Wang Q, Shvedova M, Abdelkader M
… +1 more, Roh DS
J Invest Dermatol
· 2026 Apr · PMID 41665592
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Although accumulating evidence implicates cellular senescence in acute wound healing, the precise roles of senescent cells within distinct cell lineages during this process remain elusive. To address this, we employed th...Although accumulating evidence implicates cellular senescence in acute wound healing, the precise roles of senescent cells within distinct cell lineages during this process remain elusive. To address this, we employed the p16-tdTomato reporter mouse model for labeling and isolating senescent cells from wound tissue. Longitudinal in vivo imaging monitoring revealed the temporal dynamics of tdTomato (tdTom) fluorescence, with signal detection as early as postoperative day 3, peaking by day 6. Utilizing an optimized tissue digestion protocol, we achieved high-viability FACS isolation of p16-expressing cells (tdTom+), which exhibited characteristic senescent cell morphology and marker expression. Single-cell analysis demonstrated that tdTom+ wound cells enriched with p16 expression were primarily characterized as fibroblasts and displayed common features of senescence. These findings validate the p16-tdTomato reporter mouse as a reliable model for identifying and isolating senescent cells from the wound microenvironment at single-cell resolution.
Circulating cell-free DNA fragmentomics-the analysis of cell-free DNA fragment-length profiles-has been explored as a biomarker across cancers, but evidence in melanoma is limited. We conducted a longitudinal prospective...Circulating cell-free DNA fragmentomics-the analysis of cell-free DNA fragment-length profiles-has been explored as a biomarker across cancers, but evidence in melanoma is limited. We conducted a longitudinal prospective study of 235 patients with American Joint Committee on Cancer stages II-IV melanoma (549 plasma samples) and 11 phenotypic high-risk healthy controls, quantifying 6 fragment-size ranges by routine capillary electrophoresis. Linear mixed-effects modeling and receiver operating characteristic analyses evaluated associations with disease status; time-dependent receiver operating characteristic and mixed-effects Cox regression assessed prognostic value in resected patients. Active-disease samples showed a fragmentation shift: enrichment and increased heterogeneity of short (20-150 bp) and short-dinucleosome (250-320 bp) fragments, with depletion of mononucleosome fragments (160-180 bp), consistent with tumor-associated nuclease/chromatin processing. Discrimination of active disease versus disease-free samples was modest (area under the curve up to 0.64), comparable with serum S100 (area under the curve 0.68) and higher than lactate dehydrogenase (area under the curve 0.60). In resected patients, 250-320 bp variability and short-fragment ratios predicted relapse-free and distant-metastasis-free survival from blood draw (hazard ratio ≈ 1.5-2.4 per 1 SD increase) after clinical adjustment, with strongest performance over ∼3-6 months. Correlations with S100/lactate dehydrogenase were weak, supporting independent biological information. Low-cost electrophoresis-based fragmentomics captures clinically meaningful shifts and provides complementary short-term prognostic information, supporting integration into higher-resolution or multimodal cell-free DNA assays for risk-adapted follow-up.
In contrast to chronic diabetic ulcers that are trapped in persistent heightened inflammation, diabetic wounds early after injury suffer from inadequate inflammatory responses. We previously identified defective chemotac...In contrast to chronic diabetic ulcers that are trapped in persistent heightened inflammation, diabetic wounds early after injury suffer from inadequate inflammatory responses. We previously identified defective chemotactic response in diabetic neutrophils, due to reduced signaling through the formyl peptide receptor, and diminished bioactive/bioavailable bacterial products (pathogen-associated molecular patterns), resulting from impaired bactericidal functions in diabetic neutrophils, as major culprits contributing to early inadequate inflammatory responses in diabetic wounds. Our prior work showed that topical treatments with either CCL3, a chemokine targeting auxiliary chemokine receptors to restore neutrophil trafficking, or lipopolysaccharide (LPS), a bacterial product to activate toll-like receptor, improved infection control and promoted healing by jumpstarting inflammatory responses early in diabetic wounds during the acute phase of healing. In this study, we evaluated whether combining CCL3 and LPS offers greater therapeutic benefit than either CCL3 or LPS alone. Our data show that CCL3 + LPS combination therapy was significantly more effective in reducing infection and enhancing wound healing than CCL3 or LPS monotherapies in db/db type 2 diabetic mouse model. We propose that topical application of CCL3 + LPS after surgical debridement-when chronic wounds are reset into an acute state-may offer a viable therapeutic approach for improving outcomes in diabetic wound care.
J Invest Dermatol
· 2026 Feb · PMID 41651107
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Atopic dermatitis is a chronic inflammatory skin disorder that affects over 200 million people worldwide. Although disease etiology is multifaceted, the immune checkpoint molecules OX40 and OX40L have a critical role in...Atopic dermatitis is a chronic inflammatory skin disorder that affects over 200 million people worldwide. Although disease etiology is multifaceted, the immune checkpoint molecules OX40 and OX40L have a critical role in disease development. Recent clinical trials demonstrated that the OX40-targeting antibodies rocatinlimab (KHK4083/AMG-451) and telazorlimab (GBR-830/ISB-830) and the OX40L-targeting antibody amlitelimab (KY1005) significantly improve symptoms of atopic dermatitis. However, the epitopes where these antibodies bind OX40 and OX40L remain unclear, and therefore, so do the mechanisms through which they specifically disrupt OX40-OX40L signaling. To address this, computational modeling was performed to predict antibody-protein cocomplexes, and their interaction interfaces were characterized. Binding-free energy of specific OX40 or OX40L residue-residue interactions within 5 Å of the antibody binding interface was analyzed using Molecular Mechanics Poisson-Boltzmann Surface Area with a per-residue energy decomposition analysis. Our analysis suggests that rocatinlimab and amlitelimab directly inhibit OX40-OX40L interactions by physically blocking the cognate OX40-OX40L interface through steric occlusion, whereas telazorlimab disrupts a critical OX40-OX40L bond. Together, this work provides molecular characterization of the epitopes of OX40- and OX40L-targeted biologics emerging in dermatology.
Alam R, Menon AA, Ch'en PY
… +8 more, Jabbour AJ, Gooley TA, Hippe DS, Bhakuni R, Miller N, Lachance K, Park SY, Nghiem P
J Invest Dermatol
· 2026 Feb · PMID 41644089
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Merkel cell carcinoma (MCC) recurs in 40% of patients, and 30% will require systemic therapy. Although PD-L1 immune checkpoint inhibitors (ICIs) have improved outcomes for advanced MCC, over half of patients do not exper...Merkel cell carcinoma (MCC) recurs in 40% of patients, and 30% will require systemic therapy. Although PD-L1 immune checkpoint inhibitors (ICIs) have improved outcomes for advanced MCC, over half of patients do not experience long-term disease control. MCC is radiosensitive, and there is evidence that radiation therapy (RT) can promote antitumor immunity. We performed an analysis of 27 prospectively followed patients whose MCC progressed on ICI use and who then received RT while continuing ICI use. The median progression-free survival on ICI alone was 2.8 months. After disease progression, continuation of ICI, and addition of RT, these same patients had median progression-free survival of 5.1 months (P = .09). Patients with acquired ICI resistance had lower risk of progression than those with primary resistance (hazard ratio = 0.35, 95% confidence interval = 0.14-0.89, P = .02). Patients who received a single dose of RT (8 Gy; n = 13) had a risk of disease progression similar to those of patients who received multiple fractions (≥20 Gy, n = 14) (hazard ratio = 0.87, 95% confidence interval = 0.37-2.00, P = .73). RT to all disease sites (n = 10) was associated with longer post-RT progression-free survival versus RT to a subset of sites (5.3 vs 2.8 months). RT was well-tolerated without significant toxicity and is a clinically useful salvage option for ICI-refractory MCC.
Atopic dermatitis (AD) is characterized by epidermal barrier dysfunction and immune dysregulation. Notably, metabolic disorders such as obesity can influence AD susceptibility; however, the specific molecular drivers und...Atopic dermatitis (AD) is characterized by epidermal barrier dysfunction and immune dysregulation. Notably, metabolic disorders such as obesity can influence AD susceptibility; however, the specific molecular drivers underlying this association, particularly those involving dysregulated RNA metabolism, remain incompletely understood. Our study demonstrates that obesity-associated upregulation of the N-methyladenosine demethylase FTO (fat mass and obesity-associated) in lesional epidermis, specifically in keratinocytes, drives AD pathology. Integrated transcriptomic and epitranscriptomic sequencing analyses identified SOCS6 (suppressor of cytokine signaling 6) as a key FTO target. Mechanistically, FTO selectively binds and demethylates N-methyladenosine modifications within the coding sequence of SOCS6 mRNA, reducing SOCS6 mRNA stability and protein expression. This site-specific epigenetic silencing activates inflammatory programs in keratinocytes. We further identified IL-1β, S100A8, and S100A9 as major downstream effectors of this FTO/SOCS6-N-methyladenosine axis, promoting keratinocyte apoptosis, barrier impairment, and inflammation. Critically, topical FTO knockdown in vivo ameliorated AD-like pathology and restored SOCS6 expression, confirming FTO's causative role. Collectively, we elucidate the FTO/SOCS6-N-methyladenosine epigenetic axis as a fundamental obesity-AD link, highlighting its components as promising therapeutic targets for precision AD management.
Photoaging, driven by chronic UVR, disrupts skin structure and function. Traditional retinoids enhance extracellular matrix regeneration but cause irritation. Hydroxypinacolone 9-cis retinoate (9-cis HPR), a derivative o...Photoaging, driven by chronic UVR, disrupts skin structure and function. Traditional retinoids enhance extracellular matrix regeneration but cause irritation. Hydroxypinacolone 9-cis retinoate (9-cis HPR), a derivative of 9-cis retinoic acid, selectively activates retinoic acid receptor α and retinoid X receptor α, improving efficacy and tolerability. In a UVR-induced SKH-1 mouse photoaging model, 9-cis HPR reduced erythema, desquamation, and loss of elasticity while promoting collagen and elastin production. Single-cell RNA sequencing and spatial transcriptomics revealed restoration of fibroblast, basal cell, and melanocyte proportions; suppression of myofibroblast differentiation; and upregulation of extracellular matrix-related genes (eg, Col1a2, Col3a1, Elastin). In addition, 9-cis HPR inhibited melanogenesis by downregulating melanogenesis-related genes (Tyr, Dct, Tyrp1), melanosome biogenesis genes (Mlana, Pmel), and the melanocyte proliferation gene Kit, likely through ROS suppression. Cell-cell interaction analysis showed that 9-cis HPR promoted fibroblast-driven repair through neuropeptide Y-NPY1R, PTN-SDC2, and POSTN-ITGA/BV signaling, while inhibiting KITL-KIT-mediated melanocyte proliferation. In a single-blind, split-face clinical trial involving 31 Chinese women, 0.03% 9-cis HPR applied daily for 4 weeks demonstrated comparable or superior improvements in wrinkles, elasticity, hydration, dermal density, and radiance versus 0.3% retinol, without observed irritation. These findings support 9-cis HPR as a safe and effective retinoid that mitigates photoaging through extracellular matrix restoration, inflammation modulation, and pigmentation control.
Di Girolamo D, Di Cicco E, Miro C
… +15 more, Murolo M, Nappi A, Cicatiello AG, Sagliocchi S, Acampora L, Restolfer F, Ferraro J, Sol S, Boncimino F, Isma J, Neel VA, Porcelli T, Blainpain C, Mandinova A, Dentice M
A hierarchical organization within a tumor underlies the varying capacities of cancer cells to proliferate, metastasize, and drive relapse. Cancer stem cells (CSCs) are resistant to conventional therapies, making them cr...A hierarchical organization within a tumor underlies the varying capacities of cancer cells to proliferate, metastasize, and drive relapse. Cancer stem cells (CSCs) are resistant to conventional therapies, making them critical targets for cancer treatment. Thyroid hormone (TH), a key regulator of proliferation and differentiation, is tightly controlled by the deiodinase enzymes. By integrating in vivo animal studies in a genetic mouse model of basal cell carcinoma (BCC) with analyses of human BCC specimens, we demonstrate that deiodinase type 3 (D3), the TH-inactivating enzyme, is expressed in the most tumorigenic CSC subpopulation. D3 genetic ablation significantly reduces the CSC population within protumorigenic niches and downregulates key stemness markers, including the transcription factor Sox9. Similarly, systemic induction of hyperthyroidism leads to a reduction of the CSC pool. Importantly, analysis of human BCC specimens revealed that D3 is highly enriched in the CSC niche. Mechanistically, we found that TH treatment suppresses Sox9 expression. These findings demonstrate that D3 sustains the tumorigenic potential of BCC CSCs by protecting them from TH-induced apoptosis and differentiation. Targeting the D3/TH axis may represent a promising therapeutic strategy to reduce the ability to self-renew of CSCs and inhibit tumor progression in BCC.
Andrades E, Iglesias A, Maqueda M
… +10 more, Lobo-Jarne T, González J, Bertran J, Conde D, Rodriguez E, Bellosillo B, Pujol RM, Bigas A, Espinosa L, Gallardo F
Eradication of Sézary syndrome (SS) is hampered by genetic and molecular heterogeneity. A better understanding of the putative commonalities underlying SS oncogenicity may help to provide more efficient therapies against...Eradication of Sézary syndrome (SS) is hampered by genetic and molecular heterogeneity. A better understanding of the putative commonalities underlying SS oncogenicity may help to provide more efficient therapies against this disease. This work analyzes the whole transcriptome of different patient-derived SS cells (n = 7) to identify expression patterns and mutational profiles that may provide clues on new therapeutic options for patients with SS. Mononuclear cells were recovered by Ficoll gradient from fresh peripheral blood of patients with SS (PBMCs). Selected pathway-based inhibitors were used for in vitro drug testing in SS cells using viability assay and flow cytometry. We validated the usefulness of MALT1 inhibitor MI2 using patient-derived SS cells xenografted into 8 NSG mice from patient #26. We identified a high variability in the mutational landscape that converge in a restricted number of altered signaling pathways. In vitro data indicated that cell lines and primary malignant SS cells display different sensitivities against pathway inhibitors. MALT1 inhibition, which impacts on NF-κB signaling, led to a robust effect in vitro that was partially reproduced in the NSG model. Our investigations revealed the actual possibility of inhibiting downstream TCR signaling by CARD11, BCL10, and MALT1 in SS therapy.
BACKGROUND: Upadacitinib (UPA), an oral selective Jak inhibitor, showed significantly greater facial repigmentation than placebo as assessed by Facial Vitiligo Area Scoring Index (F-VASI) in a phase 2 clinical trial. A n...BACKGROUND: Upadacitinib (UPA), an oral selective Jak inhibitor, showed significantly greater facial repigmentation than placebo as assessed by Facial Vitiligo Area Scoring Index (F-VASI) in a phase 2 clinical trial. A nested substudy explored a 3-dimensional (3D) imaging platform as an objective tool to quantify facial vitiligo repigmentation. METHODS: Adults with nonsegmental vitiligo received 6, 11, or 22 mg UPA or placebo for 24 weeks (period 1). For weeks 24-52 (period 2), UPA-treated patients continued UPA at assigned doses; patients receiving placebo switched to 11 or 22 mg UPA. In this substudy, efficacy was assessed by the percentage change from baseline in facial vitiligo area with 3D imaging and F-VASI. RESULTS: The substudy included 27 patients. Patients receiving UPA showed facial repigmentation at weeks 24 and 52 as assessed by 3D imaging and F-VASI. There was a high correlation between 3D imaging and F-VASI measurements at baseline (r = 0.85; P < .0001). At week 24, there was a high correlation (r = 0.71; P = .0003) between the percentage change from baseline in 3D imaging and F-VASI measurements, which diminished by week 52 (r = 0.01; P = .9600). CONCLUSIONS: 3D imaging shows potential as an objective tool for evaluating changes in facial vitiligo after UPA treatment.