Efficacy and Safety of PL-5 (Peceleganan) Spray for Wound Infections: A Phase IIb Randomized Clinical Trial.

OBJECTIVE: To assess the safety and efficacy of antimicrobial peptide PL-5 (Peceleganan) spray in the treatment of wound infections. BACKGROUND: Antimicrobial peptide PL-5 spray is a novel topical antimicrobial agent. METHODS: We conducted a multicenter, open-label, randomized, controlled phase IIb clinical trial to evaluate the efficacy and safety of PL-5 spray, as compared with silver sulfadiazine, in patients with skin wound infections. The primary efficacy outcome was the clinical efficacy rate on the first day after ending the treatment (D8). The secondary efficacy outcome was the clinical efficacy rate on the fifth day posttreatment (D5), the bacteria clearance rate, and the overall efficacy rate at the mentioned 2 time points. The safety outcomes included adverse reactions and pharmacokinetic analysis posttreatment. RESULTS: A total of 220 patients from 27 hospitals in China were randomly assigned to 4 groups. On D8, the efficacy rate was 100.0%, 96.7%, 96.7% for the 1‰ PL-5, 2‰ PL-5, 4‰ PL-5 groups, respectively, as compared with 87.5% for the control group. The efficacy rate among the 4 groups was significantly different ( P <0.05). On D5, the efficacy rate was 100.0%, 93.4%, 98.3% for the 1‰ PL-5, 2‰ PL-5, 4‰ PL-5 groups, respectively, as compared with 82.5% for the control group. The efficacy rate among the 4 groups was significantly different ( P <0.05). The blood concentration of PL-5 was not detectable in pharmacokinetic analysis. No severe adverse event related to the application of PL-5 was reported. CONCLUSIONS: Antimicrobial peptide PL-5 spray is safe and effective for the treatment of skin wound infections. TRIAL REGISTRATION: ChiCTR2000033334.

A meta-analysis examined the effect of oxidised regenerated cellulose/collagen dressing on the management of chronic skin wounds.

To assess the impact of oxidised regenerated cellulose/collagen dressing on the management of chronic skin wounds, we conducted a meta-analysis. A thorough review of the literature up to September 2022 revealed that 1521 participants had chronic skin wounds at the start of the investigations; 763 of them used oxidised regenerated cellulose/collagen dressing, while 758 received control. Using dichotomous or contentious methods and a random or fixed-effect model, odds ratios (OR) and mean difference (MD) with 95% confidence intervals (CIs) were estimated to evaluate the impact of oxidised regenerated cellulose/collagen dressing on the management of chronic skin wounds. The oxidised regenerated cellulose/collagen dressing had significantly higher complete wound healing (OR, 1.74; 95% CI, 1.06-2.85; P = .03), higher wound relative reduction percent (MD, 13.50; 95% CI, 2.39-24.61; P = .02), and lower adverse events in wound healing (OR, 0.63; 95% CI, 0.41-0.98; P = .04) compared with control in chronic skin wounds. The oxidised regenerated cellulose/collagen dressing had significantly higher complete wound healing, higher wound relative reduction percent and lower adverse events in wound healing compared with control in chronic skin wounds. The low sample size of 8 out of 10 researches in the meta-analysis and the small number of studies in several comparisons calls for care when analysing the results.

Regulating the mechanics of silk fibroin scaffolds promotes wound vascularization.

Functional blood vessels are crucial to wound healing, and faster vascularization means faster tissue repair to some extent. Increasing numbers of pro-vascularization wound coverings are being developed and studied. Moreover, mechanical properties of the extracellular matrix can guide the behaviour of related cells to some degree. Studies have shown that the mechanical range of 1-7 kPa contributes to the differentiation of stem cells into endothelial cells and thus to the process of wound vascularization. Unfortunately, the regulatory mechanics of vascularizing wound coverings have been poorly studied. Silk fibroin (SF) has attracted much attention because of its good biocompatibility, degradability and adjustable mechanical properties. In this paper, silk scaffolds with mechanical properties of 2 kPa and 5.9 kPa were prepared by adjusting the mechanics of silk scaffolds in terms of freezing temperature and aligned structure. The mechanical properties of the 5.9 kPa aligned silk scaffold (ASS) showed good vascularization ability. By adjusting the intermediate conformation and physical structure of Silk fibroin (SF), the mechanical strength of the silk scaffold could be increased, enabling us to better understand the mechanical regulation mode. At the same time, the aligned structure of the aligned silk scaffold (ASS) promoted the migration and proliferation of cells related to wound repair to a certain extent. By adjusting the mechanical properties and physical structure of the material, an aligned silk scaffold with vascularization function was constructed, providing more possibilities for faster wound repair.

Epithelial-mesenchymal transition in the formation of hypertrophic scars and keloids.

Abnormal wound healing is likely to induce the formation of hypertrophic scars and keloids, which leads to dysfunction, deformity, and mental problem in the patients. Despite the advances in prevention and management of hypertrophic scar and keloids, the mechanism underlying scar and keloid formation has not been fully elucidated. Recent insights into the role of the epithelial-mesenchymal transition (EMT) in development, wound healing, stem cell regulation, fibrosis, and tumorigenesis have increased our understanding of the pathophysiology of hypertrophic scarring and keloids and suggested new therapeutic targets. This review summarizes recent progress in the elucidation of the role of EMT in physiologic wound healing and pathologic scar formation. This knowledge will facilitate an understanding of EMT roles in scar formation and shed new light on the modulation and potential treatment of hypertrophic scars and keloids.

A prospective observation on nutrition support in adult patients with severe burns.

Nutrition therapy is considered an important treatment of burn patients. The aim of the study was to delineate the nutritional support in severe burn patients and to investigate association between nutritional practice and clinical outcomes. Severe burn patients were enrolled (n 100). In 90 % of the cases, the burn injury covered above 70 % of the total body surface area. Mean interval from injury to nutrition start was 2·4 (sd 1·1) d. Sixty-seven patients were initiated with enteral nutrition (EN) with a median time of 1 d from injury to first feed. Twenty-two patients began with parenteral nutrition (PN). During the study, thirty-two patients developed EN intolerance. Patients received an average of about 70 % of prescribed energy and protein. Patients with EN providing <30 % energy had significantly higher 28- d and in-hospital mortality than patients with EN providing more than 30 % of energy. Mortality at 28 d was 11 % and in-hospital mortality was 45 %. Multiple regression analysis demonstrated that EN providing <30 % energy and septic shock were independent risk factors for 28- d prognosis. EN could be initiated early in severe burn patients. Majority patients needed PN supplementation for energy requirement and EN feeding intolerance. Post-pyloric feeding is more efficient than gastric feeding in EN tolerance and energy supplement. It is difficult for severe burn patients to obtain enough feeding, especially in the early stage of the disease. More than 2 weeks of underfeeding is harmful to recovery.

RETRACTED: Residual pomegranate affecting the nonspecific immunity of juvenile Darkbarbel catfish.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of Editors-in-Chief and first Author. The article duplicates significant parts of a paper that had already appeared in Fish & Shellfish Immunology, Volume 93 (2019) 726-731, https://doi.org/10.1016/j.fsi.2019.06.052. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. The first author informed the journal that the article was published without the knowledge of the co-authors.

GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth.

GDC-0084 is a novel and potent small-molecule PI3K-mTOR dual inhibitor. The present study examined its potential activity in cutaneous squamous cell carcinoma (cSCC) cells. Our results show that GDC-0084 treatment at nanomole concentrations potently inhibited survival and proliferation of established (A431, SCC-13 and SCL-1 lines) and primary human cSCC cells. GDC-0084 induced apoptosis activation and cell cycle arrest in the cSCC cells. It was more efficient than other known PI3K-Akt-mTOR inhibitors in killing cSCC cells, but was non-cytotoxic to the normal human skin fibroblasts/keratinocytes. In A431 cells and primary cSCC cells, GDC-0084 blocked phosphorylation of key PI3K-Akt-mTOR components, including p85, Akt, S6K1 and S6. GDC-0084 also inhibited DNA-PKcs activation in cSCC cells. Significantly, restoring DNA-PKcs activation by a constitutively active-DNA-PKcs (S2056D) partially inhibited GDC-0084-induced cell death and apoptosis in A431 cells. In vivo, GDC-0084 daily gavage potently inhibited A431 xenograft tumor growth in mice. In GDC-0084-treated tumor tissues PI3K-Akt-mTOR and DNA-PKcs activation were significantly inhibited. In summary, GDC-0084 inhibits human cSCC cell growth in vitro and in vivo through blocking PI3K-Akt-mTOR and DNA-PKcs signalings.

Enhancing Infected Diabetic Wound Healing through Multifunctional Nanocomposite-Loaded Microneedle Patch: Inducing Multiple Regenerative Sites.

Infected diabetic wound (DW) presents a prolonged and challenging healing process within the field of regenerative medicine. The effectiveness of conventional drug therapies is hindered by their limited ability to reach deep tissues and promote adequate wound healing rates. Therefore, there is an imperative to develop drug delivery systems that can penetrate deep tissues while exhibiting multifunctional properties to expedite wound healing. In this study, w e devised a soluble microneedle (MN) patch made of γ-PGA, featuring multiple arrays, which w as loaded with core-shell structured nanoparticles (NPs) known as Ag@MSN@CeO2, to enhance the healing of infected DWs. The NP comprises a cerium dioxide (CeO2) core with anti-inflammatory and antioxidant properties, a mesoporous silica NP (MSN) shell with angiogenic characteristics, and an outermost layer doped with Ag to combat bacterial infections. W e demonstrated that the MN platform loaded with Ag@MSN@CeO2 successfully penetrated deep tissues for effective drug delivery. These MN tips induced the formation of multiple regenerative sites at various points, leading to antibacterial, reactive oxygen species-lowering, macrophage ecological niche-regulating, vascular regeneration-promoting, and collagen deposition-promoting effects, thus significantly expediting the healing process of infected DWs. Considering these findings, the multifunctional MN@Ag@MSN@CeO2 patch exhibits substantial potential for clinical applications in the treatment of infected DW.

Peceleganan Spray for the Treatment of Skin Wound Infections: A Randomized Clinical Trial.

Importance: Peceleganan spray is a novel topical antimicrobial agent targeted for the treatment of skin wound infections. However, its efficacy and safety remain unclear. Objective: To assess the safety and efficacy of peceleganan spray for the treatment of wound infections. Design, Setting, and Participants: This multicenter, open-label, phase 3 randomized clinical trial recruited and followed up 570 adult patients diagnosed with secondary open wound infections from 37 hospitals in China from August 23, 2021, to July 16, 2022. Interventions: Patients were randomized to 2 groups with a 2:1 allocation. One group received treatment with 2% peceleganan spray (n = 381) and the other with 1% silver sulfadiazine (SSD) cream (n = 189). Main Outcomes and Measures: The primary efficacy outcome was the clinical efficacy rate (the number of patients fulfilling the criteria for efficacy of the number of patients receiving the treatment) on the first day following the end of treatment (day 8). The secondary outcomes included the clinical efficacy rate on day 5 and the bacterial clearance rate (cases achieving negative bacteria cultures after treatment of all cases with positive bacteria cultures before treatment) on days 5 and 8. The safety outcomes included patients' vital signs, physical examination results, electrocardiographic findings, blood test results, and adverse reactions. Results: Among the 570 patients randomized to 1 of the 2 groups, 375 (98.4%) in the 2% peceleganan treatment group and 183 (96.8%) in the 1% SSD control group completed the trial (n = 558). Of these, 361 (64.7%) were men, and the mean (SD) age was 48.6 (15.3) years. The demographic characteristics were similar between groups. On day 8, clinical efficacy was achieved by 339 patients (90.4%) in the treatment group and 144 (78.7%) in the control group (P < .001). On day 5, clinical efficacy was achieved by 222 patients (59.2%) in the treatment group and 90 (49.2%) in the control group (P = .03). On day 8, bacterial clearance was achieved by 80 of 334 patients (24.0%) in the treatment group and in 75 of 163 (46.0%) in the control group (P < .001). On day 5, bacterial clearance was achieved by 55 of 334 patients (16.5%) in the treatment group and 50 of 163 (30.7%) in the control group (P < .001). The adverse events related to the application of peceleganan spray and SSD cream were similar. Conclusions and Relevance: This randomized clinical trial found that peceleganan spray is a safe topical antimicrobial agent with a satisfactory clinical efficacy rate for the treatment of skin wound infections, while the effectiveness of bacterial clearance remains uncertain. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100047202.

Prospective study and validation of early warning marker discovery based on integrating multi-omics analysis in severe burn patients with sepsis.

Background: Early detection, timely diagnosis and rapid response are essential for case management and precautions of burn-associated sepsis. However, studies on indicators for early warning and intervention have rarely been conducted. This study was performed to better understand the pathophysiological changes and targets for prevention of severe burn injuries. Methods: We conducted a multi-center, prospective multi-omics study, including genomics, microRNAomics, proteomics and single-cell transcriptomics, in 60 patients with severe burn injuries. A mouse model of severe burn injuries was also constructed to verify the early warning ability and therapeutic effects of potential markers. Results: Through genomic analysis, we identified seven important susceptibility genes (DNAH11, LAMA2, ABCA2, ZFAND4, CEP290, MUC20 and ENTPD1) in patients with severe burn injuries complicated with sepsis. Through plasma miRNAomics studies, we identified four miRNAs (hsa-miR-16-5p, hsa-miR-185-5p, hsa-miR-451a and hsa-miR-423-5p) that may serve as early warning markers of burn-associated sepsis. A proteomic study indicated the changes in abundance of major proteins at different time points after severe burn injury and revealed the candidate early warning markers S100A8 and SERPINA10. In addition, the proteomic analysis indicated that neutrophils play an important role in the pathogenesis of severe burn injuries, as also supported by findings from single-cell transcriptome sequencing of neutrophils. Through further studies on severely burned mice, we determined that S100A8 is also a potential early therapeutic target for severe burn injuries, beyond being an early warning indicator. Conclusions: Our multi-omics study identified seven susceptibility genes, four miRNAs and two proteins as early warning markers for severe burn-associated sepsis. In severe burn-associated sepsis, the protein S100A8 has both warning and therapeutic effects.

In vivo and in vitro studies of a propolis-enriched silk fibroin-gelatin composite nanofiber wound dressing.

In this study, electrospun nanofibers (NFs) used in trauma dressings were prepared using silk fibroin (SF) and gelatin (GT) as materials and highly volatile formic acid as the solvent, with three different concentrations of propolis extracts (EP), which were loaded through a simple process. The resulting samples were characterized by surface morphology, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), contact angle meter, water absorption, degradation rate, and mechanical property tests. The incorporation of propolis improved its antibacterial properties against Escherichia coli, and Staphylococcus aureus, compared to those of the silk gelatin nanofiber material (SF/GT) alone. In vitro biocompatibility assays showed that SF/GT-1%EP had good cytocompatibility and hemocompatibility. In addition, it can also significantly promote the migration of L929 cells. SF/GT-1%EP was applied to a mouse model of full thickness skin defects, and it was found to significantly promote wound healing. These results indicate that the SF/GT-EP nanofiber material has good biocompatibility, migrating-promoting capability, antibacterial properties, and healing-promoting ability, providing a new idea for the treatment of full thickness skin defects.

Heparin-based sericin hydrogel-encapsulated basic fibroblast growth factor for in vitro and in vivo skin repair.

The treatment of full-thickness cutaneous wounds remains a significant challenge in clinical therapeutics. Exogenous growth factor (GF) has been applied in clinics to promote wound healing. However, the retention of GF on the wound bed after its direct application to the wound surface is difficult. Moreover, growth factors (GFs) are always inactivated in the complex wound healing microenvironment due to various factors, which significantly decrease the therapeutic effect. Sericin hydrogel (S) can be used as an effective carrier for GFs owing to its low immunogenicity, good biocompatibility, and good healing-promoting ability. Here, we designed a heparin-based sericin hydrogel (HS) -encapsulated basic fibroblast growth factor (bFGF-HS) to facilitate wound healing and skin regeneration. The hydrogel exhibited a three-dimensional (3D) microporous structure, excellent biodegradability, good adhesiveness, and low cytotoxicity. In vitro release of bFGF from bFGF-HS coacervates revealed that bFGF-HS might control the release of bFGF within 25 days through heparin regulation. bFGF-HS significantly promoted vascularization and re-epithelialization and improved collagen deposition, ultimately accelerating wound healing in vivo in mice. bFGF-HS treated wounds were also found to have more hair follicles and milder inflammatory reactions. Overall, this study provides a new therapeutic approach for full-thickness skin defect wounds using bFGF-HS.

Human leukocyte antigen E in human cytomegalovirus infection: friend or foe?

Human cytomegalovirus (HCMV) is a well-studied ß-herpesvirus virus, which adopts a variety of strategies to evade immune surveillance. It has been reported that in HCMV-infected cells, classical major histocompatibility (MHC) class I molecules are down-regulated, but the MHC class Ib molecule human leukocyte antigen (HLA)-E is normally expressed or even overexpressed on the cell surface. HLA-E has been first described to interact with CD94/NKG2 receptors expressed mainly on the surface of natural killer (NK) cells, thus confining its role to the regulation of NK-cell function. The engagement of CD94/NKG2A with HLA-E, with a signal peptide of the HCMV glycoprotein UL40, usually induces inhibitory signals. However, HLA-E also serves as a ligand for the TCR expressed by αßCD8(+) T cells. Recognition of peptides presented by HLA-E may result in CD8(+) effector T-cell activation. These findings will help to understand more on both pathogenic and protective roles of HLA-E in HCMV infection. In this review, we discussed recent studies about the roles of HLA-E in HCMV infection.

Unilateral Sciatic Nerve Crush Induces White Blood Cell Infiltration of the Contralateral Nerve.

Nerve injury leads to the accumulation of white blood cells derived from the bone marrow in the lesioned nerve, but it is still unknown whether there are similar responses in unlesioned nerves. To address this question, sciatic nerves of mice expressing enhanced green fluorescent protein (EGFP) in their bone marrow were crushed unilaterally to observe the invasion of bone marrow-derived cells into the contralateral unlesioned nerve. Two days after surgery, EGFP+ cells began to infiltrate both the damaged and undamaged nerves. These cells gradually amplified to the highest point within 14 days and slowly lowered. In ipsilateral (lesioned) and contralateral (unlesioned) nerves, the time course of infiltration of EGFP+ cells was similar, but the magnitude was much less for the unlesioned one. Through CD68 staining, some cells were identified as macrophages. Transmission electron microscopy revealed slight demyelination and phagocytosing macrophages in the contralateral nerve. The data showed that infiltration by white blood cells is a response to nerve injury, even in uninjured nerves.

Effectiveness and Safety of Compound Polymyxin B Ointment in Treatment of Burn Wounds: A Meta-analysis.

Burn injuries represent a global public health concern. The guidelines for burn care mention that the treatment of burn injuries depends on the type of burn injury, depth of tissue, area of wounds, and site on the body. At present, several topical antimicrobial agents are used in the treatment of burn wounds as a first choice. This study aims to investigate the effectiveness of the compound polymyxin B topical agents for the treatment of burn wounds. PubMed, Web of Science, ProQuest, and China National Knowledge Infrastructure databases were searched for articles published until January 2021. The studies that conducted clinical trials comparing compound polymyxin B ointment with other treatment reagents for burn wound treatment were included. A total of three outcomes, which were investigator-assessed clinical response, including mortality, bacterial counts, efficacy and safety were included for analysis in this study. In total, 12 randomized controlled trials, 1 clinical trial, 2 prospective studies, and 1 retrospective study were extracted. The result of mortality showed no significant difference (risk ratio [RR]: 0.70, 95% CI: 0.21-2.31, P = .56); wound healing revealed an RR of 1.59 (95% CI: 1.40-1.81, P < .001); time to heal revealed a mean difference of -5.09 (95% CI: -6.31 to -3.86) days (P < .001); scar incidence was not significantly lower in the treatment group (RR: 0.70, 95% CI: 0.38-1.30, P = .26); and adverse event incidence was significantly lower in the treatment group (RR: 0.26, 95% CI: 0.09-0.72, P < .01). The compound polymyxin B ointment shows the effectiveness of increase in the wound healing and accelerates the time of healing with fewer adverse effects.

A keratin/chitosan sponge with excellent hemostatic performance for uncontrolled bleeding.

Uncontrolled bleeding leads to a higher fatality rate in the situation of surgery, traffic accidents and warfare. Traditional hemostatic materials such as bandages are not ideal for uncontrolled or incompressible bleeding. Therefore, it is of great significance to develop a new medical biomaterial with excellent rapid hemostatic effect. Keratin is a natural, biocompatible and biodegradable protein which contains amino acid sequences that induce cell adhesion. As a potential biomedical material, keratin has been developed and paid attention in tissue engineering fields such as promoting wound healing and nerve repair. Herein, a keratin/chitosan (K/C) sponge was prepared to achieve rapid hemostasis. The characterizations of K/C sponge were investigated, including SEM, TGA, liquid absorption and porosity, showing that the high porosity up to 90.12 ± 2.17 % resulted in an excellent blood absorption. The cytotoxicity test and implantation experiment proved that the K/C sponge was biocompatible and biodegradable. Moreover, the prepared K/C sponge showed better hemostatic performance than chitosan sponge (CS) and the commercially available gelatin sponge in both rat tail amputation and liver trauma bleeding models. Further experiments showed that K/C sponge plays a hemostatic role through the endogenous coagulation pathway, thus shortening the activated partial thromboplastin time (APTT) effectively. Therefore, this study provided a K/C sponge which can be served as a promising biomedical hemostatic material.