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Objective: Rarefaction of blood and lymphatic vessels in the skin has been reported in systemic sclerosis (SSc) (scleroderma). E26 transformation–specific–related factor (ERG) and Friend leukemia virus–induced erythroleukemia 1 (FLI‐1) are important regulators of angiogenesis, but their role in lymphatic vasculature is lesser known. The goal of this study was to determine the role of ERG and FLI‐1 in postnatal lymphangiogenesis and SSc lymphatic system defects. Methods: Immunofluorescence was used to detect ERG and FLI‐1 in skin biopsy samples from patients with SSc and healthy controls. Transcriptional analysis of ERG or FLI‐1–silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG and FLI‐1 deficiency on in vitro tubulogenesis in human dermal LECs were examined using a Matrigel assay. ERG and FLI‐1 endothelial–specific knockouts and ERG lymphatic–specific knockouts were generated to examine vessel regeneration in mice. Results: ERG and FLI‐1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsy samples. ERG levels were shown to regulate genes involved in lymphatic vessel specification, including vascular endothelial growth factor receptor 3/FLT‐4, lymphatic vessel endothelial hyaluronan receptor 1, SOX‐18, and prospero homeobox 1 (PROX‐1), whereas FLI‐1 enhanced the function of ERG. The ERG–FLT‐4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of ERG or FLI‐1 similarly impaired the function of blood vessels in mice. However, only ERG deficiency affected the regeneration of lymphatic vessels during wound healing. Conclusion: ERG and FLI‐1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI‐1 in SSc endothelial cells may contribute to the impairment of blood and lymphatic vasculature in patients with SSc. [ABSTRACT FROM AUTHOR]

Growth retardation, Alopecia, Pseudoanodontia and Optic atrophy (GAPO) syndrome is a rare autosomal recessive condition whose cardinal features include a recognizable craniofacial dysmorphosis, growth retardation, alopecia, pseudoanodontia, and premature aging. We report on a 2‐year‐old Pakistani man affected with GAPO syndrome who additionally shows an androgenetic‐like alopecia with normal testosterone levels and telogen hair loss. These are novel findings in GAPO syndrome. [ABSTRACT FROM AUTHOR]

The nature of effector cells and the potential immunogenicity of Leishmania major excreted/secreted proteins (LmES) were evaluated using peripheral blood mononuclear cells (PBMCs) from healed zoonotic cutaneous leishmaniasis individuals (HZCL) and healthy controls (HC). First, we found that PBMCs from HZCL individuals proliferate and produce high levels of IFN-γ and granzyme B (GrB), used as a marker of activated cytotoxic T cells, in response to the parasite antigens. IFN-γ is produced by CD4+ T cells, but unexpectedly GrB is also produced by CD4+ T cells in response to stimulation with LmES, which were found to be as effective as soluble Leishmania antigens to induce proliferation and cytokine production by PBMCs from immune individuals. To address the question of regulatory T cell (Tregs) involvement, the frequency of circulating Tregs was assessed and found to be higher inHZCL individuals compared to that of HC. Further more, bothCD4+CD25+ and CD4+CD25-- T cells, purified fromHZCL individuals, produced IFN-γ and GrB when stimulated with LmES. Additional experiments showed that CD4+CD25+CD127dim/- Tregs were involved in GrB production. Collectively, our data indicate that LmES are immunogenic in humans and emphasize the involvement of CD4+ T cells including activated and regulatory T cells in the immune response against parasite antigens [ABSTRACT FROM AUTHOR]

Senescent cells accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescence markers p16 and p21, accompanied by reductions in SA-β-gal- and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

The nature of effector cells and the potential immunogenicity of Leishmania major excreted/secreted proteins (LmES) were evaluated using peripheral blood mononuclear cells (PBMCs) from healed zoonotic cutaneous leishmaniasis individuals (HZCL) and healthy controls (HC). First, we found that PBMCs from HZCL individuals proliferate and produce high levels of IFN-γ and granzyme B (GrB), used as a marker of activated cytotoxic T cells, in response to the parasite antigens. IFN-γ is produced by CD4(+) T cells, but unexpectedly GrB is also produced by CD4(+) T cells in response to stimulation with LmES, which were found to be as effective as soluble Leishmania antigens to induce proliferation and cytokine production by PBMCs from immune individuals. To address the question of regulatory T cell (Tregs) involvement, the frequency of circulating Tregs was assessed and found to be higher in HZCL individuals compared to that of HC. Furthermore, both CD4(+)CD25(+) and CD4(+)CD25(-) T cells, purified from HZCL individuals, produced IFN-γ and GrB when stimulated with LmES. Additional experiments showed that CD4(+)CD25(+)CD127(dim/-) Tregs were involved in GrB production. Collectively, our data indicate that LmES are immunogenic in humans and emphasize the involvement of CD4(+) T cells including activated and regulatory T cells in the immune response against parasite antigens.

The Dubin-Johnson syndrome (DJS) is an autosomal recessive liver disorder characterized by a chronic conjugated hyperbilirubinemia a dark greenish appearance of liver tissue, a double peaked sulfobromophthalein clearance curve, and a characteristic lysosomal accumulation of black pigment "melanine-like" in the hepatocytes. Laboratory datas indicated an increased urinary excretion of coproporphrin isomer I and leukotriene metabolites. In an effort to understand the morphological pattern and the pathogenesis of this disease we reviewed four cases of DJS.