Shanghai Skin Disease Hospital

Supraglottic jet ventilation (SJV) is used during flexible bronchoscopy to improve oxygenation, but its impact on overall lung ventilation is unclear. Thoracic electrical impedance tomography (EIT) offers real-time monitoring of respiratory function. This prospective pilot study enrolled patients undergoing flexible bronchoscopy. End-expiratory lung impedance (EELI) changes from baseline (ΔEELI) were measured at baseline (T0), oxygenation with Wei nasal jet (WNJ) (T1), SJV (T2), during bronchoscopy (T3), and post-bronchoscopy (T4). The primary outcome was ΔEELI at T2 vs. T3. Secondary outcomes included ΔEELI at other time points, ventilation distribution (ventral vs. total lung, ROIventral), hemodynamics, oxygen saturation (SpO2) at each point, and adverse events. Among 27 patients, 5 experienced transient desaturation (no laryngeal mask ventilation needed). ΔEELI and SpO2 significantly decreased from T2-T3 (ΔEELI: -2.65, 95% CI -4.27 to -1.02, p < 0.001; SpO2: -2.5%, 95% CI -4.7 to -0.3%, p < 0.001). Conversely, ΔEELI and SpO2 significantly increased from T1-T2 (ΔEELI: 1.84, 95% CI 1.02-2.66, p < 0.001; SpO2: 3.3%, 95% CI 1.3-5.2%, p < 0.001), with ROIventral rising from 43.7 to 60.4% (16.6% increase, 95% CI 4.4-28.9%, p < 0.001). While SJV did not prevent the negative effects of bronchoscopy on lung ventilation and oxygenation, it maintained adequate SpO2. Pre-bronchoscopy SJV improved these measures, but shifted ventilation towards ventral lung regions compared to WNJoxygenation. Chinese Clinical Trial Registry (URL: Chictr.org.cn), Identifier: ChiCTR2100050285. Date of registration: Aug 25th, 2021.

Chronic spontaneous urticaria (CSU) poses a significant burden on both patient and caregiver. Currently treatments for CSU are inadequate for some patients. TLL-018, an oral TYK2/JAK1 inhibitor, is under investigation for CSU treatment. To evaluate the efficacy and safety of TLL-018 for treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines. In this multicenter, double-blind, randomized, placebo-controlled, parallel-group pilot study (NCT05373355), patients with CSU who showed an inadequate response to antihistamines received either 10 mg or 30 mg of TLL-018, or placebo orally twice daily. After 4 weeks, patients on placebo were switched to 20 mg of TLL-018, and continuing treatment for an additional 8 weeks. The primary endpoint was safety, while secondary endpoints included efficacy measures, such as weekly Urticaria Activity Score (UAS7) ≤ 6, UAS7 = 0, and a Dermatology Life Quality Index of 0 or 1 at weeks 4 and 12. The study involved of 41 patients. At week 4, the ANCOVA versus change from placebo of UAS7/weekly Itch Severity Score/weekly Hive Severity Score were -11.5/-8.0/-3.8 in the 10-mg groups and -16.0/-9.0/-7.0 in the 30-mg groups. At week 12, the percentages achieving UAS7 ≤ 6 and UAS7 = 0 were 53.8%/38.5%, 71.4%/64.3%, and 61.5%/53.8% in the placebo-to-20 mg, the 10-mg, and the 30-mg TLL-018 groups, respectively. Common treatment-emergent adverse events included elevated serum creatine kinase and blood lipid levels, hyperglycemia, and urinary occult blood. TLL-018 was well-tolerated and effective in treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines.

Hair follicle stem cells (HFSCs) in androgenetic alopecia (AGA) patients exhibit functional impairment, reduced quantity, dysregulation, and androgen sensitivity, which hinder therapeutic strategies targeting HFSCs activation for hair regeneration. This study aims to elucidate the molecular mechanisms underlying HFSCs dysfunction in AGA and identify novel therapeutic targets. We compared the expression of insulin-like growth factor 1 (IGF-1) in hair follicle tissues between AGA patients and healthy controls, analyzing transcriptional and protein-level differences. Bioinformatics, luciferase assays, and correlation analyses were employed to investigate the AR/miR-128-3p/IGF-1 pathway. Mechanistic studies were conducted using dermal papilla cells (DPCs) from both AGA patients and normal donors, which included RNA interaction assays and functional validation. Furthermore, the mechanism was validated by assessing the phenotypic changes in HFSCs co-cultured experiments. In vivo experiments in AGA mice were performed to evaluate hair follicle regeneration following ASLNC168501 overexpression. IGF-1 expression was markedly reduced in hair follicles of AGA patients, with transcriptional alterations occurring later than changes at the protein-level alterations. Dysregulation of the AR/miR-128-3p/IGF-1 pathway in DPCs was identified as a key driver of HFSCs dysfunction: AR transcriptionally activates miR-128-3p, which in turn suppresses IGF-1 by binding to its 3'UTR. Consequently, the ability of IGF-1 to sustain and support HFSCs activity is impaired. The endogenous ASLNC168501 functions as a ceRNA, sequestering miR-128-3p and thereby restoring IGF-1 expression and secretion. Exogenous overexpression of ASLNC168501 in DPCs significantly promoted the self-renewal, proliferative and differentiation potential of co-cultured HFSCs in vitro and reversed hair follicle atrophy in AGA mice. Our findings demonstrate that loss of ASLNC168501 accelerates the progression of AGA by activating AR/miR-128-3p/IGF-1 pathway activation. Acting as a pathway-independent RNA, ASLNC168501 holds a target significant therapeutic potential for restoring HFSCs function and promoting hair follicle regeneration. This finding highlights a novel molecular target and contributes to the advancement of precision medicine strategies for androgen-related alopecia.

ABSTRACTBackgroundModern living encouraged longer working hours and an increased sense of fatigue. In China, a rising trend called “996”, meaning working from 9 a.m. to 9 p.m., 6 days per week in succession, has raised concerns about the impact of fatigue on health, specifically on skin aging.MethodsA one‐week, single center, self‐controlled clinical study was conducted to evaluate the impact of fatigue on skin phenotypes, through the enrollment of 31 Chinese women with a 996 work‐life pattern based on Life Style questionnaires and Chalder fatigue scale. Clinical grading and instrumental measurements were conducted before the working week, after 1, 3, and 5 working days.ResultsThe fatigue score of the participants accumulated during the working week. From clinical grading, periocular fine lines, fine lines of the cheeks, and forehead wrinkles were significantly worsened in the working week compared to the weekend. Skin elasticity parameters R0, R5, and R7 were also significantly worse compared to the weekend. Significantly increased porphyrin, yellowness, and decrease of redness of skin during working times were also observed. Additionally, the clinical evaluations were well recorded with self‐perceptions from the questionnaire.ConclusionFatigue is an inescapable stressor in modern life that impacts skin's health and appearance by accelerating signs of aging, altering skin color, and increasing risk of acne. This is a pilot study analyzing the population with intensive work‐life patterns, serving as a reference to comprehensively assess the impact of modern living on skin.

Androgenetic alopecia (AGA) is characterized by hair follicle miniaturization and growth factor deficiency. However, conventional therapies such as minoxidil and finasteride fail to restore the pathological follicular microenvironment, highlighting the urgent need for novel therapeutic strategies. Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are key regulators of hair follicle regeneration, yet their expression is downregulated in the follicular microenvironment of AGA patients. This study validated the expression profile of growth factors in hair follicles of AGA patients through clinical sample analysis. Subsequently, dual‑factor engineered exosomes (EXO‑EGF/FGF) loaded with EGF and FGF were constructed using LAMP2B fusion engineering technology with 293T cells as donor cells. EXO‑EGF/FGF was characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The regulatory effects of EXO‑EGF/FGF on human dermal papilla cells (HDPCs) were evaluated in vitro. An androgen‑induced AGA mouse model was established to assess the therapeutic efficacy and safety of EXO‑EGF/FGF in vivo. Clinical sample analysis confirmed that the expression of EGF and FGF was significantly downregulated in dermal papilla cells of AGA patients, leading to reduced expression of NOTCH signaling pathway proteins associated with hair follicle regeneration. TEM and NTA results demonstrated that EXO‑EGF/FGF exhibited exosomal morphology, with significantly higher expression levels of EGF and FGF than natural exosomes. In vitro experiments revealed that EXO‑EGF/FGF promoted the proliferation and migration of HDPCs by reactivating the cell cycle and enhancing migration‑related programs. In the AGA mouse model, EXO‑EGF/FGF effectively restored hair coverage density and follicular structural integrity without inducing immunogenic reactions or systemic toxicity, and significantly increased the number of anagen‑phase hair follicles in post‑treatment tissues. This study demonstrated that LAMP2B‑engineered EXO‑EGF/FGF acted on follicular cells to repair the pathological microenvironment in AGA. This strategy overcame the inherent limitations of conventional therapies and natural exosomes, offering a novel, safe, and clinically translatable therapeutic approach for AGA treatment.

Anti-melanoma differentiation-associated gene 5 antibody-positive (MDA5+) dermatomyositis (DM) is characterized by a high incidence of rapidly progressive interstitial lung disease (RP-ILD). Unique transcriptomic signatures in patients with MDA5+ DM were investigated. Peripheral blood mononuclear cells (PBMCs), skin, and muscle biopsies from 28 patients with MDA5+/- DM were sequenced. Uniquely expressed transcripts identified using RNA sequencing analysis of PBMCs were further validated using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Receiver operating characteristic analysis was used to determine the diagnostic potential of the target genes. In MDA5+ DM samples, components of antiviral defense, neutrophil migration, and immune-associated pathways (in PBMCs), fatty acid metabolic processes (in skin), and antigen recognition (in muscle tissue) were upregulated. The expressions of defensin alpha 3 (DEFA3), ribonuclease family member 2 (RNASE2), and interferon alpha inducible protein 27 (IFI27) were upregulated and exhibited good predictive values for RP-ILD in MDA5+ DM. The activation of the IFN, virus-associated, and aberrant immune response pathways, as well as fatty acid metabolic processes may be involved in MDA5+ DM pathogenesis. IFI27, DEFA3, and RNASE2 may contribute to RP-ILD pathogenesis and serve as biomarkers of MDA5+ DM.