Skin Pathology Research Articles

Zoonotic pathogens linked with hedgehog diphtheric disease.

Hedgehog diphtheric disease (HDD), an ulcerative skin disease with a high fatality rate, is an emerging threat to European hedgehogs (Erinaceus europaeus). We explored the potential role of a panel of zoonotic pathogens in the presumed multifactorial nature of HDD in 188 hedgehogs from 3 wildlife rescue centres in Belgium. As expected, and with a prevalence of 67% in 57 hedgehogs with skin lesions, characteristic of HDD, the occurrence of Corynebacterium ulcerans was strongly associated with the disease. Remarkably, with a prevalence of 42% in affected animals, infections with Borrelia burgdorferi sensu lato were 3.92 times more likely to be detected in HDD (95% confidence interval: 1.650-9.880; p=.0024). Overall, 40 hedgehogs tested positive for the B. burgdorferi sensu lato complex, including Borrelia afzelii (n=30), Borrelia bavariensis (n=7) and Borrelia spielmanii (n=7). Other widely occurring pathogens included Salmonella (prevalence of 19%, with three pulsed-field gel electrophoresis profiles) and Leptospira sp. (prevalence of 11%, including Leptospira interrogans and Leptospira borgpetersenii), but these were not associated with the occurrence of HDD. These findings show that hedgehogs in Belgium represent a significant reservoir of multiple zoonotic bacteria, of which toxigenic C. ulcerans and B. burgdorferi sensu lato are associated with widespread hedgehog skin pathology and mortality.

The Use of Retinoids for the Prevention and Treatment of Skin Cancers: An Updated Review.

Retinoids are natural and synthetic vitamin A derivatives that are effective for the prevention and the treatment of non-melanoma skin cancers (NMSC). NMSCs constitute a heterogenous group of non-melanocyte-derived skin cancers that impose substantial burdens on patients and healthcare systems. They include entities such as basal cell carcinoma and cutaneous squamous cell carcinoma (collectively called keratinocyte carcinomas), cutaneous lymphomas and Kaposi’s sarcoma among others. The retinoid signaling pathway plays influential roles in skin physiology and pathology. These compounds regulate diverse biological processes within the skin, including proliferation, differentiation, angiogenesis and immune regulation. Collectively, retinoids can suppress skin carcinogenesis. Both topical and systemic retinoids have been investigated in clinical trials as NMSC prophylactics and treatments. Desirable efficacy and tolerability in clinical trials have prompted health regulatory bodies to approve the use of retinoids for NMSC management. Acceptable off-label uses of these compounds as drugs for skin cancers are also described. This review is a comprehensive outline on the biochemistry of retinoids, their activities in the skin, their effects on cancer cells and their adoption in clinical practice.

METASTATIC MELANOMA TO THE LUNG CURED WITH LOBECTOMY: A CASE REPORT

METASTATIC MELANOMA TO THE LUNG CURED WITH LOBECTOMY: A CASE REPORT

Pigmentary keratitis and mixed chromatophoroma in a betta fish (Betta splendens)

AbstractBetta fish (Betta splendens) are common pets selectively bred for many different anatomic morphologies and colourations. Fish fanciers on hobbyist forums have linked certain phenotypic traits to the development of eye disease and neoplasia in this species. An 8‐month‐old male giant koi dragonscale plakat betta fish presented for ocular abnormalities and a mass on the tail. Clinical signs continued to progress, and the patient was euthanized due to declining quality of life 10 weeks after initial presentation. Pigmentary keratitis, anterior uveitis, and a mixed chromatophoroma were identified histologically. A review of the anecdotal and available scientific literature revealed that both the neoplastic disease and ocular disease may have had a genetic cause in this particular colour morph. Genetic disease should remain a differential for the cause of ocular and skin pathology in bettas. Combining genetic lines of fish may result in the development of multiple health problems, and ethical fish breeders should select away from characteristics that decrease lifespan and affect quality of life.

Three-dimensional representation of triple spectral line imaging data as an option for noncontact skin diagnostics

.Significance Skin malformations in dermatology are mostly evaluated subjectively, based on a doctor’s experience and visual perception; an option for objective quantitative skin assessment is camera-based spectrally selective diagnostics. Multispectral imaging is a technique capable to provide information about concentrations of the absorbing chromophores and their distribution over the malformation in a noncontact way. Conversion of spectral images into distribution maps of chromophores can be performed by means of the modified Beer–Lambert law. However, such distribution maps represent only single specific cases, therefore, some extensive method for data comparison is needed.Aim This study aims to develop a more informative approach for identification and characterization of skin malformations using three-dimensional (3D) representation of triple spectral line imaging data.Approach The 3D-representation method is experimentally tested on eight different skin pathology types, including both benign and malignant pathologies; an imaging device ensuring uniform three laser line (448, 532, and 659 nm) illumination is used. Three spectral line images are extracted from a single snapshot RGB image data, with subsequent calculation of attenuation coefficients for each working wavelength at every image pixel and represented as 3D graphs. Skin chromophore content variations in malformations are represented in a similar way.ResultsClinical measurement results for 99 skin pathologies, including basal cell carcinomas, melanoma, dermal nevi, combined nevi, junctional nevi, blue nevi, seborrheic keratosis, and hemangiomas. They are presented as 3D spectral attenuation maps exhibiting specific individual features for each group of pathologies. Along with intensity attenuation maps, 3D maps for content variations of three main skin chromophores (melanin, oxyhemoglobin, and deoxyhemoglobin), calculated in frame of a model based on modified Beer–Lambert law, are also presented. Advantages and disadvantages of the proposed data representation method are discussed.ConclusionsThe described 3D-representation method of triple spectral line imaging data shows promising potential for objective quantitative noncontact diagnosis of skin pathologies.

Using Artificial Intelligence as a Diagnostic Decision Support Tool in Skin Disease: Protocol for an Observational Prospective Cohort Study.

BackgroundDermatological conditions are a relevant health problem. Each person has an average of 1.6 skin diseases per year, and consultations for skin pathology represent 20% of the total annual visits to primary care and around 35% are referred to a dermatology specialist. Machine learning (ML) models can be a good tool to help primary care professionals, as it can analyze and optimize complex sets of data. In addition, ML models are increasingly being applied to dermatology as a diagnostic decision support tool using image analysis, especially for skin cancer detection and classification.ObjectiveThis study aims to perform a prospective validation of an image analysis ML model as a diagnostic decision support tool for the diagnosis of dermatological conditions.MethodsIn this prospective study, 100 consecutive patients who visit a participant general practitioner (GP) with a skin problem in central Catalonia were recruited. Data collection was planned to last 7 months. Anonymized pictures of skin diseases were taken and introduced to the ML model interface (capable of screening for 44 different skin diseases), which returned the top 5 diagnoses by probability. The same image was also sent as a teledermatology consultation following the current stablished workflow. The GP, ML model, and dermatologist’s assessments will be compared to calculate the precision, sensitivity, specificity, and accuracy of the ML model. The results will be represented globally and individually for each skin disease class using a confusion matrix and one-versus-all methodology. The time taken to make the diagnosis will also be taken into consideration.ResultsPatient recruitment began in June 2021 and lasted for 5 months. Currently, all patients have been recruited and the images have been shown to the GPs and dermatologists. The analysis of the results has already started.ConclusionsThis study will provide information about ML models’ effectiveness and limitations. External testing is essential for regulating these diagnostic systems to deploy ML models in a primary care practice setting.

Effects of splenectomy on skin inflammation and psoriasis-like phenotype of imiquimod-treated mice

Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b+Ly6c+ neutrophils, Ter119+ proerythroblasts, B220+ B cells, F4/80+ macrophages, and CD11c+ dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly.

COVID-19-induced alopecia: a clinical case of diffuse focal alopecia in a patient with generalized pustular psoriasis after a new coronavirus infection

The clinical picture of dermatological diseases in synergy with the pandemic of coronavirus infection demonstrates various, additional, more striking features of the course of dermatoses. The proposed case of observation illustrates the development of diffuse alopecia in a patient with torpid generalized pustular psoriasis, metabolic syndrome, endocrinopathy against the background of a coronavirus infection complicated by polysegmental pneumonia.
 In the presented clinical observation, the severity of the lesion of the skin and skin appendages correlated with the severity of the course of COVID-19, which was the trigger point of the general pathological process ― immune-mediated T-cell inflammation. In the manifestation of psoriasis and its exacerbation, a significant role was played by viral load and a pronounced comorbid background ― autoimmune thyroid disease and metabolic syndrome. Thus, the severe course of COVID-19 with involvement in the pathological process of the microcirculatory bed, coagulopathy, hypoxia of hair follicles as a result, as well as the reduced estrogenic background of the sixty-one-year-old patient contributed not only to the exacerbation of psoriasis, but also led to diffuse hair loss. The degree of hair loss according to SALT criteria was 82%, which corresponded to a severe degree of lesion. The use of prolonged-acting injectable corticosteroids in the complex treatment of various forms of alopecia was an effective method of therapy in this patient, which is associated with the immunosuppressive effect of corticosteroids in autoimmune damage to hair follicles, a decrease in inflammation of the microvascular bed in various infectious and inflammatory conditions. In the presented case, the high efficiency may also have been associated with the mechanisms of reducing the damaging effect of cytokine inflammatory factors, expressed both with the existing background disease psoriasis and with coronavirus complicated infection.
 As numerous observations show, COVID-19 is a potential trigger for many dermatological conditions. Examination and treatment of patients with skin pathology infected with COVID-19 requires a systematic integrated approach.

A scientific approach to skin radiotherapy nursing Article 3 - The skin RT prescription and plan especially in relation to volume and dose

Nurses play an important role in the RT of skin and its diseases. This is the third of four articles that attempts to provide a scientific basis for nurses to better understand skin RT patients, skin and its diseases, and acute RT skin reactions and how to care for them to achieve the best outcomes from RT treatments. The first paper outlined the role of the nurse as an integral part of the radiation oncology team and how to conduct an effective patient assessment to ensure the patient’s optimal journey to treatment completion. The second article described the anatomy, physiology, pathology and radiobiology of skin and its diseases. This third article describes the skin RT prescription and plan, especially in relation to volume and dose. The fourth paper will show how the nurse, by applying the knowledge from the previous articles, can predict, explain and care for any side effects that may arise. This knowledge is important for establishing patient expectations, preparing the patient for side effects, and giving scientifically based reasons for complying with care protocols. Hopefully, these articles will help support the nurse to deliver best care to skin RT patients. More prospective research is needed to elucidate the many remaining facets of nursing care for skin RT patients.

A scientific approach to skin radiotherapy nursing Article 2 - The anatomy, physiology, pathology and radiobiology of skin and its diseases

Nurses play an important role in the care of patients treated with radiotherapy (RT) for skin conditions such as skin cancers. A series of four articles will aim to supplement general oncology nurse training by providing a scientific basis to better understand the skin and its diseases, the use of RT in skin, and the management of necessary acute skin RT reactions to achieve best patient outcomes. The first article focused on the role of the nurse within the radiation oncology department and the initial patient assessment. This second article describes the anatomy, physiology, pathology and radiobiology of skin and its diseases. These concepts are fundamental to the understanding of how acute effects develop during treatment and how to best care for them. The transition time of normal keratinocytes in the epidermis from creation to demise (10-14 days) is discussed as essential to understanding the timing of acute RT effects. The effect of RT on DNA, and the different effects of RT on normal cells versus tumour cells, which underscore fractionation and normal tissue conservation, are also discussed. Finally, this article addresses the late effects of RT in normal skin, accelerated repopulation, types of skin cancers and their relative radiosensitivities, and the effects of RT on benign skin diseases. The third article will describe the skin RT prescription and plan, especially in relation to volume and dose; and the fourth will show how the nurse, by applying the knowledge from the previous articles, can predict, explain and care for the acute side effects that may arise during a course of skin radiotherapy.

LB921 Role of VivaScope ® 2500 in skin pathology: Advantages, limitations, and future prospects

The purpose is to highlight the advantages, limitations and future prospects of a novel cutaneous imaging device (VIvaScope 2500) that was used in a clinical setting for 6 months. This device was used as an adjunct device in a dermatology clinic. This device was used to view margins of excised cutaneous cancers while performing Mohs surgeries; this device was also used to image many excisions that were performed in the clinic before sending them to the histology lab. The staining protocol that we used for freshly excised tissues included 1)Dipping in 20 % Acetic Acid for 30 secs , followed by 2) Dipping in 0.5 mM Acridine Orange solution for 30 secs, followed by 3) Dipping in Normal saline to remove excess dye. Ex Vivo Microscopy (EVM) expedites the process to view skin pathology. It takes approximately 5 minutes to view the excised tissue under VivaScope as compared to frozen sectioning which takes 20 minutes on average. EVM is an ideal device to view margins of cutaneous tumors. This feature allows it to be an excellent adjunct tool to be used clinically to expedite Mohs surgeries. EVM can serve as an adjunct tool to confirm the diagnosis of clinically benign lesions. The use of ex vivo microscopy is not without limitation , compared to traditional formalin-fixed paraffin-embedded (FFPE) tissue sections, the image's resolution is still incomparable. Despite good nuclear contrast, there is still a considerable gap in resolution for ex vivo imaging. In diagnostic pathology, a subtle change in the nucleus can be interpreted as mild dysplasia, which is evident in FFPE slides, not ex vivo microscopic (EVM) images. There is great potential in this new ex vivo imaging tool. It allows real time quasi histologic microscopic examination of freshly excised cutaneous tissue and does not require traditional tissue embedding, processing and sectioning.

Effect of temperature on transfer of Midichloria-like organism and development of red mark syndrome in rainbow trout (Oncorhynchus mykiss)

Red mark syndrome (RMS) is a skin disease of rainbow trout (Oncorhynchus mykiss), believed to be bacterial and caused by a Midichloria-like organism (MLO). Based on reports from farm sites, clinical signs of RMS are not observed above 15–16 °C. Here we describe the onset and progression of RMS at different temperatures under controlled experimental settings. Nine 180 L tanks at 12 °C, 15.5 °C and 19 °C were used to cohabitate 162 specific pathogen free (SPF) rainbow trout with 24 RMS seeder fish. The fish were followed for 11 weeks post cohabitation (wpc) to monitor lesion development by visual assessment and by taking samples at 3, 8 and 11 wpc for histology from skin lesions and internal organs, samples of skin lesions and spleen for MLO detection by qPCR and by digital droplet PCR (ddPCR). Skin and spleen samples for MLO detection by transmission electron microscopy (TEM) were taken from selected cases. Macroscopic and microscopic skin lesions were classified based on 4 stages: mild, moderate, severe and healing.In short, the results showed that at 12 °C the development of skin lesions peaked in severity at 11 weeks post-cohabitation. At 15.5 °C the skin pathology was most severe at 8 weeks, and 3 weeks later skin lesions were in the healing phase or completely resolved. At 19 °C RMS skin lesions developed in just few cases and these lesions were predominantly classified as mild. Concentration of MLO DNA detected by both qPCR and ddPCR techniques seem to follow the same trend of the severity of skin lesions at 12 °C and 15.5 °C. MLO was visualized by using transmission electron microscopy on selected cases showing most severe skin lesions.This publication contains the first description of the effect of temperature on the development and resolution of RMS pathology and the presence of MLO; our study both describes for the first time the presence of MLO by using TEM on samples from a controlled experimental setting and it provides strong evidences that MLO is the etiological agent of RMS.Furthermore, a recently developed novel sensitive PCR technique (ddPCR) for detecting MLO was applied successfully. Additional insights about MLO involvement in RMS and details about RMS development illustrated here can represent the foundations for novel valuable strategies on RMS management and diagnostics.

P800: BLOCKADE OF COMMON GAMMA CHAIN CYTOKINE SIGNALING WITH REGN7257, AN INTERLEUKIN 2 RECEPTOR GAMMA (IL2RG) MONOCLONAL ANTIBODY, PROTECTED MICE FROM GRAFT-VERSUS-HOST DISEASE AND IMMUNE APLASTIC ANEMIA

Background: Pathogenic T-cell responses in T cell-mediated diseases can be driven by cytokines of the common gamma chain (γc) cytokine family (IL2, IL4, IL7, IL9, IL15, and IL21). γc cytokines signal through their corresponding receptors, expressed primarily on immune cells (including T cells), that share a common coreceptor, interleukin 2 receptor subunit gamma (IL2RG) that is required for signaling. Aims: To understand the roles of γc cytokines in driving graft-versus-host disease (GVHD) and bone marrow failure disorders such as immune aplastic anemia (AA), we generated REGN7257, a fully human IL2RG monoclonal antibody that inhibits γc cytokine-induced signaling, and we tested its ability to suppress pathogenic T-cell responses in mouse models of T cell-mediated disease. Methods: We evaluated the efficacy of REGN7257 in a xenogeneic mouse model of GVHD, where immunodeficient NOD-scid-IL2RGnull mice were engrafted with human peripheral blood mononuclear cells (huPBMC). Mice were treated with REGN7257 either prophylactically or therapeutically, and monitored for weight loss and survival, peripheral human T-cell engraftment as well as serum pro-inflammatory cytokine levels over time. In a separate experiment, mice were sacrificed at day 49 post-huPBMC injection (after 4 weeks of antibody treatment) for tissue analysis (liver, lung, skin and bone marrow) of immune cell infiltration (T cells and macrophages), inflammation and/or fibrosis. Results: In a xenogeneic model of GVHD, both prophylactic and therapeutic γc cytokine signaling blockade with REGN7257 effectively protected mice from weight loss and resulted in improved survival, by reducing T-cell expansion in blood and production of pro-inflammatory cytokines in serum. Consistent with the classic pathology of GVHD, lungs, liver and skin of control mice were highly infiltrated by T cells, while γc cytokine signaling blockade strongly reduced T-cell infiltration, with reduced tissue levels of pro-inflammatory cytokines. Importantly, therapeutic γc cytokine signaling blockade in established GVHD (i.e. when mice already showed weight loss) provided similar benefit. Blockade of γc cytokine signaling also led to a reduction in the severity of chronic GVHD, with decreased macrophage infiltration in liver and associated hepatic fibrosis. In this xenogeneic model of GVHD, hemoglobin levels and platelet numbers in blood were both reduced, indicating anemia and thrombocytopenia, respectively, which are two complications associated with aplastic anemia. In addition to peripheral pancytopenia, recipient mice that were engrafted with huPBMC also showed severe marrow aplasia. Importantly, this phenotype of aplastic anemia was prevented by blockade of γc cytokine signaling. Summary/Conclusion: Blockade of γc cytokine signaling with REGN7257 protected against T cell-mediated pathology in a xenogeneic GVHD mouse model that uniquely presents hallmarks of both acute and chronic GVHD, with T-cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and immune AA.

A Murine Point Mutation of Sgpl1 Skin Is Enriched With Vγ6 IL17-Producing Cell and Revealed With Hyperpigmentation After Imiquimod Treatment.

Sphingosine-1-phosphate lyase is encoded by the Sgpl1 gene, degrades S1P, and is crucial for S1P homeostasis in animal models and humans. S1P lyase deficient patients suffer from adrenal insufficiency, severe lymphopenia, and skin disorders. In this study, we used random mutagenesis screening to identify a mouse line carrying a missense mutation of Sgpl1 (M467K). This mutation caused similar pathologies as Sgpl1 knock-out mice in multiple organs, but greatly preserved its lifespan, which M467K mutation mice look normal under SPF conditions for over 40 weeks, in contrast, the knock-out mice live no more than 6 weeks. When treated with Imiquimod, Sgpl1M467K mice experienced exacerbated skin inflammation, as revealed by aggravated acanthosis and orthokeratotic hyperkeratosis. We also demonstrated that the IL17a producing Vγ6+ cell was enriched in Sgpl1M467K skin and caused severe pathology after imiquimod treatment. Interestingly, hyperchromic plaque occurred in the mutant mice one month after Imiquimod treatment but not in the controls, which resembled the skin disorder found in Sgpl1 deficient patients. Therefore, our results demonstrate that Sgpl1M467K point mutation mice successfully modeled a human disease after being treated with Imiquimod. We also revealed a major subset of γδT cells in the skin, IL17 secreting Vγ6 T cells were augmented by Sgpl1 deficiency and led to skin pathology. Therefore, we have, for the first time, linked the IL17a and γδT cells to SPL insufficiency.

No Evidence of Induced Skin Cancer or Other Skin Abnormalities after Long-Term (66 week) Chronic Exposure to 222-nm Far-UVC Radiation.

Far-UVC radiation, typically defined as 200-235 nm, has similar or greater anti-microbial efficacy compared with conventional 254-nm germicidal radiation. In addition, biophysical considerations of the interaction of far-UVC with tissue, as well as multiple short-term safety studies in animal models and humans, suggest that far-UVC exposure may be safe for skin and eye tissue. Nevertheless, the potential for skin cancer after chronic long-term exposure to far-UVC has not been studied. Here, we assessed far-UVC induced carcinogenic skin changes and other pathological dermal abnormalities in 96 SKH-1 hairless mice of both sexes that were exposed to average daily dorsal skin doses of 400, 130 or 55 mJ cm-2 of 222 nm far-UVC radiation for 66 weeks, 5 days per week, 8 h per day, as well as similarly-treated unexposed controls. No evidence for increased skin cancer, abnormal skin growths or incidental skin pathology findings was observed in the far-UVC-exposed mice. In addition, there were no significant changes in morbidity or mortality. The findings from this study support the long-term safety of long-term chronic exposure to far-UVC radiation, and therefore its potential suitability as a practical anti-microbial approach to reduce airborne viral and bacterial loads in occupied indoor settings.

Langerhans cells are an essential cellular intermediary in chronic dermatitis.

SHARPIN regulates signaling from the tumor necrosis factor (TNF) superfamily and pattern-recognition receptors. An inactivating Sharpin mutation in mice causes TNF-mediated dermatitis. Blocking cell death prevents the phenotype, implicating TNFR1-induced cell death in causing the skin disease. However, the source of TNF that drives dermatitis is unknown. Immune cells are a potent source of TNF invivo and feature prominently in the skin pathology; however, Tcells, B cells, and eosinophils are dispensable for the skin phenotype. We use targeted invivo cell ablation, immune profiling, and extensive imaging to identify immune populations driving dermatitis. We find that systemic depletion of Langerin+ cells significantly reduces disease severity. This is enhanced in mice that lack Langerhans cells (LCs) from soon after birth. Reconstitution of LC-depleted Sharpin mutant mice with TNF-deficient LCs prevents dermatitis, implicating LCs as a potential cellular source of pathogenic TNF and highlighting a Tcell-independent role in driving skin inflammation.

Topical cannabidiol (CBD) in skin pathology - A comprehensive review and prospects for new therapeutic opportunities.

Humans have utilised cannabis products in various forms throughout the recorded history. To date, more than 500 biologically active components have been identified in the plants of the Cannabis genus, amongst which more than 100 were classified as phytocannabinoids (exocannabinoids). The plant genus Cannabis is a member of the plant family Cannabaceae, and there are three primary cannabis species which vary in their biochemical constituents: Cannabis sativa, Cannabis indica and Cannabis ruderalis. There has been a growing level of interest in research on the topical usage of a cannabis-based extract as a safer and more effective alternative to the usage of topical corticosteroids in treating some dermatoses. Together with the discovery of the cannabinoid receptors on the skin, it has been further illustrated that topical cannabis has anti-inflammatory, anti-itching, analgesics, wound healing and anti-proliferative effects on the skin.

Self-Assembled Human Skin Equivalents Model Macrophage Activation of Cutaneous Fibrogenesis in Systemic Sclerosis.

The development of precision therapeutics for systemic sclerosis (SSc) has been hindered by the lack of models that accurately mimic the disease in vitro. This study was undertaken to design and test a self-assembled skin equivalent (saSE) system that recapitulates the cross-talk between macrophages and fibroblasts in cutaneous fibrosis. SSc-derived dermal fibroblasts (SScDFs) and normal dermal fibroblasts (NDFs) were cultured with CD14+ monocytes from SSc patients or healthy controls to allow de novo stroma formation. Monocyte donor-matched plasma was introduced at week 3 prior to seeding keratinocytes to produce saSE with a stratified epithelium. Tissue was characterized by immunohistochemical staining, atomic force microscopy, enzyme-linked immunosorbent assay, and quantitative reverse transcriptase-polymerase chain reaction. Stroma synthesized de novo from NDFs and SScDFs supported a fully stratified epithelium to form saSE. A thicker and stiffer dermis was generated by saSE with SScDFs, and more interleukin-6 and transforming growth factor β (TGFβ) was secreted by saSE with SScDFs compared to saSE with NDFs, regardless of the inclusion of monocytes. Tissue with SSc monocytes and plasma had amplified dermal thickness and stiffness relative to control tissue. Viable CD163+ macrophages were found within the stroma of saSE 5 weeks after seeding. Additionally, SSc saSE contained greater numbers of CD163+ and CD206+ macrophages compared to control saSE. TGFβ blockade inhibited stromal stiffness to a greater extent in SSc saSE compared to control saSE. These data suggest reciprocal activation between macrophages and fibroblasts that increases tissue thickness and stiffness, which is dependent in part on TGFβ activation. The saSE system may serve as a platform for preclinical therapeutic testing and for molecular characterization of SSc skin pathology through recapitulation of the interactions between macrophages and fibroblasts.

Preliminary efficacy and safety analysis: 12-month results in 83 patients using a novel approach of widefield radiation therapy for extensive skin field cancerization with or without keratinocyte cancers

Purpose Evaluate the use of widefield radiation therapy (RT) in the management of extensive skin field cancerization (ESFC) with/without keratinocyte cancer (KC). Methods The National Dermatology Radiation Oncology Registry is a multidisciplinary collaboration (dermatologists and radiation oncologists). It captures disease description, prior therapies, radiation prescription, clinical effect, skin cosmesis scores, and toxicity data. This analysis included 12-month follow-up data on 89 treated fields from a subset of 83 patients. Results Clinical success (>90% field clearance) was 96% (ESFC, n = 63) and 88% (ESFC with KC, n = 26). Complete lesion response was seen in 96% of evaluable (n = 25) ESFC with KC. Recurrence (4/89 [5%]) and appearance of new lesions (10/89 [11%]) were minimal. Cosmetic outcome was excellent/good in 98% ESFC and 96% ESFC with KC. Grade 1–2 acute radiation dermatitis occurred in up to 80% of treated fields. The frequency of Grade 3 acute skin toxicities was low. Conclusions Registry data demonstrate the potential for widefield RT to treat patients with significant skin pathology who have exhausted other therapies and require durable, minimally invasive treatment options. At 12 months, observed clinical success rates were higher than those reported for topical interventions for ESFC. Ongoing follow-up is required to determine longer term outcomes.

Ta-Xi-San Suppresses Atopic Dermatitis Involved in Multitarget Mechanism Using Experimental and Network Pharmacology Analysis.

Atopic dermatitis (AD) is a relapsing and chronic skin inflammation with a common incidence worldwide. Ta-Xi-San (TXS) is a Chinese herbal formula usually used for atopic dermatitis in clinic; however, its active compounds and mechanisms of action are still unclear. Our study was designed to reveal the pharmacological activities, the active compounds, and the pharmacological mechanisms of TXS for atopic dermatitis. Mice were induced by 2,4-dinitrocluorobenzene (DNCB) to build atopic dermatitis model. The pathological evaluation, enzyme-linked immunosorbent assay (ELISA), and hematoxylin and eosin (H&E) assay were performed. The UPLC-Q-Exactive-MSE and network pharmacology analysis were performed to explore active ingredients and therapeutic mechanisms of TXS. TXS treatment decreased levels of immunoglobulin E (IgE), interleukin-4 (IL-4), and tumor necrosis factor-α (TNF-α) in serum induced by DNCB. TXS reduced scratching behavior and alleviated inflammatory pathology of skin and ear. Meanwhile, TXS decreased the spleen index and increased spleen index. The UPLC-Q-Exactive-MSE results showed that 65 compounds of TXS were detected and 337 targets were fished. We collected 1371 AD disease targets, and the compound-target gene network reveled that the top 3 active ingredients were (−)-epigallocatechin gallate, apigenin, and esculetin, and the core target genes were PTGS2, PTGS1, and HSP90AA1. The KEGG pathway and GO analysis showed that TXS remedied atopic dermatitis via PI3K-Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and Toll-like receptor (TLR) signaling pathway with the regulation of inflammatory response and transcription. Further, we found that the targets of PTGS2 and HSP90AA1 were both elevated in ears and skin of AD model mouse; however, TXS decreased the elevated expressions of PTGS2 and HSP90AA1. Our study revealed that TXS ameliorated AD based on (−)-epigallocatechin gallate, apigenin, and esculetin via targeting PTGS2 and HSP90AA1.