Follistatin-like 1 is a myokine regulating lipid mobilization during endurance exercise and recovery.

OBJECTIVE: The aim of this study was to investigate the role of the follistatin-like 1 (Fstl1) and disco-interacting protein 2 homolog A (DIP2a) axis in relation to lipid metabolism during and after endurance exercise and to elucidate the mechanisms underlying the metabolic effects of Fstl1 on adipocytes, considering its regulation by exercise and muscle mass and its link to obesity. METHODS: Twenty-nine sedentary males participated in endurance exercise, and blood samples were collected during and after the exercise. Body composition, Fstl1, glycerol, epinephrine, growth hormone, and atrial natriuretic peptide were measured. 3T3-L1 adipocytes, with or without DIP2a knockdown, were treated with Fstl1 to assess glycerol release, cyclic AMP/cyclic GMP production, and hormone sensitive lipase phosphorylation. The association between DIP2a gene expression levels in human adipose tissues and exercise-induced lipolysis was examined. RESULTS: Fstl1 levels significantly increased during endurance exercise and following recovery, correlating with lean body mass and lipolysis. In 3T3-L1 adipocytes, Fstl1 increased glycerol release, cyclic GMP production, and hormone sensitive lipase activation, but these effects were attenuated by DIP2a knockdown. DIP2a gene expression in human adipose tissues correlated with serum glycerol concentrations during endurance exercise. CONCLUSIONS: Fstl1 is a myokine facilitating lipid mobilization during and after endurance exercise through DIP2a-mediated lipolytic effects in adipocytes.

Epidemiology and survival analysis of Merkel cell carcinoma in South Korea: a nationwide, multicenter retrospective study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, of which most research has been conducted in Caucasians. Therefore, the clinicopathological features and prognosis of Merkel cell carcinoma in Asians are still scarce. The aim of this study is to investigate the epidemiology and survival of MCC in South Korea and provide representative information regarding MCC in Asia. METHODS: This was a retrospective, nationwide, multicenter study conducted in 12 centers across South Korea. Patients with pathologically proven MCC were included in the study. The clinicopathological features and clinical outcomes of the patients were investigated. Overall survival (OS) was analyzed using the Kaplan-Meier method, and independent prognostic factors were identified using Cox regression analysis. RESULTS: A total of 161 patients with MCC were evaluated. The mean age was 71 years with a female predominance. OS was significantly different among the stages. Among clinicopathological features, multivariate Cox regression analysis demonstrated that only the stage at diagnosis was associated with poorer overall survival. CONCLUSIONS: The results of our study suggest that the incidence of MCC was higher in females than in males and that there was a higher rate of local disease at the time of diagnosis. Among the variable clinicopathological features, disease stage at diagnosis was the only significant prognostic factor for MCC in South Korea. The findings of this nationwide, multicenter study suggest that MCC has distinct features in South Korea compared with other countries.

Oncogenic signaling pathways and hallmarks of cancer in Korean patients with acral melanoma.

Acral melanoma (AM), a rare subtype of cutaneous melanoma, shows higher incidence in Asians, including Koreans, than in Caucasians. However, the genetic modification associated with AM in Koreans is not well known and has not been comprehensively investigated in terms of oncogenic signaling, and hallmarks of cancer. We performed whole-exome and RNA sequencing for Korean patients with AM and acquired the genetic alterations and gene expression profiles. KIT alterations (previously known to be recurrent alterations in AM) and CDK4/CCND1 copy number amplifications were identified in the patients. Genetic and transcriptomic alterations in patients with AM were functionally converge to the hallmarks of cancer and oncogenic pathways, including 'proliferative signal persistence', 'apoptotic resistance', and 'activation of invasion and metastasis', despite the heterogeneous somatic mutation profiles of Korean patients with AM. This study may provide a molecular understanding for therapeutic strategy for AM.

Tracing metabolic flux in vivo: basic model structures of tracer methodology.

Molecules in living organisms are in a constant state of turnover at varying rates, i.e., synthesis, breakdown, oxidation, and/or conversion to different compounds. Despite the dynamic nature of biomolecules, metabolic research has focused heavily on static, snapshot information such as the abundances of mRNA, protein, and metabolites and/or (in)activation of molecular signaling, often leading to erroneous conclusions regarding metabolic status. Over the past century, stable, non-radioactive isotope tracers have been widely used to provide critical information on the dynamics of specific biomolecules (metabolites and polymers including lipids, proteins, and DNA), in studies in vitro in cells as well as in vivo in both animals and humans. In this review, we discuss (1) the historical background of the use of stable isotope tracer methodology in metabolic research; (2) the importance of obtaining kinetic information for a better understanding of metabolism; and (3) the basic principles and model structures of stable isotope tracer methodology using 13C-, 15N-, or 2H-labeled tracers.

Balanced Free Essential Amino Acids and Resistance Exercise Training Synergistically Improve Dexamethasone-Induced Impairments in Muscle Strength, Endurance, and Insulin Sensitivity in Mice.

Our previous study shows that an essential amino acid (EAA)-enriched diet attenuates dexamethasone (DEX)-induced declines in muscle mass and strength, as well as insulin sensitivity, but does not affect endurance. In the present study, we hypothesized that the beneficial effects will be synergized by adding resistance exercise training (RET) to EAA, and diet-free EAA would improve endurance. To test hypotheses, mice were randomized into the following four groups: control, EAA, RET, and EAA+RET. All mice except the control were subjected to DEX treatment. We evaluated the cumulative rate of myofibrillar protein synthesis (MPS) using 2H2O labeling and mass spectrometry. Neuromuscular junction (NMJ) stability, mitochondrial contents, and molecular signaling were demonstrated in skeletal muscle. Insulin sensitivity and glucose metabolism using 13C6-glucose tracing during oral glucose tolerance tests were analyzed. We found that EAA and RET synergistically improve muscle mass and/or strength, and endurance capacity, as well as insulin sensitivity, and glucose metabolism in DEX-treated muscle. These improvements are accomplished, in part, through improvements in myofibrillar protein synthesis, NMJ, fiber type preservation, and/or mitochondrial biogenesis. In conclusion, free EAA supplementation, particularly when combined with RET, can serve as an effective means that counteracts the adverse effects on muscle of DEX that are found frequently in clinical settings.

Pathophysiological Role of TLR4 in Chronic Relapsing Itch Induced by Subcutaneous Capsaicin Injection in Neonatal Rats.

Despite the high prevalence of chronic dermatitis and the accompanied intractable itch, therapeutics that specifically target itching have low efficacy. Increasing evidence suggests that TLRs contribute to immune activation and neural sensitization; however, their roles in chronic itch remain elusive. Here, we show that the RBL-2H3 mast cell line expresses TLR4 and that treatment with a TLR4 antagonist opposes the LPS dependent increase in mRNA levels of Th2 and innate cytokines. The pathological role of TLR4 activation in itching was studied in neonate rats that developed chronic itch due to neuronal damage after receiving subcutaneous capsaicin injections. Treatment with a TLR4 antagonist protected these rats with chronic itch against scratching behavior and chronic dermatitis. TLR4 antagonist treatment also restored the density of cutaneous nerve fibers and inhibited the histopathological changes that are associated with mast cell activation after capsaicin injection. Additionally, the expression of IL-1ß, IL-4, IL-5, IL-10, and IL-13 mRNA in the lesional skin decreased after TLR4 antagonist treatment. Based on these data, we propose that inhibiting TLR4 alleviated itch in a rat model of chronic relapsing itch, and the reduction in the itch was associated with TLR4 signaling in mast cells and nerve fibers.

Increased CD69+CCR7+ circulating activated T cells and STAT3 expression in cutaneous lupus erythematosus patients recalcitrant to antimalarials.

BACKGROUND: Antimalarials are first-line systemic therapy for cutaneous lupus erythematosus (CLE). While some patients unresponsive to hydroxychloroquine (HCQ) alone benefit from the addition of quinacrine (QC), a subset of patients is refractory to both antimalarials. METHODS: We classified CLE patients as HCQ-responders, HCQ+QC-responders, or HCQ+QC-nonresponders to compare immune profiles. Immunohistochemistry, immunofluorescence, and qRT-PCR were used to characterize inflammatory cells and cytokines in lesional skin. RESULTS: Immunohistochemistry showed that CD69+ T cells were higher in HCQ+QC-nonresponders compared to HCQ- and HCQ+QC-responders (p < 0.05). Immunofluorescence further identified these cells as CD69+CCR7+ circulating activated T cells. Myeloid dendritic cells were significantly higher in HCQ+QC-responders compared to both HCQ-responders and HCQ+QC-nonresponders. Plasmacytoid dendritic cells were significantly increased in HCQ-responders compared to HCQ- and HCQ+QC-nonresponders. No differences were found in the number of autoreactive T cells, MAC387+ cells, and neutrophils among the groups. CLASI scores of the HCQ+QC-nonresponder group positively correlated with CD69+CCR7+ circulating activated T cells (r = 0.6335, p < 0.05) and MAC387+ cells (r = 0.5726, p < 0.05). IL-17 protein expression was higher in HCQ+QC-responders compared to HCQ-responders or HCQ+QC-nonresponders, while IL-22 protein expression did not differ. mRNA expression demonstrated increased STAT3 expression in a subset of HCQ+QC-nonresponders. CONCLUSION: An increased number of CD69+CCR7+ circulating activated T cells and a strong correlation with CLASI scores in the HCQ+QC-nonresponders suggest these cells are involved in antimalarial-refractory skin disease. STAT3 is also increased in HCQ+QC-nonresponders and may also be a potential target for antimalarial-refractory skin disease.

Use of hydroxychloroquine in dermatology: A multicenter retrospective study in Korea.

Despite the expanding clinical application of hydroxychloroquine in dermatology, the overall data on hydroxychloroquine use among dermatologists are limited. With retrospective review of the medical records of the 790 patients who were prescribed hydroxychloroquine, we classified the diagnoses into 12 disease categories, the lupus erythematosus group being the largest. The lupus erythematosus group had the longest prescription duration (median, 6.2 months), whereas the photodermatitis group had a significantly shorter prescription duration (median, 0.5 months). The overall good response rate was 77.1%. The photodermatitis group had the best response (88.7%), followed by the lupus panniculitis (85.1%) and lichen planus (84.4%). In conclusion, hydroxychloroquine has proven utility for various inflammatory skin diseases, including but not limited to cutaneous lupus erythematosus.

STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes.

Skin barrier dysfunction induces skin inflammation. Signal transducer and activator of transcription 3 (STAT3) is known to be involved in Th17-mediated immune responses and barrier integrity in the cornea and intestine; however, its role in the skin barrier remains largely unknown. In this study, we elucidated the potential role of STAT3 in the skin barrier and its effect on kallikrein-related peptidase 5 (KLK5) and serine protease inhibitor Kazal-type 5 (SPINK5) expression using a mouse model with keratinocyte-specific ablation of STAT3. Keratinocyte-specific loss of STAT3 induced a cutaneous inflammatory phenotype with pruritus and intense scratching behaviour in mice. Transcriptomic analysis revealed that the genes associated with impaired skin barrier function, including KLK5, were upregulated. The effect of STAT3 on KLK5 expression in keratinocytes was not only substantiated by the increase in KLK5 expression following treatment with STAT3 siRNA but also by its decreased expression following STAT3 overexpression. Overexpression and IL-17A-mediated stimulation of STAT3 increased the expression of SPINK5, which was blocked by STAT3 siRNA. These results suggest that the expression of SPINK5 and KLK5 in keratinocytes could be dependent on STAT3 and that STAT3 might play an essential role in the maintenance of skin barrier homeostasis.

2020 Korean Consensus Guidelines for Diagnosis and Treatment of Chronic Hand Eczema.

BACKGROUND: Hand eczema refers to eczema located on the hands, regardless of its etiology or morphology. Despite its high prevalence and significant impact on patients' quality of life, treatment is frequently challenging because of its heterogeneity, chronic and recurrent course, and lack of well-organized randomized controlled trials of the various treatment options. OBJECTIVE: These consensus guidelines aim to provide evidence-based recommendations on the diagnosis and management of hand eczema to improve patient care by helping physicians make more efficient and transparent decisions. METHODS: A modified Delphi method, comprising two rounds of email questionnaires with face-to-face meetings in between, was adopted for the consensus process that took place between February and September 2020. Forty experts in the field of skin allergy and contact dermatitis were invited to participate in the expert panel. RESULTS: Consensus was reached for the domains of classification, diagnostic evaluation, and treatment; and a therapeutic ladder to manage chronic hand eczema was developed. CONCLUSION: These are the first consensus guidelines for chronic hand eczema in the Asian population, which will help standardize care and assist clinical decision-making in the diagnosis and treatment of chronic hand eczema.

Clinical characteristics of itch in cutaneous lupus erythematosus: A prospective, multicenter, multinational, cross-sectional study.

OBJECTIVE: Pruritus is an important symptom frequently accompanying various inflammatory skin conditions and some recent data indicated that it may be associated with autoimmune connective tissue diseases. The aim of this study was to assess the frequency and clinical presentation of itch in CLE. METHODS: A multinational, prospective, cross-sectional study was performed to assess the prevalence, intensity and clinical characteristic of pruritus in various subtypes of CLE. A total of 153 patients with active CLE lesions were included. Their age ranged between 17 and 82 years (mean 49.8 ± 15.4 years), and 115 patients (75.2%) were women. The disease activity and damage were assessed according to the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Pruritus severity was assessed with Numeric Rating Scale (NRS) and the 12-Item Pruritus Severity Scale. Dermatology Life Quality Index and EQ-5D questionnaire were used to measure quality of life. RESULTS: Pruritus was present in 116 (76.8%) of patients of whom half had NRS scoring equal or above 4 points indicating moderate or severe pruritus. Most commonly itch was localized on the scalp, face (excluding ears and nose) and arms (40.5%, 36.2%, 31.9%, respectively). Sensations connected with pruritus were most frequently described as burning, tingling and like ants crawling feeling, but 31.9% patients described it as "pure itch". More than half of patients reported that pruritus was present every day, and it was most frequent during the evenings. The pruritus scoring and the CLASI activity score were significantly correlated (r = 0.42, p = 0.0001), while no correlation was found with the CLASI damage score (p = 0.16). Both the maximum and average itch intensity were correlated with systemic lupus erythematosus (SLE) activity measured with the Systemic Lupus Erythematosus Disease Activity Index. CONCLUSIONS: Pruritus is a common, but frequently overlooked symptom of CLE. Its intensity correlates with the activity of CLE, but not with the skin damage. In more than a half of patients it occurs on a daily basis. The correlation between the intensity of pruritus and the activity of the skin lesions and the systemic involvement indicate that pruritus could be an individual indicator of both SLE and CLE activity.

Expression pattern of tissue-resident memory T cells in cutaneous lupus erythematosus.

BACKGROUND: Tissue resident memory T cells (TRMs) persist long-term in peripheral tissues without recirculation, triggering an immediate protective inflammatory state upon the re-recognition of the antigen. Despite evidence incriminating the dysregulation of TRMs in autoimmune diseases, few studies have examined their expression in cutaneous lupus erythematosus (CLE). OBJECTIVES: We aimed to examine whether there are differences among TRM populations in CLE depending on different clinical conditions, such as the CLE subtype or association with systemic lupus erythematosus, and to determine the effect of type I interferon (IFN) on the development of TRMs in CLE. METHODS: CLE disease activity was evaluated using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. The expression of the TRM markers CD69 and CD103 in CLE lesions was evaluated by immunofluorescence. Flow cytometry was performed on peripheral blood mononuclear cells after IFNα treatment. RESULTS: The number of TRMs expressing either CD69 or CD103 was significantly higher in CLE lesions than in control skin; however, it was not significantly different between discoid lupus erythematosus and subacute CLE, or dependent on the presence of concomitant systemic lupus. Lesional severity was not correlated with an increase in TRMs in CLE. IFNα treatment induced a conspicuous increase in CD69 expression in skin-homing T cells, more profoundly in CD4+ T cells than in CD8+ T cells. CONCLUSIONS: Skin TRMs, either CD69 or CD103-positive cells, showed increased levels in the lesional skin of CLE, and IFNα increased the expression of CD69 in T cells.

Pruritus in autoimmune connective tissue diseases.

Pruritus is one of the most common and bothersome symptoms of skin disorders, and its clinical characteristics and related pathomechanisms have been well described in certain dermatologic conditions, such as atopic dermatitis and urticaria. Although pruritus is believed to be as common in cutaneous autoimmune connective tissue diseases (ACTDs) as in other inflammatory skin disorders, its true characteristics have not been elucidated either qualitatively or quantitatively. Pruritus is present in ACTDs with various prevalence rates, characteristics, and mechanisms depending on the disease types. Pruritus most frequently and severely affects the patients with dermatomyositis, in which itch is strongly correlated with disease activity and severity, thus increased itch could also indicate a disease flare. Patients with other ACTDs, including lupus erythematosus (LE), Sjögren syndrome (SS), morphea, and systemic sclerosis (SSc), also suffer from their fair share of pruritus. Unfortunately, the currently available treatments for ACTDs seem to have only limited and unsatisfactory effects to control pruritus. The extensive impact of pruritus on the patients' quality of life (QOL) and functioning warrants more targeted and individualized approaches against pruritus in ACTDs. This review will address the prevalence, suggested pathogenesis based on currently available evidences, and potential treatment options of pruritus in various ACTDs of the skin.

Creation and Validation of Classification Criteria for Discoid Lupus Erythematosus.

Importance: Classification criteria are the standardized definitions that are used to enroll uniform cohorts for research studies. They emphasize high specificity and are distinct from diagnostic criteria. No universally recognized classification criteria currently exist for discoid lupus erythematosus (DLE), which has led to problematic heterogeneity in observational and interventional clinical studies across the field. Objective: To create and validate classification criteria for DLE using 12 previously defined candidate criteria items. Design, Setting, and Participants: For this diagnostic study, candidate criteria items were prospectively applied by dermatologists and dermatopathologists at clinical visits of patients with DLE or a condition that could be confused for DLE, termed a DLE mimicker, at academic dermatology practices across the United States, Poland, Japan, and South Korea. Data were collected from December 1, 2017, to February 1, 2019, and analyzed from March 1 to September 19, 2019. Main Outcomes and Measures: Clinical features among these 2 groups were calculated and compared with χ2 or Fisher exact tests. Candidate models were identified using best subsets logistic regression analysis. Improvement tests, fit statistics, and discrimination were considered to choose a final model. Results: Nine sites contributed 215 patients, 15 of whom had missing or incomplete data. The final model for DLE classification criteria includes only clinical variables: atrophic scarring (3 points), location in the conchal bowl (2 points), preference for the head and neck (2 points), dyspigmentation (1 point), follicular hyperkeratosis and/or plugging (1 point), and erythematous to violaceous in color (1 point), with an area under the receiving operating characteristic curve of 0.91 (95% CI, 0.87-0.95). A score of at least 5 points yields a sensitivity of 84.1% and a specificity of 75.9% in the classification of DLE, with increasing scores yielding higher specificity. Conclusions and Relevance: These findings provide the initial validation of classification criteria for DLE for use in observational and clinical trials.

Corrigendum: Eosinophil Activation by Toll-Like Receptor 4 Ligands Regulates Macrophage Polarization.

[This corrects the article DOI: 10.3389/fcell.2019.00329.].

Development and clinical study of the use of infrared radiation to accelerate the dissolution rate of a microneedle array patch (MAP).

The dissolution rate of a microneedle array patch (MAP) determines how long a MAP must remain attached to the skin (often called "wear time"). In this study, the dissolution rate of a MAP was increased, not by changing the drug formulation but by employing an infrared (IR) device that is widely used for hospital treatment and in-home therapy. A MAP with microneedles 480 µm in height was prepared using hyaluronic acid (HA). Changes in transepidermal water loss (TEWL), the surface temperature of the skin, and the dissolution rate of the MAP tips with IR irradiation were evaluated on human skin in vivo. Time for recovery from erythema that occurred after MAP attachment and IR irradiation was also evaluated. TEWL increased more than fourfold with IR irradiation. Water that evaporated as a result of IR irradiation was trapped in the skin layer by the patch, resulting in the increased dissolution rate of the MAP tips. After 10 min of IR irradiation, the height of the dissolving tips compared with their initial height increased from 41 to 56%, and the dissolved volume of the tips compared with their initial volume increased from 7 to 18%. During the 10 min of irradiation, the skin surface temperature rose from 32 to 40 °C. Erythema occurred in the early stage of treatment with IR irradiation and MAP attachment, but it abated within 2 h after removal of the MAP and cessation of IR irradiation. Through this study, it was possible to shorten the administration time of MAPs by using an IR device that could be easily accessed. This method can be applied to various types of MAPs in order to reduce the time that the MAPs must remain attached to the skin without changing the drug formulation. Graphical abstract The increase in dissolution rate of dissolving microneedle array patch (MAP) as a result of infrared radiation. a Water-soluble tips of MAP dissolved in water in skin without infrared irradiation. Dotted line indicates the initial dissolving microneedles. b Water in skin and subcutaneous layer evaporated actively with infrared irradiation and was stored under patch of MAP. Increased amount of water in skin induced faster dissolution of MAP tips.

Eccrine Porocarcinoma: A Multicenter Retrospective Study with Review of the Literatures Reported in Korea.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare malignant cutaneous adnexal tumor. Other than several scattered case reports, no comprehensive review on EPC has been conducted in Korea. OBJECTIVE: To clinicopathologically review all EPC cases from our institutions as well as those reported in Korea. METHODS: Medical records and histopathological slides of EPC cases in the skin biopsy registries of our institutions were retrospectively reviewed. Additionally, EPC cases reported in Korea before June 2019 were retrieved by searching the PubMed, KoMCI, KoreaMed, and KMbase databases. RESULTS: Nine EPC cases from our institutions were included in the study. In addition, 27 reports of 28 patients with EPC were reported in Korea. A total of 37 patients with EPC were identified, consisting of 19 males (male:female ratio, 1.06:1; mean age at diagnosis, 65.6 years). The most common site of primary tumor was the head and neck (29.7%). Wide excision was the most common (78.4%) treatment method. Initial metastasis work-up imaging studies were performed in 18 patients (48.6%), and metastasis was confirmed in eight patients (21.6%). CONCLUSION: EPC is a rare cutaneous carcinoma in Korea. EPC usually affects elderly patients, with no sexual predilection. Due to possible metastasis, careful diagnosis and appropriate metastasis work-ups are warranted in EPC.

Cutaneous lupus erythematosus and its association with systemic lupus erythematosus: A nationwide population-based cohort study in Korea.

Although lupus erythematosus is known to be more common among women of color, the study populations in previous reports were predominantly Caucasian and there is scarce information on Asian patients. Therefore, we performed a retrospective study using a nationwide population-based cohort in South Korea. The average annual incidence of cutaneous lupus was 4.36/100 000. Among 634 patients with cutaneous lupus, 20.8% had systemic disease: cutaneous lupus was diagnosed before systemic lupus in 4.26% and after systemic lupus in 8.52%. More female patients than male patients developed systemic lupus erythematosus. The average time to progression to systemic lupus was 1.53 ± 1.46 years.