The Journal of investigative dermatology最新文献

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.

Photoaging, driven by chronic ultraviolet radiation (UVR), disrupts skin structure and function. Traditional retinoids enhance extracellular matrix (ECM) regeneration but cause irritation. Hydroxypinacolone 9-cis retinoate (9-cis HPR), a derivative of 9-cis retinoic acid, selectively activates RARα and RXRα, 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 ECM-related genes (e.g., Col1a2, Col3a1, Elastin). Additionally, 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 via ROS suppression. Cell-cell interaction analysis showed that 9-cis HPR promoted fibroblast-driven repair via NPY-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 ECM restoration, inflammation modulation, and pigmentation control.

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. The present 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 SS patients. Mononuclear cells were recovered by Ficoll gradient from fresh peripheral blood of SS patients (PBMCs). Selected pathway-based inhibitors were used for in vitro drug testing in SS cells using viability assay and flow cytometry (FC). We validated the usefulness of MALT1 inhibitor MI2 using patient-derived SS cells xenografted into eight 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.

Segmental vitiligo (SV) is characterized by unilateral depigmentation, frequent leukotrichia, early stabilization, and unique pathomechanisms that differentiate it from nonsegmental vitiligo. This review systematically examines the epidemiology, clinical features, diagnosis, pathogenesis, and therapeutic advances in SV, emphasizing its classification as a distinct disease entity. Emerging evidence has provided significant insights into SV pathogenesis, including neurovascular factors, immune dysregulation, oxidative stress, and melanocyte dysfunction. Clinically, SV requires differentiation from other hypopigmentation disorders owing to its distinct progression and therapeutic challenges. Although conventional therapies exhibit limited efficacy, emerging approaches such as cellular grafting and targeted immunomodulation hold promise. This review advocates for future research to focus on the integration of multiomics data to establish SV-specific biomarkers and personalized diagnostic and therapeutic strategies.

Background: Upadacitinib, an oral selective Janus kinase inhibitor, showed significantly greater facial repigmentation vs 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 non-segmental vitiligo received upadacitinib 6mg, 11mg, or 22mg or placebo for 24 weeks (period 1). For weeks 24-52 (period 2), upadacitinib-treated patients continued upadacitinib at assigned doses; patients receiving placebo switched to upadacitinib 11mg or 22mg. In this substudy, efficacy was assessed by the percent change from baseline in facial vitiligo area with 3D imaging and F-VASI.

Results: The substudy included twenty-seven patients. Patients receiving upadacitinib 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 percent 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 upadacitinib treatment.

Clinical trial registration number: NCT04727975.

Dermatological conditions can become extremely serious and cause life-threatening situations for affected patients, thereby necessitating intensive care. However, data regarding the specialized dermatology intensive care unit (DICU) remain scarce. We conducted a retrospective analysis of electronic medical records from July 2017 to September 2023, covering 825 patients admitted to the DICU at Huashan Hospital, one of China's largest tertiary hospitals and the only facility in the country equipped with a dedicated DICU. The median (interquartile range, [IQR]) patient age was 60.0 (43.0-72.0) years, with a male-to-female ratio of 1.4. The predominant diagnoses were severe cutaneous adverse reactions to drugs (29.2%), bullous skin diseases (18.4%), and psoriasis (16.5%). The overall in-hospital mortality rate was 0.36%. The median (IQR) length of stay was 11.0 (7.0-15.0) days, and the median (IQR) total cost per patient was $4196 ($2655-7278). Analysis indicated that the length of stay and total hospitalization costs were primarily influenced by the main diagnosis and comorbidities. This study provides insights into the clinical characteristics, outcomes, and economic implications of managing severe dermatoses in a specialized intensive care setting, highlighting the significant impact of comorbidities on resource utilization.

Localized scleroderma (LoS) is a chronic dermal disease with fibrotic skin and subcutaneous tissues. Due to the largely undefined pathogenesis, there is no specific medical treatment for LoS. Recent investigator-initiated tests have revealed the clinical efficacy of botulinum neurotoxin type A1 (BoNT/A1) on treating LoS. However, the mechanism of action of BoNT/A1-based LoS intervention has not been fully illustrated. Herein, we used a bleomycin-induced skin fibrosis mouse model for evaluating the therapeutic effects and mechanism of actions of BoNT/A1 relevant to LoS. It was found that BoNT/A1 treatment could alleviate the pathological changes in mice in a dose-dependent manner. Further analysis showed that BoNT/A1 could suppress the proliferation of primary human dermal fibroblasts (HDFs) by arresting the cell cycle at G0/G1 phase. RNA-Seq and subsequent western blotting analysis of HDFs revealed PI3K-Akt signaling as one of the most affected pathways in BoNT/A1 treatment groups. Experiments with PI3K-Akt agonist 740Y-P showed that BoNT/A1 suppressed skin fibrosis by inhibiting PI3K-Akt signaling. Collectively, our study provides experimental evidence at the animal, cellular and molecular levels for the clinical use of BoNT/A1 for treating LoS.