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This study explores the potential for adipocyte-derived stem cells (ASCs) to be used in bladder reconstruction. Current methods, such as enterocystoplasty, have significant limitations, making new approaches necessary. Tissue engineering, specifically using acellular scaffolds such as the bladder acellular matrix, offers a promising basis for this development. For this study, ASCs were isolated from adipose tissue derived from liposuction and co-cultured with urothelial cells (UC; SV-HUC) to induce transdifferentiation. Results indicate successful isolation and characterization of ASCs, displaying positive markers for stem cells. The co-culture of ASCs with SV-HUC cells resulted in changes resembling epithelial cells, indicating a potential transdifferentiation process, and is corroborated by the mRNA and protein levels. For the functional assay, urothelial-like cells were seeded onto decellularized bladder tissues. These findings demonstrate the successful transdifferentiation of ASCs into functional UC, presenting a promising strategy for bladder reconstruction and a potential alternative to current approaches.

Granzyme B (GzmB) is a serine protease that has long been thought to function exclusively in lymphocyte-mediated apoptosis. In recent years, this paradigm has been revisited due to the recognition that GzmB accumulates in the extracellular milieu in many autoimmune and chronic inflammatory disorders, and contributes to impaired tissue remodeling due to the cleavage of extracellular matrix proteins. Knockout studies suggest that GzmB-mediated cleavage of decorin (DCN) contributes to impaired collagen fibrillogenesis and remodeling. As DCN is anti-fibrotic and contributes to reduced hypertrophic scarring, GzmB-induced DCN cleavage could play a role in wound healing following burn injury. In the present study, a novel, gel-formulated, first-in-class small-molecule inhibitor of GzmB, VTI-1002, was assessed in a murine model of impaired, diabetic burn wound healing. VTI-1002 exhibited high specificity, potency, and target selectivity. Gel-formulated VTI-1002 was able to penetrate the stratum corneum and was retained in the skin with minimal systemic absorption. Daily topical administration of VTI-1002 gel for 30 days following thermal injury showed significantly accelerated wound closure, increased DCN protein levels, and collagen organization that was translated into significantly increased wound tensile strength compared to controls. Overall, VTI-1002 gel was well-tolerated in vivo and no adverse events were observed. Topical application of VTI-1002 represents a novel therapeutic approach for the treatment of cutaneous burn wounds. Chronic wounds: Gel encourages healing and reduces scarring A promising, recently developed topical treatment prevents detrimental enzyme activity in burn wounds, accelerates healing and reduces scarring. Chronic wounds that do not heal fully and require ongoing medical attention are common in the elderly, obese, and/or diabetic populations, resulting in enormous costs to healthcare services. Recent research indicates that an enzyme called granzyme. (GzmB) accumulates in chronically inflamed wounds, impairing collagen organization and disrupting tissue remodeling. David Granville at the University of British Columbia, Vancouver, Canada, and co-workers trialed a topical gel designed to inhibit GzmB activity in burn injuries in diabetic mice. When applied to the wounds for 30 days, the gel improved wound closure and remodeling while reducing scarring. The gel targeted wounds directly with no effect on surrounding tissues, and no adverse effects were observed during treatment.

Pressure injuries, also known as pressure ulcers, are regions of localized damage to the skin and/or underlying tissue. Repeated rounds of ischemia–reperfusion (I/R) have a major causative role for tissue damage in pressure injury. Ischemia prevents oxygen/nutrient supply, and restoration of blood flow induces a burst of reactive oxygen species that damages blood vessels, surrounding tissues and can halt blood flow return. Minimizing the consequences of repeated I/R is expected to provide a protective effect against pressure injury. Sulfaphenazole (SP), an off patent sulfonamide antibiotic, is a potent CYP 2C6 and CYP 2C9 inhibitor, functioning to decrease post-ischemic vascular dysfunction and increase blood flow. The therapeutic effect of SP on pressure injury was therefore investigated in apolipoprotein E knockout mice, a model of aging susceptible to ischemic injury, which were subjected to repeated rounds of I/R-induced skin injury. SP reduced overall severity, improved wound closure and increased wound tensile strength compared to vehicle-treated controls. Saliently, SP restored tissue perfusion in and around the wound rapidly to pre-injury levels, decreased tissue hypoxia, and reduced both inflammation and fibrosis. SP also demonstrated bactericidal activity through enhanced M1 macrophage activity. The efficacy of SP in reducing thermal injury severity was also demonstrated. SP is therefore a potential therapeutic option for pressure injury and other ischemic skin injuries.

Purpose The demographic proportions of plastic surgery trials approximating real-world disease have not well been studied. Judicious trial representation is essential in evaluation of treatments across diverse patient populations. Herein, we investigate sex, racial, and ethnic disparities in patient enrollment across burn trials. Methods Cross-sectional analysis of participants enrolled in high-quality, with reduced risk of bias, randomized controlled trials (RCT) on burns registered on clinicaltrials.gov under the query “burn.” Completed RCTs reporting at least two demographic groups, employing double masking or greater, and with results accessible through the registry or publications were included. Trial characteristics (sponsor country, site location, initiation year, study phase, masking) and demographic data (sex, race, ethnicity per US reporting guidelines) were collected. The Global Burden of Disease database provided sex-based burn disease burdens. The primary outcome was the population-to-prevalence ratio of enrolled female participants. Secondary outcomes included representation of racial and ethnic populations as related to study blinding, phase, and study/sponsor locations. Results Of 546 records, 39 trials met the inclusion criteria (2919 participants). All trials reported sex demographics, with females comprising 37.02% of all participants (PPR = 0.71, 95% CI [0.59, 0.82], likely indicating underrepresentation against their empiric disease burden). Only 7 and 9 trials reported ethnicity and race, respectively, although not comprehensively. Among trials reporting race or ethnicity, Caucasians and Black persons comprised 57.52% and 21.80% of participants, respectively, while only 9.80% had Hispanic/Latino ethnicity. Severe underreporting of race and ethnicity precluded much of secondary significance testing across study variables. Conclusions Females are likely underrepresented in high-quality, US-registered burn trials, unreflective of their real-world disease burden. Further, severe underreporting of race and ethnicity was noted. Future trials should enroll diverse demographics and equitable populations for promotion of study generalizability.

Pressure injuries (PIs), also known as bedsores or pressure ulcers, are a major cause of death and morbidity in the elderly. The serine protease, Granzyme B (GzmB), contributes to skin aging and impaired wound healing. Aging is a major risk factor for PIs; thus, the role of GzmB in PI pathogenesis was investigated. GzmB levels in human PI tissue and wound fluids were markedly elevated. A causative role for GzmB was assessed in GzmB knockout (GzmB−/−) and wild-type (WT) mice using a murine model of PI. An apolipoprotein E knockout (ApoE−/−) model of aging and vascular dysfunction was also utilized to assess GzmB in a relevant age-related model better resembling tissue perfusion in the elderly. PI severity displayed no difference between young GzmB−/− and WT mice. However, in aged mice, PI severity was reduced in mice lacking GzmB. Mechanistically, GzmB increased vascular wall inflammation and impaired extracellular matrix remodeling. Together, GzmB is an important contributor to age-dependent impaired PI healing.

This chapter contains sections titled: Introduction Burn Injury Skin Anatomy Burn Depth Wound Healing Treatment Special Features in Perioral Burns Conclusions References

Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear 1 . The long non-coding RNA Xist establishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus 2 and binding diverse proteins 3 – 5 to achieve X-chromosome inactivation (XCI) 6 , 7 . The XCI process therefore serves as a paradigm for understanding how RNA-mediated recruitment of various proteins induces a functional compartment. The properties of the inactive X (Xi)-compartment are known to change over time, because after initial Xist spreading and transcriptional shutoff a state is reached in which gene silencing remains stable even if Xist is turned off 8 . Here we show that the Xist RNA-binding proteins PTBP1 9 , MATR3 10 , TDP-43 11 and CELF1 12 assemble on the multivalent E-repeat element of Xist 7 and, via self-aggregation and heterotypic protein–protein interactions, form a condensate 1 in the Xi. This condensate is required for gene silencing and for the anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist . Notably, these E-repeat-binding proteins become essential coincident with transition to the Xist- independent XCI phase 8 , indicating that the condensate seeded by the E-repeat underlies the developmental switch from Xist -dependence to Xist -independence. Taken together, our data show that Xist forms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing. A protein condensate formed by multivalent interactions between the long non-coding RNA Xist and specific RNA-binding proteins drives the compartmentalization required to perpetuate gene silencing on the inactive X chromosome.

Introduction Treating plaque psoriasis (PsO) with guselkumab (GUS) promotes skin clearance and is associated with improvements in health-related quality of life (HRQoL), anxiety, and depression. It is unclear whether improvements in patient-reported outcomes are due to resolution of skin symptoms or the direct result of GUS treatment. Methods Two phase 3, placebo- and active-comparator-controlled studies randomized patients with moderate-to-severe PsO to GUS, placebo (crossing over to GUS at week 16), or adalimumab. Post hoc mediation analyses examined direct and indirect effects of GUS, versus adalimumab, on Dermatology Life Quality Index (DLQI) or Hospital Anxiety and Depression Scale (HADS) after adjusting for indirect effects mediated by skin clearance, evaluated via Psoriasis Area and Severity Index (PASI), to determine the direct effect of GUS on dermatology HRQoL, depression, and anxiety. Results Compared with adalimumab, the natural direct effect (NDE) of GUS on change in DLQI from baseline was − 2.04 ( P  < 0.001), using PASI improvement as a mediator, indicating 89.2% of the total treatment effect was due to direct effects of GUS; using PASI 90 as a mediator, NDE of GUS was − 1.43 ( P  < 0.001), with 62.2% of the total treatment effect attributed to direct effects of GUS. Compared with adalimumab, 25.5% of change in HADS anxiety score was mediated through PASI improvement (NDE − 0.74; P  = 0.002), indicating 74.5% of the total effect was independent of PASI improvement. Similarly, 24% of treatment effect was mediated through PASI 90 (NDE − 0.76; P  = 0.002). Comparable proportions of the total improvement in HADS depression scores were due to direct and indirect effects of GUS mediated through PASI improvement (direct, 50.2%; indirect, 49.8%) or PASI 90 (direct, 59.5%; indirect, 40.5%). Conclusions GUS-mediated improvements in anxiety, depression, and overall HRQoL are not solely mediated by resolution of PsO signs, suggesting GUS use has a potential direct effect on anxiety and depression.

Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When data that will withstand objective scrutiny are not available, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of choices in any health-care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. Expert opinion is solicited from the outset for the document. The quality of evidence upon which a specific recommendation is based is as follows: Grade A: Homogeneous evidence from multiple well-designed randomized (therapeutic) or cohort (descriptive) controlled trials, each involving a number of participants to be of sufficient statistical power. Grade B: Evidence from at least one large well-designed clinical trial with or without randomization, from cohort or case-control analytic studies, or well-designed meta-analysis. Grade C: Evidence based on clinical experience, descriptive studies, or reports of expert committees. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time.

Acinetobacter baumannii is a feared, drug-resistant pathogen, characterized by its ability to resist extreme environmental and nutrient-deprived conditions. Previously, we showed that human serum albumin (HSA) can increase foreign DNA acquisition specifically and alter the expression of genes associated with pathogenicity. Moreover, in a recent genome-wide transcriptomic study, we observed that pleural fluid (PF), an HSA-containing fluid, increases DNA acquisition, can modulate cytotoxicity, and control immune responses by eliciting changes in the A . baumannii metabolic profile. In the present work, using more stringent criteria and focusing on the analysis of genes related to pathogenicity and response to stress, we analyzed our previous RNA-seq data and performed phenotypic assays to further explore the impact of PF on A . baumannii ’s microbial behavior and the strategies used to overcome environmental stress. We observed that PF triggered differential expression of genes associated with motility, efflux pumps, antimicrobial resistance, biofilm formation, two-component systems (TCSs), capsule synthesis, osmotic stress, and DNA-damage response, among other categories. Phenotypic assays of A . baumannii A118 and two other clinical A . baumannii strains, revealed differences in their responses to PF in motility, biofilm formation, antibiotic susceptibility, osmotic stress, and outer membrane vesicle (OMV) production, suggesting that these changes are strain specific. We conclude that A . baumannii’s pathoadaptive responses is induced by HSA-containing fluids and must be part of this bacterium armamentarium to persist in hostile environments.