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Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a unifocal mucosal or cutaneous ulcer that is histologically characterized by proliferating EBV-positive atypical B cells. While EBVMCU demonstrates a histology similar to that of EBV-positive diffuse large B-cell lymphoma (DLBCL), their clinical behavior differs. Thus, characterizing distinguishing features of EBVMCU and EBV-positive DLBCL is critical. To identify unique characteristics between EBVMCU and lymphoma, we analyzed the clinicopathological and genetic features of 34 Japanese patients with EBVMCU and compared them to those of 24 EBV-positive DLBCL patients and 25 EBV-negative DLBCL patients. All patients with EBVMCU had localized ulcerative lesions, and 31 patients (91%) were using immunosuppressants, such as methotrexate (MTX) or hydroxycarbamide. All patients that were followed up with exhibited good prognosis following immunosuppressant reduction or chemotherapy. In addition, 17 EBV-positive DLBCL patients, and 15 EBV-negative DLBCL patients, received chemotherapy (P < 0.001, P < 0.001, respectively). Our data showed that EBVMCU did not increase indicators associated with lymphoma prognosis, such as soluble interleukin 2 receptor (sIL-2R) and lactate dehydrogenase (LDH) compared to those in the EBV-positive DLBCL or EBV-negative DLBCL groups (sIL-2R, P < 0.001, P = 0.025; LDH, P = 0.018, P = 0.038, respectively). However, histologically, EBVMCU exhibited EBV-positive, variable-sized, atypical B-cell proliferation. Thus, EBVMCU was histologically classified as: (1) polymorphous; (2) large cell-rich; (3) classic Hodgkin lymphoma-like; and (4) mucosa-associated lymphoid tissue lymphoma-like. Moreover, genetic analysis showed that immunoglobin heavy chain (IGH) gene rearrangement did not differ significantly between EBVMCU and EBV-positive DLBCL (44% vs. 32%; P = 0.377), or between EBVMCU and EBV-negative DLBCL (44% vs. 58%; P = 0.280). Therefore, it is difficult to distinguish EBVMCU from EBV-positive DLBCL using only pathological and genetic findings, suggesting that clinical information is important in accurately distinguishing between EBVMCU and EBV-positive DLBCL.

The host immune response has a critical role not only in protection from human leishmaniasis but also in promoting disease severity. Although candidate gene approaches in mouse models of leishmaniasis have been extremely informative, a global understanding of the immune pathways active in lesions from human patients is lacking. To address this issue, genome-wide transcriptional profiling of Leishmania braziliensis-infected cutaneous lesions and normal skin controls was carried out. A signature of the L. braziliensis skin lesion was defined, which includes over 2,000 differentially regulated genes. Pathway-level analysis of this transcriptional response revealed key biological pathways present in cutaneous lesions, generating a testable ‘metapathway’ model of immunopathology and providing new insights for treatment of human leishmaniasis.

Chronic skin ulcers, although rare, pose severe and debilitating challenges. The identification of causal metabolite biomarkers presents an opportunity to refine effective risk assessment strategies for this condition. In this study, we conducted a comprehensive Two-Sample Mendelian Randomization (TSMR) investigation to delineate the potential causal effects of plasma metabolites on chronic skin ulcer risk. Exposure data comprised 14,296 participants with 913 metabolites from INTERVAL/EPIC-Norfolk, and 8,299 participants with 1,091 metabolites and 309 ratios from the Canadian Longitudinal Study on Aging (CLSA). Outcome data came from the finngen_R9_L12_CHRONICULCEROFSKIN (1,840 cases, 353,088 controls) and UK Biobank Chronic ulcer of skin (495 cases, 455,853 controls) cohorts. Leveraging the inverse-variance weighted (IVW) method, alongside MR-Egger and MR-PRESSO sensitivity analyses, we evaluated metabolite associations with chronic skin ulcer risk. Further assessment involved a phenome-wide MR (Phe-MR) analysis to explore potential repercussions of targeting identified metabolites for intervention. Our study identified 12 distinct metabolites significantly associated with chronic skin ulcers, demonstrating consistent and replicable results. Notably, X-19,141 exhibited the highest reproducibility. These findings highlight novel plasma metabolites relevant to chronic skin ulcers, offering theoretical underpinnings for mechanistic research and clinical strategies in prevention and treatment.

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class. A chemical screen identified BET bromodomain inhibitors as promoters of keratinocyte regenerative function and skin wound healing. Specifically, low-dose transient treatment with BET inhibitors imposes an activated, migratory state in keratinocytes.

Psoriasis and chronic ulcers not only significantly impair quality of life but also pose a challenge in dermatological treatment. This study aimed to identify new therapeutic targets and biomarkers for psoriasis and chronic ulcers by comparing their gene expression profiles. The gene expression profiles of psoriatic, wound and chronic ulcer patients, as well as healthy controls, were determined via RNA extraction and next‐generation sequencing of biopsies. In order to identify biomarkers, functional enrichment, differential expression analysis and machine learning algorithms were implemented. It is worth mentioning that the genes IL17A, TNF, KRT16, MMP9, and CD44 exhibited substantial correlations with the pathogenesis of the conditions being studied. As evidenced by their AUC‐ROC values approaching 0.90, machine learning models accurately identified these biomarkers. The differential gene expression was consequently validated via qRT‐PCR, which highlighted the increased expression of matrix remodelling enzymes and inflammatory cytokines. Additionally, genes essential for maintaining epidermis integrity and facilitating wound healing exhibited downregulation. These insights into the molecular mechanisms of psoriasis and chronic ulcers pave the way for the development of targeted therapies, offering hope for improved treatment strategies.

The etiology of non-healing ulcers depends on both systemic and local factors. The introduction of advanced dressing, negative wound therapy and compression therapy have undoubtedly improved clinical outcomes. The principal aim of study was to demonstrate the efficacy of dermal micrografts in the treatment of ulcers with different etiologies. The second aim was to investigate in vitro the action of micrografts in the regenerative process. The dermal micro-grafts were obtained from mechanical disaggregation of small pieces of skin tissue through a medical device called Rigeneracons. We observed in vivo the ability of dermal autologous micrografts to improve the healing of venous, diabetic, pressure and post-traumatic ulcers after few week of treatment accomplished in general with a better quality of life for the patients. In vitro results showed that these micrografts express mesenchymal stem cells (MSCS) marker such as CD34, CD73, CD90 and CD105, and are able to form a viable and proliferative biocomplex with collagen sponge. Finally, the site of ulcers displayed a different expression of epidermal growth factors, insulin-like growth factors, platelet-derived growth factors and their receptors and tumor necrosis factor-β with respect to healthy skin samples. We reported a good outcome for the treatment of chronic ulcers using dermal autologous micrografts. Finally, we suggest that the positivity to MSCs markers and the ability to interact with a scaffold can play a key role in their regenerative properties.

Ulceration is an important prognostic factor in melanoma whose biologic basis is poorly understood. Here we assessed the prognostic impact of pleckstrin homology domain-interacting protein (PHIP) copy number and its relationship to ulceration. PHIP copy number was determined using fluorescence in situ hybridization (FISH) in a tissue microarray cohort of 238 melanomas. Elevated PHIP copy number was associated with significantly reduced distant metastasis-free survival (DMFS; P=0.01) and disease-specific survival (DSS; P=0.009) by Kaplan–Meier analyses. PHIP FISH scores were independently predictive of DMFS (P=0.03) and DSS (P=0.03). Increased PHIP copy number was an independent predictor of ulceration status (P=0.04). The combined impact of increased PHIP copy number and tumor vascularity on ulceration status was highly significant (P<0.0001). Stable suppression of PHIP in human melanoma cells resulted in significantly reduced glycolytic activity in vitro, with lower expression of lactate dehydrogenase 5, hypoxia-inducible factor 1 alpha subunit, and vascular endothelial growth factor, and was accompanied by reduced microvessel density in vivo. These results provide further support for PHIP as a molecular prognostic marker of melanoma, and reveal a significant linkage between PHIP levels and ulceration. Moreover, they suggest that ulceration may be driven by increased glycolysis and angiogenesis.

The successful analysis of weak biological stains by means of highly sensitive short tandem repeat (STR) amplification has been increased significantly over the recent years. Nevertheless, the percentage of reliably analysable samples varies considerably between different crime scene investigations even if the nature of the stains appears to be the same. It has been proposed that the amount and quality of DNA left at a crime scene may be due to individual skin conditions (among other factors). Therefore, we investigated DNA from handprints from 30 patients acutely suffering from skin diseases like atopic dermatitis, psoriasis or skin ulcer before and after therapy by STR amplification using the new and highly sensitive Powerplex® ESX17 kit in comparison to 22 healthy controls. Handprints from atopic dermatitis patients showed a correct and reliable DNA profile in 90% and 40% of patients before and after therapy, respectively. Regarding psoriasis patients, we detected full DNA profiles in only 64% and 55% of handprints before and after therapy. In contrast, in ulcus patients and controls, full DNA profiles were obtained in much lower numbers. We conclude that active skin diseases like atopic dermatitis or psoriasis have a considerable impact on the amplificable DNA left by skin contact with surfaces. Since up to 7% of adults in European countries suffer from one of these diseases, this could explain at least partially the varying quality of DNA from weak stains.

Ulceration is a common negative prognostic marker of solid tumors including melanoma. The signaling basis of ulceration is being elucidated. PHIP has been found to be amplified in wild-type melanomas, resulting in Akt activation and aerobic glycolysis (Warburg effect), associated with ulceration. The ulceration phenotype likely represents the genotype of the reactive oxygen driven tumor, in which reactive oxygen drives angiopoietin-2 production, tumor growth, and invasion. This phenotype is amenable to pharmacologic intervention.

Similar to other mycobacterial diseases, susceptibility to Buruli ulcer ( Mycobacterium ulcerans infection) may be determined by host genetic factors. We investigated the role of SLC11A1 ( NRAMP1 ) in Buruli ulcer because of its associations with both tuberculosis and leprosy. We enrolled 182 Buruli ulcer patients (102 with positive laboratory confirmation) and 191 healthy neighbourhood-matched controls in Ghana, and studied three polymorphisms in the SLC11A1 gene: 3′ UTR TGTG ins/del , D543N G/A , and INT4 G/C . Finger prick blood samples from study subjects were dried on filter papers (FTA) and processed. D543N was significantly associated with Buruli ulcer: the odds ratio (adjusted for gender, age, and region of the participant) of the GA genotype versus the GG genotype was 2.89 (95% confidence intervals (CI): 1.41–5.91). We conclude that a genetic polymorphism in the SLC11A1 gene plays a role in susceptibility to develop Buruli ulcer, with an estimated 13% population attributable risk.