphocyte ratio (NLR), Dermatology Life Quality Index (DLQI), steroid dependency, and adverse events. Inter-group comparisons and longitudinal analyses were performed using non-parametric tests. Correlations between NLR, EESS, and DLQI were assessed using Spearmans rank correlation. Results Relapse occurred in 36.7% of patients in Group A and 71.0% in Group B (p=0.007). The mean number of relapses was significantly lower in Group A (0.70{+/-}1.06 vs 1.84{+/-}1.51, p=0.002). At 3 and 6 months, Group A demonstrated significantly lower NLR values (p=0.017 and p<0.001, respectively). DLQI and EESS scores improved in both groups; however, sustained improvement was more consistent in Group A. Steroid-free status at 6 months was achieved in 93.3% of Group A compared with 58.1% of Group B (p<0.001). NLR showed a positive correlation with EESS ({rho}=0.269, p=0.018) and DLQI ({rho}=0.604, p<0.001) at 6 months. On multivariable logistic regression analysis adjusting for baseline confounders, patients receiving tofacitinib had significantly higher odds of relapse compared with those receiving thalidomide (adjusted OR 9.87, 95% CI 1.73-27.12; p = 0.006).Adverse events were predominantly mild to moderate, with differing safety profiles between groups. Conclusion Thalidomide demonstrated superior relapse prevention and steroid-sparing efficacy compared with tofacitinib in ENL. NLR correlated with disease severity and quality of life, supporting its role as a useful biomarker for monitoring disease activity during follow-up.

Pigmentation is a critical protective mechanism that safeguards the skin against UV-induced damage, whereas dysregulated pigmentation predisposes to pigmentary disorders and skin malignancies. Although calcium signaling has emerged as an important regulator of melanogenesis, the identity of the calcium-handling proteins and the molecular mechanisms linking calcium dynamics to pigmentation remain poorly understood. Here, we identify the ER calcium pump SERCA2b as a negative regulator of pigmentation through modulation of ER stress and mitochondrial calcium uptake. We demonstrate that SERCA2b expression inversely correlates with pigmentation levels, and gain- and loss-of-function studies establish SERCA2b as a suppressor of melanogenesis. Mechanistically, SERCA2b depletion induces adaptive ER stress, enhances ER-mitochondrial proximity, and promotes mitochondrial calcium uptake. Notably, mutations in SERCA2b are associated with Darier disease, a condition characterized by hyperpigmented skin lesions, although the underlying mechanism remains unknown. To address this, we generated SERCA2b mutants corresponding to variants identified in Indian Dariers disease patients and examined their effects on pigmentation, ER stress, and mitochondrial calcium dynamics. The mutant phenotypes closely recapitulated SERCA2b loss-of-function effects, demonstrating that adaptive ER stress and enhanced mitochondrial calcium signaling underlie hyperpigmentation associated with Dariers disease. Importantly, treatment with 4-phenylbutyrate (4-PBA), an FDA-approved ER stress alleviator, rescued mutant-induced hyperpigmentation, reduced ER stress, and normalized mitochondrial calcium uptake. Collectively, our findings uncover a previously unrecognized role of SERCA2b in skin pigmentation, establish a mechanistic link between SERCA2b mutations and hyperpigmentation, and identify adaptive ER stress pathways as potential therapeutic target for pigmentary disorders.

An autocrine pro-adhesive/pro-contractile signaling loop, through the mechanosensitive transcriptional cofactor YAP, promotes fibrosis. The CCN family of matricellular proteins modify adhesive signaling. Of these, CCN3 is antifibrotic. We show that BLR-200, a CCN3-derived peptide, has anti-fibrotic properties in the bleomycin-induced model of scleroderma skin fibrosis. In vitro, BLR-200 delayed, but did not abolish, fibroblast adhesion to collagen and nuclear YAP localization. In vivo, BLR-200 prevented/treated bleomycin-induced skin fibrosis, and reduced bleomycin-induced expression of profibrotic genes including alpha-smooth muscle actin, CCN1 and CCN2. Lineage tracing and scRNA-seq analyses revealed that the myofibroblasts in this model were quantitatively derived from collagen-lineage Pi16+/Col15+ve fibroblasts. BLR-200 prevented myofibroblast differentiation in this model and trajectory of fibroblasts toward a Sfrp2-positive subset, a cell type associated with poor clinical outcome. BLR-200 impairs YAP activation in vitro and appearance of translationally-relevant fibroblast subtypes in vivo and is a novel anti-fibrotic agent for SSc skin fibrosis.

Background: Cutaneous melanoma is the most aggressive malignant skin tumor, and metastasis represents the primary cause of patient mortality. Bisphenol S (BPS) has an unclear influence on melanoma metastasis and its underlying molecular mechanisms. Methods: Potential BPS targets were predicted using the SEA, SwissTargetPrediction, and SuperPred databases. Based on TCGA-SKCM transcriptomic data, differential expression analysis was performed, and Weighted Gene Co-expression Network Analysis (WGCNA) was employed to construct a gene co-expression network. Candidate genes were obtained by integrating BPS-related targets, differentially expressed genes (DEGs), module genes, and univariate Cox regression genes, followed by Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network construction. Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression was applied to screen core prognostic genes and construct a risk prediction model. Further analyses included network construction, molecular docking, and 100 ns molecular dynamics (MD) simulation. Results: Integration of BPS-related targets, DEGs, WGCNA module genes, and Cox regression results yielded 13 candidate genes enriched in kinase activity regulation and melanoma-related pathways. LASSO-Cox regression ultimately identified three core prognostic genes--ABCB1, PIM2, and TSHR--all significantly upregulated in metastatic tissues, with area under the curve (AUC) values of approximately 0.7. High-expression patients exhibited significantly better overall survival than low-expression patients (P < 0.05). A nomogram incorporating the three genes and clinical parameters demonstrated good calibration performance. Within the ceRNA network, MALAT1 and hsa-miR-155-5p were identified as key regulatory molecules, and 37 potential transcription factors were predicted, including CEBPA, JUN, and STAT3. Molecular docking revealed strong binding affinities of BPS toward ABCB1 , PIM2, and TSHR, and MD simulations confirmed the structural stability of all three complexes. Conclusion: ABCB1, PIM2, and TSHR are the core target genes through which BPS influences melanoma metastasis via multidrug resistance, kinase signaling, and receptor-mediated signal transduction. The prognostic model based on these three genes demonstrates good clinical applicability, and the ceRNA and transcription factor regulatory networks provide a systematic molecular basis for understanding the association between BPS exposure and melanoma metastasis.

Early detection of suspicious moles remains the most effective means of reducing mortality from skin cancer, yet systematic screening is constrained by the time and expertise required for manual mole assessment. This paper presents an end-to-end computational pipeline that utilizes wide-angle skin photographs (including consumer-grade smartphone images) and produces quantitative ABCD (Asymmetry, Border irregularity, Color variegation, Diameter) feature scores for every detected mole. The pipeline operates in four stages: mole detection via adaptive thresholding and blob analysis, super-resolution enhancement using EDSR, false-positive filtering using a brightness-based statistical criterion, and lesion segmentation using the Boundary Attention Mapper (BAM). BAM generates high-resolution segmentation masks by fusing early-layer activations with GradCAM heatmaps from a trained EfficientNet-B7 classifier, achieving 90.45% accuracy on the ISIC2017 dataset, outperforming both conventional GradCAM (87.78%) and dedicated segmentation architectures, including DeepLabv3 and SAM v2 by more than 5 percentage points in Dice score. The EfficientNet-B7 backbone achieves a micro-average AUC of 0.97 across eight lesion classes, with a melanoma AUC of 0.99. Color quantification uses K-means clustering with a threshold calibrated on the PH2 dataset (MSE = 1.425). Applied to 87 wide-angle images, the mole detection module achieved an F1 score of 86%. The system outputs a structured CSV of per-lesion ABCD scores suitable for clinical triage and longitudinal tracking. A clinical validation study with dermatologists and surgeons is underway to assess concordance between automated and expert assessments.

Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.

The innate immune system controls bacterial growth and modulates inflammation during wound healing. TCP-25 is a synthetic thrombin-derived host-defense peptide that combines direct antibacterial activity with neutralization of microbial products and modulation of CD14-dependent inflammatory signaling. We investigated whether this dual mechanism translates to human wounds using longitudinal samples from 24 healthy volunteers enrolled in a randomized, double-blind, within-participant, placebo-controlled phase I dose-escalation study of topical TCP-25 gel in matched epidermal suction blister wounds. We assessed inflammatory cytokines, neutrophil-derived proteins, wound exudation, cultivable bacterial burden, spatial bacterial distribution, and microbiome composition. TCP-25 reduced multiple cytokines, myeloperoxidase, and heparin-binding protein, with the strongest effects observed during the peak inflammatory phase. These changes were accompanied by reduced wound exudation and significant reductions in cultivable bacterial burden. Despite this antibacterial effect, microbiome composition and diversity remained largely unchanged, and participant-specific microbial profiles were preserved. TCP-25 therefore coordinated bacterial control, modulation of the physiological inflammatory response, and reduced wound leakage without major disruption of the resident microbiota composition. These findings provide clinical support for translating nature's endogenous host-defense principles into new therapies for complex wounds.

Melanoma, one of the most metastatic and multidrug resistant cancer, is the first leading cause of death from skin cancer. This complex disease requires identification of additional cooperating events that contribute to progression, invasion and metastasis to reinforce therapeutics. RhoGTPases play key roles in cancer development and metastasis. Rhophilin-2 (RHPN2), a Rho effector, is amplified in various human cancers and its role in melanoma remains unexplored. Here, we combined knock-down experiments in human melanoma cells, with knock-out and overexpression experiments in zebrafish to uncover the roles of RHPN2 in melanoma development. We show that in human melanoma cells RHPN2 contributes to growth, and to clonogenic, migratory and invasive properties of the cells. Using NRASQ61L and BRAFV600E zebrafish models, we provide the first in vivo evidence that Rhpn2 promotes melanoma onset and development. Histological analysis of the Rhpn2 deficient tumors showed decreased cellular density and absence of primary cilia structures at the invasive tumor/stroma borders. Transcriptomic profiling of the Rhpn2-KO melanoma revealed increased expression of the IFN1-responsive genes and modulation of genes involved in lipid metabolism and cilia function. Together these findings position RHPN2 as a modulator of melanoma, offering new perspectives in considering it as a target to impair the development of the tumor.

Corneal epithelial integrity depends on continuous epithelial renewal by limbal epithelial stem cells (LESCs), a process tightly linked to sensory innervation. Loss or impairment of innervation causes neurotrophic keratopathy (NK), a sight-threatening degenerative disease for which rhNGF, the only FDA-approved pharmacologic therapy, often has limited efficacy in advanced or refractory disease. The mechanistic basis for this limited response remains unclear. Using surgical, genetic, and pharmacologic approaches in a rodent model of NK with corneal Schwann cell ablation or structural and functional denervation, together with primary human LESCs, we examined how denervation alters NGF receptor signaling during epithelial repair. In innervated corneas, NGF promoted epithelial regeneration through TrkA. Denervation, however, increased expression of a second NGF receptor, anti-regenerative p75NTR, and activation of its effector JNK, and reduced the activity of the TrkA effector AKT in LESCs. In this altered receptor context, denervation-induced elevation of endogenous NGF amplified p75NTR signaling, thereby explaining the failure of topical rhNGF to rescue severely denervated NK phenotype corneas. Conversely, selective TrkA activation, either with the clinical-stage agonist tavilermide, or pharmacologic or genetic inhibition/ablation of p75NTR, restored AKT signaling and rescued epithelial healing in denervated corneas independent of reinnervation. These findings identify a nerve-dependent NGF receptor switch as a key regulator of corneal epithelial renewal and establish receptor-selective modulation as a mechanistically rational therapeutic strategy for treating NK. One Sentence SummaryCorneal denervation shifts limbal epithelial stem cell signaling from pro-regenerative TrkA-AKT toward anti-regenerative p75NTR-JNK, explaining the limited efficacy of recombinant human nerve growth factor (rhNGF; cenegermin), the only approved pharmacologic therapy for neurotrophic keratopathy, in severely denervated corneas and identifying receptor-selective modulation as a mechanistically distinct therapeutic strategy.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that frequently carries integrated Merkel cell polyomavirus DNA and expresses oncogenic viral small T antigen (sTAg) and truncated large T antigen (tLTAg). We previously reported a mouse model of MCC with skin-targeted expression of sTAg, tLTAg, and the Merkel cell transcription factor ATOH1, combined with deletion of Trp53. Here, we optimized this model to achieve 100% tumor penetrance with lymph node metastases, established four mouse MCC cell lines, and selected one line, mMCC2, for pilot preclinical trials. In immunocompetent C57BL/6J mice, mMCC2 cells reliably produce MCCs and lymph node metastases following subcutaneous or intradermal (orthotopic) injection, and liver and lung metastases after tail vein injection. Mouse MCC allografts resemble parental tumors histologically and express a full complement of MCC differentiation markers. Treatment of allografted mice with anti-PD-1 resulted in variable inhibition of tumor growth. In contrast, treatment with lysine-specific histone Wdemethylase 1 (LSD1) inhibitors, with or without anti-PD-1, led to consistently lower tumor volumes by 5.7-fold in both groups (P < 0.0001) and smaller or undetectable lymph node metastases. Growth-inhibited tumors in all groups showed a marked reduction in proliferating tumor cells and increased infiltration by F4/80+ macrophages and CD8+ T cells. These findings support a role for immune-cell recruitment in treatment response and underscore the importance of immunocompetent preclinical models, even in studies using targeted therapies. This unique virus-positive MCC allograft model, which produces local tumors as well as regional and distant metastases in immunocompetent hosts, provides a critical platform for preclinical evaluation of new therapeutic strategies and sets the stage for much-needed translational studies to inform future clinical trials.

Background: Chronic and non-healing wounds remain a major clinical challenge with limited therapeutic options. Angiogenesis and inflammation are central to tissue repair, and mesenchymal stem cells (MSC) contribute to these processes through their trophic and immunomodulatory secretome. Cannabidiol (CBD) exhibits antioxidant and immunomodulatory properties. However, whether CBD-rich Cannabis sativa extract stimulate MSC toward a pro-angiogenic secretome remains unclear. Purpose: This study aims to determine whether purified CBD or a phytochemically CBD-rich full spectrum extract stimulate umbilical cord-derived human MSC (UC-hMSC) to secrete pro-angiogenic factors and enhance endothelial responses relevant to wound healing. Methods: UC-hMSC were preconditioned with either purified CBD or a CBD-rich full-spectrum extract. Transcriptional changes were assessed by qPCR. The functional impact of the resulting secretome was evaluated in vitro using HUVEC-based proliferation and tube formation assays, and in vivo through the chick chorioallantoic membrane assay. To explore underlying mechanisms, we examined HIF-1 stabilization and VEGFA release in UC-hMSC, and VEGFR-2/ERK signaling in HUVEC. Results: Purified CBD and full-spectrum CBD extract preconditioned UC-hMSC secretomes, increased HUVEC proliferation, tube formation, and enhanced vascular branching in the CAM assay. Mechanistic analyses indicated activation of the HIF-1/VEGF axis in UC-hMSC, and ERK1/2 activation in HUVEC that was sensitive to VEGFR-2 blockade. Conclusion: Purified CBD and CBD-rich full-spectrum extract prime UC-hMSC toward a pro-angiogenic secretome that promotes endothelial activation and neovascularization. These findings suggest that cannabinoid-based preconditioning of UC-hMSC involves the HIF-1/VEGF axis and VEGFR-2/ERK signaling pathways in endothelial cells, supporting further investigation of this approach in wound healing and regenerative therapies.

Background: HIV infection has long been associated with increased incidence of severe cutaneous adverse reactions (SCAR). It remains unknown whether this increased incidence is a direct biological result of HIV infection, differences in drug exposure, or other demographic factors. Objective: To evaluate the association between HIV and SCAR and determine whether this relationship persists after adjusting for demographic factors and structured drug exposure. Methods: We analyzed reports from the FDA Adverse Event Reporting System (FAERS) from 2013-2023. SCAR outcomes included Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE). HIV status was determined using antiretroviral exposure, indication text, and machine-learning imputation. Logistic regression models were constructed sequentially: unadjusted, demographic-adjusted, and fully adjusted with drug principal components to account for polypharmacy. Drug-level disproportionality and HIV-drug interaction analyses were also performed. Results: In unadjusted models, HIV was strongly associated with SCAR (OR ~2.0-2.7). Adjustment for demographics attenuated this association, and further adjustment for drug exposure reduced the effect to near null for overall SCAR and DRESS. A modest residual association persisted for SJS/TEN (OR ~1.3). Disproportionality analyses demonstrated enrichment of specific high-risk drugs in PLWH. Interaction modeling revealed drug-specific amplification of SCAR risk in HIV, notably for carbamazepine and clarithromycin, whereas other drugs showed minimal interaction. Conclusion: The association between HIV and SCAR is largely explained by differences in drug exposure and demographic factors. Residual risk is drug-specific rather than uniform, supporting a model in which HIV modifies susceptibility to select drug triggers rather than acting as a global risk factor. Further prospective and retrospective studies are required to quantify associations.

Analyses of human breast carcinomas (BCs) and premalignant breast lesions show that the loss of RASSF1A is an early event in the development of ER+ BCs, which correlates linearly with malignant progression. This observation suggests that RASSF1A inhibition is important for the development and progression of ER+ BCs. In addition to RASSF1A, concurrent caveolin-1 (Cav-1) inhibition may further promote ER+ breast carcinogenesis. In the present study, transgenic Rassf1a-/- and Cav-1(-/-) single as well as Rassf1a-/-, Cav-1(-/-) double knockout mice were used to investigate the impact of single or combined Rassf1a and Cav-1 inactivation on BC initiation. Loss of either one or both proteins led to different, pre-malignant histopathological alterations within the mammary glands of the mice, but not to fully developed BC, confirming that Rassf1a and Cav-1 are both important for maintaining the integrity of mammary gland epithelial structure, but suggesting that further intracellular changes or extracellular factors are required for the development of luminal BC when both genes are lost.