The Journal of investigative dermatology最新文献

Circulating cell-free DNA (cfDNA) fragmentomics-the analysis of cfDNA 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 AJCC stage II-IV melanoma patients (549 plasma samples) and 11 phenotypic high-risk healthy controls, quantifying six fragment-size ranges by routine capillary electrophoresis. Linear mixed-effects modelling and ROC analyses evaluated associations with disease status; time-dependent ROC 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 tumour-associated nuclease/chromatin processing. Discrimination of active disease versus disease-free samples was modest (AUC up to 0.64), comparable to serum S100 (AUC 0.68) and higher than LDH (AUC 0.60). In resected patients, 250-320 bp variability and short-fragment ratios predicted relapse-free and distant-metastasis-free survival from blood draw (HR ≈ 1.5-2.4 per 1 SD increase) after clinical adjustment, with strongest performance over ∼3-6 months. Correlations with S100/LDH 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 cfDNA 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 chemotactic response in diabetic neutrophils, due to reduced signaling through the formyl peptide receptor (FPR), and diminished bioactive/bioavailable bacterial products (PAMPs), 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. Here, 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 compared to CCL3 or LPS monotherapies in db/db type 2 diabetic mice. 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.

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 by which they specifically disrupt OX40-OX40L signaling. To address this, computational modeling was performed to predict antibody-protein co-complexes, 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 were analyzed using MM-PBSA with a per-residue energy decomposition analysis. Our analysis suggests rocatinlimab and amlitelimab directly inhibit OX40-OX40L interactions by physically blocking the cognate OX40-OX40L interface via 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.

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 N⁶-methyladenosine (m⁶A) demethylase FTO in lesional epidermis, specifically in keratinocytes (KCs), drives AD pathology. Integrated transcriptomic and epitranscriptomic sequencing analyses identified Suppressor of Cytokine Signaling 6 (SOCS6) as a key FTO target. Mechanistically, FTO selectively binds and demethylates m⁶A modifications within the coding sequence (CDS) of SOCS6 mRNA, reducing SOCS6 mRNA stability and protein expression. This site-specific epigenetic silencing activates inflammatory programs in KCs. We further identified IL-1β, S100A8, and S100A9 as major downstream effectors of this FTO/SOCS6-m⁶A axis, promoting KCs 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-m⁶A epigenetic axis as a fundamental obesity-AD link, highlighting its components as promising therapeutic targets for precision AD management.

Merkel cell carcinoma (MCC) recurs in 40% of patients and 30% will require systemic therapy. While PD-(L)1 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 anti-tumor immunity. We performed an analysis of 27 prospectively-followed patients whose MCC progressed on ICI, and who then received RT while continuing ICI. The median progression-free survival (PFS) on ICI alone was 2.8 months. Following disease progression, continuation of ICI, and addition of RT, these same patients had median PFS of 5.1 months (p=0.09). Patients with acquired ICI resistance had lower risk of progression than those with primary resistance (hazard ratio (HR) 0.35, 95% CI: 0.14-0.89, p=0.02). Patients who received a single dose of RT (8 Gray; n=13) had a similar risk of disease progression to those who received multiple fractions (≥20 Gray, n=14; HR 0.87, 95%CI: 0.37-2.00, p = 0.73). RT to all disease sites (n=10) was associated with longer post-RT PFS 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.

A hierarchical organization within 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 the 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 pro-tumorigenic 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.