Endogenous stimuli-responsive separating microneedles to inhibit hypertrophic scar through remodeling the pathological microenvironment.

Hypertrophic scar (HS) considerably affects the appearance and causes tissue dysfunction in patients. The low bioavailability of 5-fluorouracil poses a challenge for HS treatment. Here we show a separating microneedle (MN) consisting of photo-crosslinked GelMA and 5-FuA-Pep-MA prodrug in response to high reactive oxygen species (ROS) levels and overexpression of matrix metalloproteinases (MMPs) in the HS pathological microenvironment. In vivo experiments in female mice demonstrate that the retention of MN tips in the tissue provides a slowly sustained drug release manner. Importantly, drug-loaded MNs could remodel the pathological microenvironment of female rabbit ear HS tissues by ROS scavenging and MMPs consumption. Bulk and single cell RNA sequencing analyses confirm that drug-loaded MNs could reverse skin fibrosis through down-regulation of BCL-2-associated death promoter (BAD), insulin-like growth factor 1 receptor (IGF1R) pathways, simultaneously regulate inflammatory response and keratinocyte differentiation via up-regulation of toll-like receptors (TOLL), interleukin-1 receptor (IL1R) and keratinocyte pathways, and promote the interactions between fibroblasts and keratinocytes via ligand-receptor pair of proteoglycans 2 (HSPG2)-dystroglycan 1(DAG1). This study reveals the potential therapeutic mechanism of drug-loaded MNs in HS treatment and presents a broad prospect for clinical application.

Identification and validation of CCR5 linking keloid with atopic dermatitis through comprehensive bioinformatics analysis and machine learning.

There is sufficient evidence indicating that keloid is strongly associated with atopic dermatitis (AD) across ethnic groups. However, the molecular mechanism underlying the association is not fully understood. The aim of this study is to discover the underlying mechanism of the association between keloid and AD by integrating comprehensive bioinformatics techniques and machine learning methods. The gene expression profiles of keloid and AD were downloaded from the Gene Expression Omnibus (GEO) database. A total of 449 differentially expressed genes (DEGs) were found to be shared in keloid and AD using the training datasets of GEO (GSE158395 and GSE121212). The hub genes were identified using the protein-protein interaction network and Cytoscape software. 20 of the most significant hub genes were selected, which were mainly involved in the regulation of the inflammatory and immune response. Through two machine learning algorithms of LASSO and SVM-RFE, CCR5 was identified as the most important key gene. Subsequently, upregulated CCR5 gene expression was confirmed in validation GEO datasets (GSE188952 and GSE32924) and clinical samples of keloid and AD. Immune infiltration analysis showed that T helper (Th) 1, 2 and 17 cells were significantly enriched in the microenvironment of both keloid and AD. Positive correlations were found between CCR5 and Th1, Th2 and Th17 cells. Finally, two TFs of CCR5, NR3C2 and YY1, were identified, both of which were downregulated in keloid and AD tissues. Our study firstly reveals that keloid and AD shared common inflammatory and immune pathways. Moreover, CCR5 plays a key role in the pathogenesis association between keloid and AD. The common pathways and key genes may shed light on further mechanism research and targeted therapy, and may provide therapeutic interventions of keloid with AD.

Peeling from a liquid.

We establish the existence of a cusp in the curvature of a solid sheet at its contact with a liquid subphase. We study two configurations in floating sheets where the solid-vapor-liquid contact line is a straight line and a circle, respectively. In the former case, a rectangular sheet is lifted at its one edge, whereas in the latter a gas bubble is injected beneath a floating sheet. We show that in both geometries the derivative of the sheet's curvature is discontinuous. We demonstrate that the boundary condition at the contact is identical in these two geometries, even though the shape of the contact line and the stress distribution in the sheet are very different.

Risk factors of long-term alopecia after pulsed-dye laser treatment for infantile scalp hemangiomas: A retrospective study.

Pulsed-dye laser (PDL), as an effective and frequently-used treatment modality for infantile hemangiomas (IH), could render patients at risk of developing long-term alopecia. Data on alopecia caused by PDL treatment remain scant and the contributing factors are not clear. Our objective was to identify the risk factors associated with long-term alopecia resulting from PDL treatment for scalp IH. We conducted a retrospective study incorporating patients with IH diagnosis and PDL intervention via thoroughly reviewing the clinical database of the dermatology department. Scalp IH patients were further screened and their medical records were collected. Long-term alopecia was defined as no signs of terminal hair regrowth for at least 2 years in this study. Of the 1293 IH patients, 47 (14 boys and 33 girls) with a mean age of 4.5 months (standard deviation, 3.2) were diagnosed as scalp IH and had subsequently undergone PDL treatments. Hair growth in the treatment area of 18 patients (38.3%) nearly returned to normal, 22 patients (46.8%) had varying degrees of hair loss, and seven patients (14.9%) had no hair regrowth (long-term alopecia). Compared with the older patients receiving treatment, IH patients younger than 3 months who started PDL treatment had a higher risk of developing long-term alopecia (odds ratio, 30.833; 95% confidence interval, 4.079-232.025; p = 0.01). The total number of PDL sessions, post-treatment blisters, and location of IH were not shown to be significantly associated with the development of long-term alopecia. Collectively, our study provides an important insight into curating treatments for IH in infants younger than 3 months. PDL treatments for scalp IH may perhaps be avoided or delayed to prevent the development of treatment-associated long-term alopecia.

Comparing the Accuracy of ABCD-10 and SCORTEN in Predicting the In-Hospital Mortality of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A Multi-Institutional Study from Central China.

BACKGROUND: The newly described ABCD-10 (age, bicarbonate, cancer, dialysis, 10% body surface area [BSA]) is a 5-item mortality prediction model for patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). It was developed in the United States, has at present been externally tested only in the United States, Spain, and Singapore, and remains to be validated in resource-restricted settings. We sought to compare the accuracy of ABCD-10 and Score of Toxic Epidermal Necrolysis (SCORTEN) in predicting in-hospital mortality in a cohort from central China. Due to disease progression affecting the accuracy of the prediction model during hospitalization, for example, higher predictive accuracy of SCORTEN based on parameters collected on day 3 of hospitalization, we also assessed the overall predictive value of ABCD-10 on days 1 and 3, respectively. METHODS: A retrospective study was performed over a 10-year period (2010-2020) from 3 medical institutions in Wuhan. The performance of predictive models was assessed by both discrimination and calibration. Receiver-operating characteristic (ROC) curves, Hosmer-Lemeshow goodness-of-fit tests and calibration plots were used to evaluate the model discrimination and calibration. RESULTS: Of 84 included patients, 11 (13.1%) did not survive. The discrimination power of ABCD-10 was not significantly different from that of SCORTEN (area under the curve: day 1, p > 0.05; day 3, p > 0.05). Although the calibration of ABCD-10 was good, it was inferior to SCORTEN as it underestimated total mortality (Hosmer-Lemeshow goodness-of-fit test: day 1, p = 0.17 vs. p = 0.63; day 3, p = 0.35 vs. p = 0.93). Besides, the performance of ABCD-10 was slightly better on day 3 relative to day 1. During hospitalization, bacteremia developed in 21 (25.0%) patients, which was associated with a higher risk of death in our cohort (odds ratio, 22.88; 95% CI, 4.38-119.40; p < 0.001). CONCLUSION: ABCD-10 showed acceptable overall performance, but revealed mortality underestimation and was inferior to the performance of SCORTEN. In consistence with SCORTEN, ABCD-10 was a better model when using values collected at day 3 of hospitalization relative to day 1.

Injectable and pH-Sensitive Hyaluronic Acid-Based Hydrogels with On-Demand Release of Antimicrobial Peptides for Infected Wound Healing.

Antibiotics' abuse in bacteria-infected wounds has threatened patients' lives and burdened medical systems. Hence, antibiotic-free hydrogel-based biomaterials, which exhibit biostability, on-demand release of antibacterial agents, and long-lasting antimicrobial activity, are highly desired for the treatment of chronic bacteria-infected wounds. Herein, we developed a hyaluronic acid (HA)-based composite hydrogel, with an antimicrobial peptide [AMP, KK(SLKL)3KK] as a cross-linking agent through Schiff's base formation, which exhibited an acidity-triggered release of AMP (pathological environment in bacteria-infected wounds, pH ∼ 5.5-5.6). During the self-assembly process, AMP adopted an antiparallel ß-sheet secondary structure due to the alternate arrangement of hydrophobic and hydrophilic residues of amino acids. Owing to Schiff's base formation between the primary amines derived from lysine residues and the aldehydes in oxidized HA, the AMP-HA composite hydrogel exhibited injectability, high biostability, and enhanced mechanical strength. Importantly, both AMP and the AMP-HA composite showed excellent broad-spectrum antibacterial activity in vitro and in vivo. Specifically, the AMP-HA composite hydrogel exhibited on-demand full thickness wound healing in an infected mice model. Therefore, this work provides an efficient strategy to fabricate antibiotic-free hydrogel-based biomaterials for the management of chronic bacteria-infected wounds.

Apoptotic cell-mimicking gold nanocages loaded with LXR agonist for attenuating the progression of murine systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.

The Unknown Aspect of BAFF: Inducing IL-35 Production by a CD5+CD1dhiFcγRIIbhi Regulatory B-Cell Subset in Lupus.

IL-35 is a critical immunosuppressive cytokine that plays an important role in various autoimmune diseases. The purpose of this study was to determine whether BAFF, a key pathogenic factor in systemic lupus erythematosus, also a dichotomous regulator for B-cell immune responses, has an effect on IL-35-producing regulatory B cells and their underlying mechanisms in lupus. We found that exogenous BAFF could induce IL-35 production by splenic B cells from MRL-Faslpr/lpr mice. BAFF-induced IL-35-producing B cells were mainly from the marginal zone B-cell subset and exhibited a CD5+CD1dhiFcγRIIbhi phenotype. These IL-35-producing regulatory B-cell subsets exhibited regulatory effects on both CD4+CD25- T cells and CD4+CD25+ regulatory T cells. We further identified that BAFF-TACI interaction could induce the production of IL-35 through the classical NF-κB1 pathway. In vivo study also showed that BAFF could facilitate IL-35 secretion in marginal zone B cells, whereas anti-BAFF treatment could decrease the frequency of IL-35-producing CD5+CD1dhiFcγRIIbhi B cells in MRL-Faslpr/lpr mice. We showed that BAFF could induce IL-35 production by a unique CD5+CD1dhiFcγRIIbhi regulatory B-cell subset mainly through TACI activation in lupus, providing an advanced understanding of the regulatory effect of BAFF in autoimmune diseases.