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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., (© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Diabetic skin ulcer is one of the most common complications in patients suffering diabetes mellitus. Xanthohumol (XN), a hop-derived prenylated dietary flavonoid, has multiple health beneficial bioactivities. In the present study, we reported XN alleviates oxidative damage and accelerates diabetic wound healing via Nrf2 activation. In vitro, XN attenuated hydrogen peroxide (H 2 O 2 )-induced cytotoxicity, ROS production, cell apoptosis, as well as high glucose-induced cell damage. Mechanistic studies further demonstrated that XN could stabilize nuclear factor erythroid 2-related factor 2 (Nrf2) and promote its nuclear translocation, which was associated with AMPKα activation and covalent modification of Keap1 by XN. In vivo, XN increased Nrf2 expression and accelerated diabetic wound healing. Our study revealed a novel function of XN in diabetic wound healing as well as the underlying molecular mechanisms, suggesting XN is a promising lead compound and a potential food and/or drug candidate for the treatment of diabetic skin ulcers., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tumor ulceration is considered one of the most prognostically significant findings in primary cutaneous melanoma, associated with decreased disease-free and overall survival. However, the unique features associated with ulcerated melanoma that contribute to a poor prognosis in affected patients remain poorly defined. microRNAs are small, non-coding RNAs that function to inhibit expression of specific gene targets, therefore altering the functions of cells in which they are expressed. miR-1469 is a novel miR with significantly decreased expression in ulcerated melanoma tissue relative to non-ulcerated tumors. We hypothesized that loss of miR-1469 expression in melanoma contributes to altered tumor cell functions mediating disease progression. Transfection of a miR-1469 mimic resulted in a significant reduction in the migratory and invasive capacity of the CHL1 and MEL39 melanoma cell lines (>58.1% reduction, p < 0.0332), as well as the invasive capacity of the A375 melanoma cell line (>50% reduction, p < 0.0021). Expression of myeloid cell leukemia-1 (MCL1), a miR-1469 target gene, was reduced in the A375 and MEL39 cell lines by immunoblot. No significant differences in viability, resistance to apoptotic stimuli, or proliferation were observed following transfection. These findings together demonstrate how migration and invasion are specific functions through which miR-1469 expression in melanoma cells can contribute to the differences in disease progression associated with tumor ulceration., Competing Interests: The authors have declared no competing interests exist.

In the present study, the effects of NLRP3 on radiation-induced tissue damage, including colon and skin damage in mice, and the possible mechanisms were explored in vivo and in vitro. The mice were subjected to whole abdomen radiation by timed exposure to X-ray at a cumulative dose of 14 Gy. The survival rate showed that NLRP3 deficiency increased the mortality rate in mice. Furthermore, colon damage, evaluated by H&E staining and barrier function analysis, were significantly aggravated by NLRP3 deficiency. Enhanced phosphorylation of p-TBK1 and p-IRF3 in colonic tissue as well as elevated IFN-β levels in the serum indicated hyperactivation of cGAS-STING signaling. Moreover, radiation-induced expression of p-TBK1, p-IRF3, and IFN-β in BMDMs increased in vitro after NLRP3 knockout. Thus, our study outcomes suggest that NLRP3 may protect mice from radiation-induced tissue damage via attenuating cGAS-STING signaling., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

Objective: Monogenic Behçet's disease (BD)-like conditions are increasingly recognized and to date have been found to predominantly involve loss-of-function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls)., Methods: Whole-exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v-rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA -/- mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF-κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild-type and truncated RELA in experimental systems and patient samples., Results: A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA -/- mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild-type RELA; however, there was no difference in RELA nuclear translocation. In RelA -/- MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98-fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild-type RELA (P = 0.036)., Conclusion: Our data indicate that RELA loss-of-function mutations cause BD-like autoinflammation and NMO via impaired NF-κB signaling and increased apoptosis., (© 2020, American College of Rheumatology.)

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

BACKGROUND Diabetic wound (DW) treatment is a serious challenge for clinicians, and the underlying mechanisms of DWs remain elusive. We sought to identify the critical genes in the development of DWs and provide potential targets for DW therapies. MATERIAL AND METHODS Datasets of GSE38396 from the Gene Expression Omnibus (GEO) database were reviewed. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology term analyses were carried out, and Cytoscape software (Cytoscape 3.7.2) was used to construct the protein interaction network. Serum samples from patients with diabetes and control participants were collected, and the expression of estrogen receptor 1 (ESR1) was measured by quantitative reverse-transcription polymerase chain reaction. In addition, the function of ESR1 in human skin fibroblasts was investigated in vitro. RESULTS Eight samples were analyzed using the Morpheus online tool, which identified 637 upregulated and 448 downregulated differentially expressed genes. The top 5 KEGG pathways of upregulated differentially expressed genes were associated with sphingolipid metabolism, estrogen signaling, ECM-receptor interaction, MAPK signaling, and PI3K-Akt signaling. The hub genes for DWs were JUN, ESR1, CD44, SMARCA4, MMP2, BMP4, GSK3B, WDR5, PTK2, and PTGS2. JUN, MMP2, and ESR1 were the upregulated hub genes, and ESR1 was found to be consistently enriched in DW patients. Inhibition of ESR1 had a stimulative role in human skin fibroblasts. CONCLUSIONS ESR1 was identified as a crucial gene in the development of DWs, which suggests potential therapeutic targets for DW healing.

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.

Behçet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namely HLA-B*51, ERAP1, IL-10, IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNFα, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-κB activation (eg TNFAIP3, NFKB1, OTULIN, RELA, IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-κB pathway suggesting new elements in the elusive BD etiopathogenesis., (© 2020 The Scandinavian Foundation for Immunology.)

Staphylococcus aureus fatty acid kinase FakA is necessary for the incorporation of exogenous fatty acids into the lipid membrane. We previously demonstrated that the inactivation of fakA leads to decreased α-hemolysin (Hla) production but increased expression of the proteases SspAB and aureolysin in vitro , and that the Δ fakA mutant causes larger lesions than the wild type (WT) during murine skin infection. As expected, necrosis is Hla dependent in the presence or absence of FakA, as both hla and hla Δ fakA mutants are unable to cause necrosis of the skin. At day 4 postinfection, while the Δ fakA mutant maintains larger and more necrotic abscesses, bacterial numbers are similar to those of the WT, indicating the enhanced tissue damage of mice infected with the Δ fakA mutant is not due to an increase in bacterial burden. At this early stage of infection, skin infected with the Δ fakA mutant has decreased levels of proinflammatory cytokines, such as interleukin-17A (IL-17A) and IL-1α, compared to those of WT-infected skin. At a later stage of infection (day 7), abscess resolution and bacterial clearance are hindered in Δ fakA mutant-infected mice. The paradoxical findings of decreased Hla in vitro but increased necrosis in vivo led us to investigate the role of the proteases regulated by FakA. Utilizing Δ aur and Δ sspAB mutants in both the WT and fakA mutant backgrounds, we found that the absence of these proteases in a fakA mutant reduced dermonecrosis to levels similar to those of the WT strain. These studies suggest that the overproduction of proteases is one factor contributing to the enhanced pathogenesis of the Δ fakA mutant during skin infection., (Copyright © 2020 American Society for Microbiology.)

Background: Genetic skin diseases in cattle are rare., Clinical Summary: A 7-week-old female Holstein calf was presented with epidermal lesions and alopecia in the caudal region of the ears and on the neck, as well as deep bilateral ulcerative lesions on the palmar aspect of the metacarpi and dorsal aspect of the right metacarpus. Clinical, pathological and histopathological examination of the calf was suggestive of a subepidermal vesicular dermatosis. Genetic analysis identified a de novo non-sense variant affecting the aspartate dehydrogenase domain containing (ASPDH) gene, which might be associated with the formation of subepidermal vesicles in this case., Conclusion and Clinical Importance: The observed phenotype in the calf may represent a novel form of a vesicular skin disorder. Haploinsufficiency of the ASPDH gene might be considered as a possible cause., (© 2019 the European Society of Veterinary Dermatology and the American College of Veterinary Dermatology.)

Stimulator of interferon genes associated vasculopathy with onset in infancy (SAVI), caused by heterozygote gain-of-function mutations in TMEM173, is characterized by fever attacks with ulcerating cutaneous manifestations on cold-sensitive areas and interstitial lung disease. A six-month-old boy was admitted to our hospital with fever, cough, and rash on the external surface of both upper and lower extremities. Respiratory symptoms consistent with ILD developed and skin lesions evolved to eschar formation particularly on acral regions. Ultimately, diagnosis of SAVI was confirmed at the age of 10 months due to the high level of interferon-score and a heterozygous N154S mutation in TMEM173. Since systemic corticosteroid and ruxolitinib were not effective, baricitinib was initiated at the age of 15 months, resulting in alleviation of fever attacks, cutaneous manifestations and respiratory symptoms within 2 months. In conclusion, we reported an infant diagnosed with SAVI at the age of 10 months and treated with baricitinib., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To investigate the expressions of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 alpha (HIF-1α), and epidermal growth factor receptor (EGFR) in different morphological regions of Marjolin ulcer and their clinical relationship with angiogenesis. Methods: From January 2012 to December 2017, the patients admitted to our hospital who met the inclusion criteria were selected, including 92 patients with Marjolin ulcer [56 males and 36 females, aged (55±15) years], 100 patients with chronic non-cancerous skin ulcer [59 males and 41 females, aged (51±16) years], and 100 patients performed with other skin-related surgery [58 males and 42 females, aged (52±15) years], and they were enrolled into Marjolin ulcer group (MU), chronic non-cancerous ulcer group (CNU), and other skin surgery group (OSS) respectively. The etiology, pathogenic site, ulcer diameter, and course of patients in group MU were retrospectively analyzed. Ulcer tissue specimens from patients of group MU and group CNU and specimens of normal skin tissue attached to the tissue resected during operation from patients of group OSS were collected. The expressions of VEGF, HIF-1α, EGFR, and CD34 in the above-mentioned tissue and the surrounding normal skin, ulcer, epitheliomatous hyperplasia, and canceration areas in Marjolin ulcer tissue were detected by immunohistochemical method, and the positive expression rate and protein expression level were calculated. Data were processed with Pearson chi-square test, Mann-Whitney U test, Bonferroni method, and Bonferroni correction, and Spearman correlation analysis was used to analyze the relationship among the total protein expression levels. Results: In group MU, burns accounted for 91.3% (84/92) of the causes of patients, 44.6% (41/92) of the patients had tumors in the lower extremities, 62.0% (57/92) of the patients had skin ulcer diameter of 2.1-5.0 cm, and 75.0% (69/92) of the patients had a course of disease of more than 20 years. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group CNU were 41.0% (41/100), 77.0% (77/100), and 83.0% (83/100), respectively, significantly higher than those of normal skin tissue of patients in group OSS [12.0% (12/100), 45.0% (45/100), and 67.0% (67/100), χ (2)=21.589, 21.522, 6.827, P <0.01]. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group MU were 91.3% (84/92), 100.0% (92/92), and 100.0% (92/92), respectively, which were significantly higher than those in corresponding tissue of patients in group CNU and group OSS ( χ (2)=53.372, 24.772, 17.159; 120.543, 72.777, 36.661, P <0.01). In ulcer tissue of patients in group MU, the positive expression rates of VEGF in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area ( χ (2)=87.120, 42.368, 89.624, P <0.01); the positive expression rates of VEGF in canceration and ulcer areas were significantly higher than the rate in epitheliomatous hyperplasia area ( χ (2)=22.586, 16.060, P <0.01). In ulcer tissue of patients in group MU, the positive expression rates of EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area ( χ (2)=21.679, 27.600, 27.600, P <0.01), but the positive expression rates of HIF-1α in four morphological areas were similar ( χ (2)=3.008, P >0.05). In ulcer tissue of patients in group MU, the protein expression levels of VEGF and CD34 in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area ( Z =-6.765, -6.819; -6.765, -6.640; -6.765, -6.819, P <0.01), the protein expression levels of VEGF and CD34 in epitheliomatous hyperplasia area were significantly lower than those in ulcer area ( Z =-4.484, -5.266, P <0.01), and the protein expression levels of VEGF and CD34 in canceration area were significantly higher than those in ulcer area ( Z =-6.427, -6.723, P <0.01) and epitheliomatous hyperplasia area ( Z =-6.427, -6.462, P <0.01). In ulcer tissue of patients in group MU, the protein expression levels of HIF-1α and EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area ( Z =-6.819, -6.393; -6.819, -6.393; -6.819, -6.393, P <0.01), the protein expression levels of HIF-1α and EGFR in ulcer area were significantly lower than those in epitheliomatous hyperplasia and canceration areas ( Z =-6.118, -5.638; -6.640, -6.393, P <0.01), and the protein expression levels of HIF-1α and EGFR in canceration area were significantly higher than those in epitheliomatous hyperplasia area ( Z =-6.558, -6.819, P <0.01). In ulcer tissue of patients in group MU, the total protein expression levels of VEGF, HIF-1α, and EGFR were significantly positively correlated with the total protein expression level of CD34 ( r =0.772, 0.415, 0.502, P <0.01) respectively; the total protein expression level of EGFR was significantly positively correlated with that of HIF-1α ( r =0.839, P <0.01), both of which were significantly positively correlated with the total protein expression level of VEGF ( r =0.531, 0.440, P <0.01) respectively. Conclusions: The expressions of VEGF, HIF-1α, and EGFR are the highest in Marjolin ulcer canceration area, and EGFR may promote angiogenesis through HIF-1α or directly increasing the expression of VEGF.

Cellular senescence can be broadly defined as a stable, but essentially irreversible, loss of proliferative capacity. Historically, senescence has been described as a negative outcome of advanced cellular age. It is now clear, however, that senescence represents a dynamic autonomous stress response, integral to long-term tumor suppression. Transient induction of a senescent phenotype has actually been suggested to promote regeneration in both liver and skin. Here, we explored the role of senescence in pathological aged and diabetic murine wound healing. Aged and diabetic wounds had greater numbers of senescent cells, and diabetic macrophages maintained altered retention of polarization and produced a CXCR2-enriched senescence-associated secretory phenotype (i.e., SASP). Of translational relevance, targeted expression of CXCR2 in primary human dermal fibroblasts led to paracrine induction of nuclear p21. Furthermore, a selective agonist to CXCR2 was able to reverse delayed healing in diabetic mice and accelerate ex vivo human skin wound healing. Collectively, these data suggest a hitherto unappreciated role for CXCR2 in mediating cellular senescence in pathological wound repair., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Pyoderma gangrenosum (PG)-like ulcerations are a rare clinical manifestation of methylenetetrahydrofolate reductase (MTHFR) mutation. We describe a patient considered to have PG who was treated with long-term high doses of systemic corticosteroids and multiple immunosuppressive agents for several years. In spite of this continuous aggressive therapy, the lesions did not improve but continued to get worse. She developed many significant and catastrophic side effects to them. When referred to our dermatology centre, on investigation, it was discovered that she has an MTHFR mutation. It seemed reasonable to presume that PG-like lesions were related to it. Treatment with a biologically active form of folate-[6S]-5-MTHF-with vitamins B6 and B12 was initiated. It was considered to be beneficial and capable of reducing hyperhomocysteinaemia and endothelial damage consequent from it. Since the institution of this treatment, the patient has begun to show very gradual but slow and incremental improvement., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Slow lymphangiogenesis is one crucial reason for the impaired wound healing process in diabetes. Accumulative evidence showed that long noncoding RNA-antisense noncoding RNA in the INK4 locus (ANRIL) could influence lymphangiogenesis. Besides, miR-181a has been reported to regulate Prox1 that is essential for lymphangiogenesis. However, the relationship between ANRIL and miR-181a as well as the definitive function of ANRIL in lymphangiogenesis is not clear., Methods: The diabetic mouse model was set up to assess the wound healing rate in vivo. Quantitative real-time polymerase chain reaction was performed to measure the expressions of ANRIL, miR-181a, and Prox1. Western blot analysis was used to assess the expressions of vascular endothelial growth factor receptor-3, lymphatic vessel hyaluronan receptor-1, Prox1, and epithelial-mesenchymal transition (EMT)-related proteins. Flow cytometry was used to assess the cell apoptosis. Wound healing assay was used to determine the effect of ANRIL on cell migration. Tube-formation assay and immunofluorescence staining were performed to determine tube-formation capacity of human dermal lymphatic endothelial cells (LECs)., Results: ANRIL and Prox1 were downregulated, whereas miR-181a was upregulated in the diabetic wound healing mouse model and high glucose (HG)-induced LECs. The wound healing rate and EMT were inhibited during the diabetic wound healing process. Dual-luciferase assay proved that miR-181a could bind Prox1 to repress its expression, whereas ANRIL could sponge miR-181a to recover Prox1 expression. Overexpression of ANRIL or inhibition of miR-181a rescued the impairments of survival, migration, EMT formation, and tube formation of LECs caused by HG., Conclusion: ANRIL could promote lymphangiogenesis during the diabetic wound healing process via sponging miR-181a to enhance Prox1 expression, which might help design new therapy to improve the wound healing efficacy for diabetes., (© 2018 Wiley Periodicals, Inc.)

Cutaneous lymphoproliferative disorders remain a challenging aspect of dermatopathology, in part due to the rarity of the entities and extreme variability in clinical outcomes. Although many of the entities remain unchanged, the approach to some of them has changed in the new 2016 classification scheme of the World Health Organization. Chief among these are Epstein-Barr virus-associated lymphoproliferative disorders such as Epstein-Barr virus-associated mucocutaneous ulcer and hydroa vacciniforme-like lymphoproliferative disorder, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous acral CD8+ T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, and breast implant-associated anaplastic large cell lymphoma. In addition, translocations and gene rearrangements such as those involving the 6p25.3 locus have started to inform diagnosis and classification of anaplastic large cell lymphoma and lymphomatoid papulosis. In this review, we will examine what is new in the diagnostic toolbox of cutaneous lymphoproliferative disorders.

Objective: Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown., Approach and Results: Here, we characterized the kinetics and function of Ly6C Hi [Lin - (CD3 - CD19 - NK1.1 - Ter-119 - ) Ly6G - CD11b + ] and Ly6C Lo [Lin - (CD3 - CD19 - NK1.1 - Ter-119 - ) Ly6G - CD11b + ] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted tdTomato -labeled Ly6C Hi monocyte/macrophages, we show Ly6C Hi cells transition to a Ly6C Lo phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6C Hi cells that fail transition to Ly6C Lo . The second wave of Ly6C Hi cells in diabetic wounds corresponded to a spike in MCP-1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6C Hi influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6C Hi [Lin - Ly6G - CD11b + ] and Ly6C Lo [Lin - Ly6G - CD11b + ] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6C Hi cells demonstrated differences in proinflammatory and profibrotic genes compared with controls., Conclusions: Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11b + Ly6C Hi monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds., (© 2018 American Heart Association, Inc.)

Apostichopus japonicus is one of the most important aquaculture species in China. Skin ulceration syndrome (SUS) of sea cucumber is a common and serious disease affected the development of A. japonicus culture industry. To better understand the response mechanisms of A. japonicus during SUS progression, the protein variations in the body wall of A. japonicus at different stages of SUS were investigated by a comparative proteomic approach based on isobaric tags for relative and absolute quantification. A total of 1449 proteins were identified from the samples at different SUS stages. Among these proteins, 145 proteins were differentially expressed in the SUS-related samples compared to those of healthy A. japonicus. These differentially expressed proteins involved a wide range of functions. Among these differentially expressed proteins, only two proteins, alpha-5-collagen and an unknown function protein, were differentially expressed during the whole progression of SUS compared with healthy A. japonicus. In addition, ATP synthase subunit beta (ATP5β) interacted with a variety of proteins with different functions during the SUS progression. These results implied that alpha-5-collagen and ATP5β could play important roles during the SUS progression of A. japonicus. Our study provided a new sight to understand the molecular responses of sea cucumber during the SUS progression and accumulated data for the prevention of SUS in sea cucumber aquaculture., Biological Significance: The current study aimed to reveal how the body wall of Apostichopus japonicus response to skin ulceration syndrome (SUS). To the best of our knowledge, this is the first proteomic study analyzing the differences in protein profile of sea cucumber during the whole SUS progression. By analyzing the expression differences of the proteome via isobaric labeling-based quantitative proteomic, we identified some proteins which may play important roles during the SUS progression. According to the enrichment analyses of these proteins based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, a draft view of how the sea cucumber affected by SUS has been drawn. The common and unique differentially expressed proteins by Venn analysis showed that alpha-5-collagen was down-regulated at all stages of SUS, which had the potential as a target component for the host-directed SUS therapy. In addition, ATP5β, a subunit of mitochondrial ATP synthase, interacting with a variety of proteins with different functions during the SUS progression. This result illustrated that energy production and metabolism could play an important role in the formation of skin ulceration and resistance to pathogens in sea cucumber. The results of this study will be helpful for researchers to gain insights into the complex molecular mechanism of SUS in sea cucumber., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Inflammatory bowel disease (IBD) can be divided into Crohn disease, ulcerative colitis and inflammatory bowel disease unclassified (IBDU). In most patients, these disorders present in adolescence or early adulthood. Patients with infantile IBD can have an associated underlying immunodeficiency disorder caused by a mutation in interleukin (IL)-10 or its receptor. We describe a child presenting with intractable bloody diarrhoea since 2 weeks of age and with severe nappy ulceration, who was ultimately diagnosed as having inflammatory bowel disease (IBD) due to an immunodeficiency in the IL-10 receptor. This report highlights the importance of considering this rare immunodeficiency in patients with infantile IBD presenting with severe perianal disease to a dermatologist., (© 2017 British Association of Dermatologists.)

Monogenic autoinflammatory diseases are a heterogeneous emergent group of conditions that are currently under intensive study. We review the etiopathogenesis of these syndromes and their principal manifestations. Our aim is to propose a classification system based on the clinicopathologic features of typical skin lesions for routine clinical use in dermatology. Our focus is on diagnosis in pediatric practice given that this is the period when the signs and symptoms of these syndromes first appear. In Part 1 we discuss the course of urticaria-like syndromes, which include cryopyrin-associated periodic conditions and hereditary periodic fever syndromes. Pustular syndromes are also covered in this part. Finally, we review the range of therapies available as well as the genetic mutations associated with these autoinflammatory diseases., (Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor κB (NF-κB)-dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA , encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients' fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-κB activation, and defective expression of NF-κB-dependent antiapoptotic genes. Rela +/- mice have similarly impaired NF-κB activation, develop cutaneous ulceration from TNF exposure, and exhibit severe dextran sodium sulfate-induced colitis, ameliorated by TNF inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF inhibition in this disease., (© 2017 Badran et al.)

Background: Diabetic wounds are intractable due to complex factors, such as the inhibition of angiogenesis, dysfunction of phagocytosis by macrophages and abnormal inflammatory responses. It is recognized that mesenchymal stem cells (MSCs) promote wound healing in diabetic mice. We previously demonstrated that MSCs produce large amounts of MFG-E8., Object: The objective was to ascertain the role of MSCs-derived MFG-E8 in murine diabetic wounds., Methods: MFG-E8 WT/KO MSCs or rMFG-E8 were subcutaneously injected around the wound in diabetic db/db mice, and wound areas were analyzed. Quantification of angiogenesis, infiltrating inflammatory cells, apoptotic cells at the wound area was performed by immunofluorescence staining and real-time PCR. Phagocytosis assay was performed using peritoneal macrophages from WT or db/db mice., Results: MFG-E8 expression in granulation tissue in diabetic mice was significantly reduced compared with that in non-diabetic mice. We next examined the effect of subcutaneous injection of MFG-E8 WT/KO MSCs around the wound. Diabetic wound healing was significantly accelerated by the injection of MSCs. Diabetic wound healing in MFG-E8 KO MSCs-injected wounds was significantly delayed compared to that in WT MSCs-injected wounds. The numbers of CD31 + EC and NG2 + pericytes, as well as M2 macrophages in wounds in KO MSCs-injected mice were significantly decreased. MFG-E8 WT MSCs treatment suppressed the number of apoptotic cells and TNF-α + cells in wounds. In an in vitro assay, MFG-E8 WT MSCs-conditioned medium enhanced phagocytosis of apoptotic cells by peritoneal macrophages from diabetic mice., Conclusion: MSCs-derived MFG-E8 might accelerate diabetic wound healing by promoting angiogenesis, the clearance of apoptotic cells, and the infiltration of M2 macrophages, and by suppressing inflammatory cytokines in wound area., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Aim: Thrombosis and inflammation play an important role in pathophysiology of livedoid vasculopathy (LV). Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of fibrinolysis and is a pivotal modulator in a broad range of biological processes., Method: The study specimens were retrospectively selected from archives of pathology department. We investigated PAI-1 mRNA expression in the paraffin blocks of patients with biopsy-proven LV and controls. We analyzed the presence of thrombus, fibrinoid necrosis, ulcer, and epidermal atrophy in study samples. The correlation between histologic findings and PAI-1 expression was investigated., Results: Analyses were performed in 14 LV patients (mean age 31±20, 79% female) and 4 controls (mean age 64±19, 50% female). PAI-1 gene expression was significantly higher in LV compared to the control group (median 7.74 (Iqr:13.94) vs 1.0 (0.31)), P=.011. Histological analysis displayed that fibrinoid necrosis was present on all patients with LV, 61.5% displayed thrombus, 46.2% displayed ulcer, and 15.4% displayed epidermal atrophy. Overall, we did not observe any discerning difference in PAI-1 expression between the LV blocks with or without thrombus, fibrinoid necrosis, or epidermal atrophy, yet the LV specimens that displayed ulcer histologically had higher PAI-1 mRNA expression compared to those without ulcer (median 13.98 (Iqr:19.21) vs 2.86 (5.59)), (P=.046)., Conclusion: PAI-1 mRNA expression is significantly increased in cutaneous lesions of patients with LV. Histological finding of ulcer is associated with increased PAI-1 expression in LV specimen. In the current era of PAI-1 inhibitors, enhanced local PAI-1 expression can form a novel and local therapeutic target in LV., (© 2017 John Wiley & Sons Ltd.)

Background: 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., Methods: The dermal micro-grafts were obtained from mechanical disaggregation of small pieces of skin tissue through a medical device called Rigeneracons., Results: 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., Conclusion: 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.

Chronic wounds are a serious healthcare problem. As non-healing wounds involve continuous pathologic inflammatory stage, research is focused on anti-inflammatory treatments. Our objective was to analyze the effect of S42909, a potent NADPH oxidase inhibitor activity, with vascular anti-inflammatory properties. An ischemic rabbit ear ulcer model (24 New Zealand white rabbits) was used to evaluate the reepithelialization/contraction areas, anti-/pro-inflammatory cytokines mRNA (TGF-β1/IL-10/IFN-γ/VEGF) by qRT-PCR, collagen I/III deposition, and neovascularization (TGF-β1/VEGF) by morphological and immunohistochemical analyses. Three different doses were administered by gavage for 2 weeks: 10 and 30 mg/kg/d in self-microemulsion drug delivery system (SMEDDS) and 100 mg/kg/d in arabic gum. Each vehicle was used as control. No signs of infection or necrosis were found. Reepithelialization was almost complete whatever the groups reaching 95% at the dose of 100 mg/kg. Wound contraction was significantly reduced in all S42909-treated groups. A significant increase in anti-inflammatory cytokines TGF-β1 mRNA and IL-10 mRNA was observed at the dose of 100 and 30 mg/kg/d, respectively. No changes were observed in pro-inflammatory factors INF-γ and VEGF mRNA. Ischemic skin wound areas had scarce expression of collagen I/III and showed rich glycosaminoglycans content. Treatment increased the collagen deposition and TGF-β1 protein expression and decreased glycosaminoglycan content dose dependently; however, no effect in VEGF was appreciated. Therefore, our results indicate that S42909 improved healing process by dampening excessive inflammation and facilitating collagen deposition without wound contraction phenomena. S42909 might be a promising therapy to treat chronic wounds as venous leg ulcers., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Marjolin's ulcer (MU) is an aggressive malignancy arising within chronic wounds. A major cause is unhealed burn injuries. This results in well-differentiated squamous cell carcinoma (SCC). This study aimed to elucidate transcriptional changes leading to malignancy by investigating differentially expressed genes in squamous cells present in a SCC compared with MU. MU tumor cells were isolated from histologically confirmed biopsy of SCC within an unhealed burn scar. Epithelial cells (ECs) adjacent to the tumor were co-isolated and a SCC cell line was commercially purchased. mRNA from all three samples was isolated and its expression was quantified using RNASeq. A threshold of log2fold change >2-fold in either direction was considered "differentially expressed." Gene expression analysis revealed distinct differences in gene expression in MU cells compared with EC (665 genes), EC and SCC (1673 genes). Enrichment analysis confirmed that pathways most affected included 1) elevation of genes associated with extracellular matrix organization/degradation, 2) activation of DNA damage, and 3) activation of cytokine signaling. Our analysis revealed two key insights about chronic wound microenvironment conducive to ulceration. First, in EC vs. MU comparison, downregulation of Collagen and Matrix metalloproteinase families suggests chronically impaired extracellular matrix turnover giving rise to a fibrotic microenvironment. Second, in SCC vs. MU comparison, dysregulation of cadherin-mediated cell-cell adhesions is suggestive of epithelial-to-mesenchymal transitions, similar to those during development. Acquisition of epithelial-to-mesenchymal transition may underlie the high metastatic rate in MU tumors. Taken together, this sheds light on mechanisms that underlie the divergent clinical features of these cutaneous cancers.

Despite years of effort, current therapies for diabetic wounds are still not fully efficacious. Emerging evidence has suggested that microRNAs (miRNAs) play key roles in multiple physiological and pathological processes in eukaryotes, and could potentially be powerful therapeutic tools. This study investigated the differential expression profiling of miRNAs in cutaneous wounds in streptozotocin-induced diabetic rats and normal rats, and its significance in diabetic wound healing. Using microarrays, 18 miRNAs were identified as being upregulated and 65 as being downregulated in the diabetic group. The miRNA profiling results were validated by quantitative reverse transcriptase polymerase chain reaction. Finally, functional annotation analysis using the DAVID and miR2Subpath databases revealed that the differentially expressed miRNAs were involved in MAPK signaling pathways, the Wnt signaling pathway, and other signaling pathways that may be closely linked to wound healing. This study provides an experimental foundation for further investigation of mechanisms that underlie poor diabetic wound healing, and of miRNA-based therapies that are associated with wound healing.

Background: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described β2-microglobulin (β2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed., Objective: We sought to describe the molecular and immunologic features of β2m deficiency in 2 Turkish siblings with new diagnoses., Methods: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry., Results: Here we provide the first extensive clinical and immunologic description of β2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of β2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except β2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill.", Conclusion: The clinical presentation of patients with β2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of β2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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.

Objective: Impaired wound healing is a major complication of diabetes mellitus. The mechanisms that govern wound healing, however, are complex and incompletely understood. In the present study, we determined the inhibitory role of protein tyrosine phosphatase 1B (PTP1B) in the process of diabetic wound healing., Approach and Results: First, by comparing the wound healing process in PTP1B knockout (PTP1B(-/-)) mice, ob/ob mice and their wild-type littermates in the presence or absence of streptozotocin treatment, we showed that the inhibition of mouse wound healing in streptozotocin-induced diabetic conditions is because of the upregulation and activation of PTP1B. Second, the impaired wound healing in ob/ob mice and streptozotocin-treated wild-type mice was rescued by a PTP1B inhibitor. Third, PTP1B, which is upregulated under hyperglycemic condition, inhibited the tube formation, proliferation, and migration of human microvascular endothelial cells induced by vascular endothelial growth factor, whereas this inhibition was largely abolished by the PTP1B inhibitor. Finally, mechanism study further indicated that PTP1B likely suppressed the proliferation, migration, and tube formation of vascular endothelial cells through dephosphorylation of vascular endothelial growth factor receptor 2., Conclusions: Our study demonstrated that PTP1B negatively modulated the diabetic wound healing process by dephosphorylating the endothelial cell vascular endothelial growth factor receptor 2 and that the specific inhibitor of PTP1B might serve as a potential novel therapeutic tool for diabetic wound healing., (© 2014 American Heart Association, Inc.)

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.

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.

Objective: The present study is designed to understand the contribution of peripheral vascular disease and peripheral neuropathy to the wound-healing impairment associated with diabetes. Using a rabbit model of diabetic neuroischemic wound healing, we investigated rate of healing, leukocyte infiltration, and expression of cytokines, interleukin-8 and interleukin-6, and neuropeptides, substance P, and neuropeptide Y., Methods: Diabetes was induced in New Zealand White rabbits by administering alloxan while control rabbits received saline. Ten days later, animals in both groups underwent surgery. One ear served as a sham, and the other was made ischemic (ligation of central+rostral arteries) or neuroischemic (ischemia+ resection of central+rostral nerves). Four 6-mm punch biopsy wounds were created in both ears and wound healing was followed for 10 days using computerized planimetry., Results: Nondiabetic sham and ischemic wounds healed significantly more rapidly than diabetic sham and ischemic wounds. Healing was slowest in neuroischemic wounds, irrespective of diabetic status. A high M1/M2 macrophage ratio and a high proinflammatory cytokine expression, both indicators of chronic proinflammatory state, and low neuropeptide expression were seen in preinjury diabetic skin. Postinjury, in diabetic wounds, the M1/M2 ratio remained high, the reactive increase in cytokine expression was low, and neuropeptide expression was further decreased in neuroischemic wounds., Conclusions: This rabbit model illustrates how a combination of a high M1/M2 ratio, a failure to mount postinjury cytokine response as well as a diminished neuropeptide expression, contribute to wound-healing impairment in diabetes. The addition of neuropathy to ischemia leads to equivalently severe impaired wound-healing irrespective of diabetes status, suggesting that in the presence of ischemia, loss of neuropeptide function contributes to the impaired healing associated with diabetes., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

The main function of the epidermis is to protect us against a multitude of hostile attacks from the environment. Its main cell type, the keratinocytes have a sophisticated system of different proteins and lipids available to form the cornified envelope, which is responsible for the barrier function of the skin. During ageing, dramatic changes are taking place. Some proteins of the SPRR-, S100- and LCE3-family are massively up-regulated, whereas others like loricrin, filaggrin and the LCE1&2 protein families are significantly down-regulated. The latter ones are known to be under control of calcium and/or 'calcium response elements'. We were able to show that the calcium peak specific for the stratum granulosum, which is the site where loricrin and the LCE1&2 families are synthesized, is reduced during ageing. The resulting cornified envelope in old skin has an extensively changed composition on the molecular level compared to young skin. This knowledge is of critical importance to understand chronic wound formation and ulcers in old age., (© 2013 John Wiley & Sons A/S.)

Chronic skin ulcers require extensive, systemic differential diagnosis; thus, they are difficult to diagnose and treat. Transient or persistent hypercoagulable states are among the rare causes of skin ulcers. Here, we present the case of a 27-year-old woman patient with recurrent, nonhealing skin ulcers of 8 years' duration, who had been treated unsuccessfully with various medications under different diagnoses at different clinics. On admission, a skin biopsy demonstrated occlusive vasculopathy, and the search for an inherited hypercoagulable state revealed a heterozygous factor V Leiden mutation. The patient was treated with anticoagulants and hyperbaric oxygen. On treatment, the skin lesions healed and did not recur.

To investigate the relationship between the expression of leptin and its long-form receptor, OB-RL, and wound healing in diabetic foot ulcers. Biopsies from 10 patients with diabetic foot ulcers (DU group), 10 with non-diabetic foot ulcers (NDU group), and 10 with normal skin (normal control, NC group) were examined. Leptin and OB-RL mRNA and protein levels were assessed using RT-PCR and immunohistochemistry analyses, respectively. The cuticle thickness was significantly greater, and the epidermal layer was significantly lesser in the DU and NDU groups. Leptin protein expression was significantly higher in the DU and NDU than NC group (P < 0.001), whereas OB-RL mRNA and protein expressions were significantly lower in the DU group and significantly higher in the NDU group (P < 0.001). Diabetic foot ulcer duration was negatively correlated with OB-RL protein expression (ρ = -0.671, P = 0.034). Decreased OB-RL may result in reduced leptin signaling in diabetic foot ulcers. Further studies are required to determine whether OB-RL levels are related to the prognosis of diabetic foot ulcers, as well as to explore the use of leptin or mimetics for promoting ulcer healing.

Background: Hypereosinophilic syndrome (HES) is defined as an eosinophil count equal to or greater than 1.5 G/L for more than 6 months with organ damage (heart, nervous system, lung, etc) after the exclusion of other common causes of eosinophilia. A myeloproliferative variant of HES with FIP1L1-PDGFRα fusion gene inducing constitutive activation of a tyrosine kinase receptor has been characterized. We report a case in which the diagnosis was revealed by mucosal erosions and ulcerations., Patients and Methods: A 50-year-old man reported bipolar erosions. He presented with an erosion on the glans, an ulceration on the lower lip and mild dermographism. He had an eosinophil count of 7.5 G/L (n<0.7) and raised LDH at 520 IU/L (n<480). Screening for the usual causes of eosinophilia was negative. Histology of the labial ulceration showed a polymorphous inflammatory infiltrate containing eosinophils. A chest scan demonstrated a ground glass-like pulmonary infiltrate and broncho-alveolar lavage revealed eosinophilic alveolitis. The myelogram showed rich bone marrow with eosinophils. FIP1L1-PDGFRα fusion transcript was detected in the blood. Imatinib (Glivec(®)) was initiated and a favourable outcome was achieved within a few months and maintained after one year of treatment., Discussion: Cutaneous signs are frequent features of HES. They are polymorphous and include pruritis, erythematous rash and urticaria. Mucosal ulcerations are uncommon and appear more frequently with the myeloproliferative FIP1L1-PDGFRα-associated variant of HES. Early diagnosis allows the onset of a targeted treatment with imatinib that may prevent the apparition of organ damage., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Transient receptor potential vanilloid 1 (TRPV1) is a highly polymodal TRP channel activated by various stimuli, including capsaicin, heat and acids. TRPV1 expression can be detected widely but is highest in sensory neurons and its activation alerts the body to noxious signals via neurogenic pain. Although TRPV1 is reportedly localized in the epidermis, it remains unclear how TRPV1 is involved in the chemical peeling processes with cytotoxic acids. Therefore, in this study, the role of TRPV1 on the effects of trichloroacetic acid (TCA) peeling was assessed using TRPV1-deficient mice. Following the confirmation of TRPV1 expression in murine keratinocytes with reverse transcription-polymerase chain reaction and immunohistochemistry, the effects of TCA on TRPV1-deficient mouse skin were compared with those on wild-type mouse skin. Our results indicated that TRPV1 expression was not required for TCA-induced DNA damage, as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, but was indispensable for the TCA-induced production of distinct growth factors and cytokines by keratinocytes. Ulceration after TCA peeling was actually more severe in the absence of TRPV1, suggesting that the TRPV1-mediated epidermal production of growth factors and cytokines affected the damaging and healing processes of TCA-peeled skin to induce rejuvenation.

Objective: To observe the effect of mild moxibustion on the number of macrophages and contents of collagen I and III in the raw surface tissue in chronic skin ulcer rats so as to study its mechanism underlying promoting scar formation., Methods: Eighty male SD rats were randomly divided into normal (n = 8), model (n = 24), TDP (n = 24) and moxibustion (n = 24) groups. Chronic refractory skin ulcer was established by making an open wound at the back and local intramuscular injection of hydrocortisone sodium succinate. For rats of the TDP and moxibustion groups, TDP irradiation or mild moxibustion was applied to the raw surface, bilateral "Shenshu" (BL 23) and "Zusanli" (ST 36) for 15 min, once daily for 7, 10 and 14 days, respectively. The number of macrophages in the raw surface tissue was counted under light microscope after H. E. staining and col- lagen I and III expressions of the raw surface tissue were detected by immunohistochemistry., Results: In comparison with the normal group, the numbers of macrophages in the raw surface tissue were increased significantly in the model group on day 7, 10 and 14 (P < 0.05); while compared with the model group, the numbers of macrophages were increased further obviously in the moxibustion group on day 7 and 10 and in the TDP group on day 10 after the treatment (P < 0.05). Compared with the model group, the numbers of macrophages in both TDP and moxibustion groups were down-regulated obviously (P < 0. 05). In regard to collagen I and III expression of the raw surface tissue, compared with the normal group, the collagen I protein expression level was down-regulated markedly in the model group on the 7th day (P < 0.01); whereas in comparison with the model group, the expression levels of collagen I and III were increased considerably in the TDP and moxibustion groups on day 7 and 14 after the treatment (P < 0.05, P < 0.01). The ratios of collagen I/III expression were remarkably higher in the model group than in the normal group on day 7 and 14 (P < 0.05), and significantly lower in the TDP group on day 7 and 14 and in the moxibustion group on day 14 than in the model group (P < 0.05, P < 0.01). The effects of moxibustion were obviously superior to those of TDP in up-regulating macrophage number on day 10, up-regulating collagen I and III expressions on day 14, and down-regulating macrophage number on day 14 after the treatment (P < 0.05, P < 0.01). No significant differences were found between the TDP and moxibustion groups in up-regulating macrophage number, and collagen I and III protein expressions, and in down-regulating the ratios of collagen I/III expression on day 7 after the treatment (P > 0.05)., Conclusion: Mild moxibustion can regulate the number of macrophages and strengthen the expression of collagen proteins in the raw surface tissue in the chronic skin ulcer rats, which may contribute to its effect in promoting wound healing and reducing scar formation.

Anaplastic large cell cutaneous lymphomas are clinically and pathologically heterogeneous, CD30 + (Ki-1) lymphoproliferative disorders. The importance of anaplastic lymphoma kinase (ALK) positivity is well known in the prognosis of primary systemic anaplastic large cell cutaneous lymphomas; however, the same in primary cutaneous anaplastic large cell cutaneous lymphomas is not much clear. Herein we report a 65-year-old male with an 18-month history of minimally pruritic localized nodulo-plaque lesion over lower back. Histology revealed cutaneous large cell lymphoma and immunohistochemical staining showed positivity for CD30, CD3 and ALK. The role of ALK positivity in pcALCL is discussed in this article.

Proper healing of cutaneous wounds progresses through a series of overlapping phases. Nonhealing wounds are defective in one or more of these processes and represent a major clinical problem. A critical issue in developing treatments for chronic wounds is the paucity of animal models to study the mechanisms underlying the defects in healing. Here we show that deletion of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) leads to impaired wounds in mice that have the characteristics of nonchronic and chronic ulcers. These wounds show: (1) excessive production of cytokines, in particular three chemokines (KC/CXCL8, MCP-1/CCL2, IP-10/CXCL10), that may be key to the abnormal initiation and resolution of inflammation; (2) defective basement membranes, explaining blood vessel leakage and disruption of dermal/epidermal interactions; and (3) granulation tissue that contains high levels of Coll III, whereas Coll I is virtually absent and does not form fibrils. We also see major differences between nonchronic and chronic wounds, with the latter populated by bacterial films and producing eotaxin, a chemokine that attracts leukocytes that combat multicellular organisms (which biofilms can be considered to be). This new mouse model captures many defects observed in impaired and chronic human wounds and provides a vehicle to address their underlying cell and molecular mechanisms., (© 2012 by the Wound Healing Society.)

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.