Epidermal Stem Cell Derived Exosomes Alleviate Excessive Autophagy Induced Endothelial Cell Apoptosis by Delivering miR200b-3p to Diabetic Wounds.

The dysfunction of endothelial cells caused by hyperglycemia is observed as a decrease in neovascularization in diabetic wound healing. Studies have found that epidermal stem cells (EpiSCs) can promote the angiogenesis of full-thickness wounds. To further explain the therapeutic effect of EpiSCs, EpiSC-derived exosomes (EpiSC-EXOs) are considered the main substance contributing to stem cell effectivity. In our study, EpiSCs and EpiSC-EXOs were supplied to the dorsal wounds of db/db mice. Results showed that EpiSCs could colonize in the wound area and both EpiSCs and EpiSC-EXOs could accelerate diabetic wound healing by promoting angiogenesis. In vitro, persistent high glucose led to the malfunction and apoptosis of endothelial cells. The apoptosis induced by high glucose is due to excessive autophagy and was alleviated by EpiSC-EXOs. RNA sequencing of EpiSC-EXOs showed that miR200b-3p was enriched in EpiSC-EXOs and alleviated the apoptosis of endothelial cells. Synapse defective rho GTPase homolog 1 was identified the target of miR200b-3p and affected the phosphorylation of ERK to regulate intracellular autophagy and apoptosis. Furthermore, animal experiments validated the angiogenic effect of miR200b-3p. Collectively, our results verified the effect of EpiSC-EXOs on apoptosis caused by hyperglycemia in endothelial cells through the miR200b-3p/synapse defective rho GTPase homolog 1 /RAS/ERK/autophagy pathway, providing a theoretical basis for EpiSC in treating diabetic wounds.

Transcriptome profiles of fatty acid metabolism-related genes and immune infiltrates identify hot tumors for immunotherapy in cutaneous melanoma.

Background: Immunotherapy with checkpoint inhibitors usually has a low response rate in some cutaneous melanoma (CM) cases due to its cold nature. Hence, identification of hot tumors is important to improve the immunotherapeutic efficacy and prognoses of CMs. Methods: Fatty acid (FA) metabolism-related genes were extracted from the Gene Set Enrichment Analysis and used in the non-negative matrix factorization (NMF), copy number variation frequency, tumor mutation burden (TMB), and immune-related analyses, such as immunophenoscore (IPS). We generate a risk model and a nomogram for predicting patient prognoses and predicted the potential drugs for therapies using the Connectivity Map. Moreover, the NMF and the risk model were validated in a cohort of cases in the GSE65904 and GSE54467. At last, immunohistochemistry (IHC) was used for further validation. Results: Based on the NMF of 11 FA metabolism-related DEGs, CM cases were stratified into two clusters. Cluster 2 cases had the characteristics of a hot tumor with higher immune infiltration levels, higher immune checkpoint (IC) molecules expression levels, higher TMB, and more sensitivity to immunotherapy and more potential immunotherapeutic drugs and were identified as hot tumors for immunotherapy. The risk model and nomogram displayed excellent predictor values. In addition, there were more small potential molecule drugs for therapies of CM patients, such as ambroxol. In immunohistochemistry (IHC), we could find that expression of PLA2G2D, ACOXL, and KMO was upregulated in CM tissues, while the expression of IL4I1, BBOX1, and CIDEA was reversed or not detected. Conclusion: The transcriptome profiles of FA metabolism-related genes were effective for distinguishing CM into hot-cold tumors. Our findings may be valuable for development of effective immunotherapy for CM patients and for proposing new therapy strategies.

In situ scarless skin healing of a severe human burn wound induced by a hCTLA4Ig gene-transferred porcine skin graft.

Preventing fibrosis or hypertrophic scar formation following tissue damage is still a big challenge despite the numerous approaches clinicians currently use. Hitherto, no written account was available of a successful case of scarless skin healing after a severe burn injury. Here, we report the first case of the "perfect regenerative healing" of a severe burn wound with no hypertrophic scar formation in which a postage stamp skin autograft was covered with human cytotoxic-T-lymphocyte associated antigen4-immunoglobulin (hCTLA4Ig) gene-transferred pig skin. We also discuss the mechanisms involved in the scarless healing of human burn wounds.

Impact of COVID-19 pandemic on fecal immunochemical test screening uptake and compliance to diagnostic colonoscopy.

BACKGROUND AND AIM: During this COVID-19 pandemic, Taiwan is one of the few countries where fecal immunochemical test and endoscopic activity for colorectal cancer screening keeps ongoing. We aimed to investigate how screening uptake and colonoscopy rate were affected in one of the biggest screening hubs in Northern Taiwan. METHODS: We conducted a prospective observational study tracing and analyzing the screening uptake and the trend of compliance to diagnostic colonoscopy in fecal immunochemical test-positive subjects in the National Taiwan University Hospital screening hub since the outbreak of COVID-19 and compared it with that of the corresponding periods in the past 3 years. Cancellation and rescheduling rates of colonoscopy and related reasons were also explored. RESULTS: Screening uptake during December 2019 to April 2020 was 88.8%, which was significantly lower than that in the corresponding period of the past 3 years (91.2-92.7%, P for trend < 0.0001). Colonoscopy rate in this period was 66.1%, which was also significantly lower than that in the past 3 years (70.2-77.5%, P for trend = 0.017). Rescheduling or cancellation rate was up to 10.9%, which was significantly higher than that in the past 3 years (P for trend = 0.023), and half of them was due to the fear of being infected. CONCLUSION: Fecal immunochemical test screening was significantly affected by COVID-19 pandemic. In order to resume the practice in COVID-19 era, screening organizers should consider various approaches to secure timely diagnosis of colorectal cancer.

TIEG1 Represses Smad7-Mediated Activation of TGF-ß1/Smad Signaling in Keloid Pathogenesis.

Transforming growth factor-ß (TGF-ß)/Smad signaling plays a key role in excessive fibrosis and keloid formations. Smad7 is a negative feedback regulator that prevents activation of TGF-ß/Smad signaling. However, the regulatory mechanism for Smad7 in the keloid pathogenic process remains elusive. Here, we show that expression of TIEG1 is markedly higher in keloid fibroblasts, whereas protein, mRNA, and promoter activity levels of Smad7 are decreased. When TIEG1 was knocked down with small interfering RNA, both the promoter activity and protein expression of Smad7 were increased, whereas collagen production and the proliferation, migration, and invasion of keloid fibroblasts were decreased. In contrast, TIEG1 overexpression led to a decrease in Smad7 expression and Smad7 promoter activity. Upon TGF-ß1 stimulation, TIEG1 promoted Smad2 phosphorylation by down-regulating Smad7. Luciferase reporter assays and chromatin immunoprecipitation assays further showed that TIEG1 can directly bind a GC-box/Sp1 site located between nucleotides -1392 and -1382 in the Smad7 promoter to repress Smad7 promoter activity. Taken together, these findings show that TIEG1 is highly expressed in human keloids and that it directly binds and represses Smad7 promoter-mediated activation of TGF-ß/Smad2 signaling, thus providing clues for development of TIEG1 blocking strategies for therapy or prophylaxis of keloids.

Composite Skin Grafting with Human Acellular Dermal Matrix Scaffold for Treatment of Diabetic Foot Ulcers: A Randomized Controlled Trial.

BACKGROUND: Composite split-thickness skin grafting (STSG) with acellular dermal matrix (ADM) has been used successfully in burn injuries and trauma, but its use in treating diabetic foot ulcers (DFUs) has not been reported to date. This study investigated the efficacy and safety of composite STSG with ADM in the treatment of DFUs. STUDY DESIGN: Fifty-two patients with DFUs were randomized into experimental and control groups. Patients in the experimental group received composite STSG over ADM; the control group received STSG alone. The primary end point was recurrence rate 12 months after grafting. Secondary end points were the healing quality of the grafted site according to Manchester Scar Scale and complete wound closure and complication rates. RESULTS: The number of patients that experienced recurrence was significantly less in the experimental group compared with the control group (4.3% vs 22.7%; p = 0.02). The autografted sites of the experimental group had better appearance and lower Manchester Scar Scale scores (median 9 [interquartile range 8 to 10.25] vs median 11 [interquartile range 10 to 12]; p = 0.006). Rates of complete wound closure by weeks 2, 4, and 8 were similar, as were the rates of complications by post-grafting week 4 (38.5% vs 26.9%; p = 0.38). CONCLUSIONS: Composite STSG over an ADM scaffold provides an effective method to treat DFUs, with lower recurrence rates and better physical attributes compared with the traditional STSG method. Complete wound closure and complication rates were comparable between these methods.