FANCI serve as a prognostic biomarker correlated with immune infiltrates in skin cutaneous melanoma.

Background: As a member of tumor, Skin cutaneous melanoma (SKCM) poses a serious threat to people's health because of its strong malignancy. Unfortunately, effective treatment methods for SKCM remain lacking. FANCI plays a vital role in the occurrence and metastasis of various tumor types. However, its regulatory role in SKCM is unclear. The purpose of this study was to explore the association of FANCI with SKCM. Methods: This study investigated the expression of FANCI in GSE46517, GSE15605, and GSE114445 from the Gene Expression Omnibus database and The Cancer Genome Atlas (TCGA)-SKCM datasets using the package "limma" or "DESeq2" in R environment and also investigated the prognostic significance of FANCI by utilizing the GEPIA database. Additionally, our research made use of real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) staining to verify FANCI expression between SKCM and normal tissues and developed the knockdown of FANCI in A375 and A875 cells to further analyze the function of FANCI. Finally, this study analyzed the correlation of FANCI and tumor-infiltrating immune cells by CIBERSORT, ESTIMATE, and ssGSEA algorithms. Results: The FANCI level was increasing in SKCM tissues from GSE46517, GSE15605, GSE114445, and TCGA-SKCM. However, high FANCI expression correlated with poor overall survival. The RT-qPCR and IHC confirmed the accuracy of bioinformatics. Knocking down FANCI suppresses A375 and A875 cell proliferation, migration, and invasion. FANCI could be involved in the immunological milieu of SKCM by regulating immune responses and infiltrating numerous immune cells, particularly neutrophils, CD8+ T cells, and B cells. Furthermore, patients with SKCM who have a high FANCI expression level are reported to exhibit immunosuppression, whereas those with a low FANCI expression level are more likely to experience positive outcomes from immunotherapy. Conclusions: The increased FANCI expression in SKCM can be a prognostic biomarker. Knockdown FANCI can reduce the occurrence and progression of SKCM. The FANCI expression provides a foundation for predicting the immune status and treatment of SKCM.

Prevalence of psoriatic arthritis in Chinese population with psoriasis: A multicenter study conducted by experienced rheumatologists.

BACKGROUND: Reports on the prevalence of psoriatic arthritis (PsA) among Chinese patients with psoriasis are very limited. This study, conducted by rheumatologists, estimated the prevalence of PsA in a large number of Chinese patients with psoriasis. METHODS: Consecutive patients with a confirmed diagnosis of psoriasis attending nine dermatology clinics in five hospitals were recruited. All psoriasis patients were asked to complete a questionnaire comprising 16 questions to identify possible cases of PsA. All patients with one or more positive answers to the questionnaire were evaluated by two experienced rheumatologists. RESULTS: A total of 2434 psoriasis patients, including 1561 males and 873 females, were enrolled. Both the questionnaire and rheumatologists' examinations were completed in the dermatology clinics. The results identified 252 patients with PsA, comprising 168 males and 84 females. The overall prevalence of PsA among psoriasis patients was 10.4% (95% confidence interval [95% CI], 9.1%-11.7%). By sex, the prevalence was 10.8% (95% CI, 9.2%-12.5%) for males and 9.6% (95% CI, 7.7%-11.9%) for females and there was no significant sex difference in the prevalence of PsA (P = 0.38). Of the 252 PsA patients, 125 (49.6%, 95% CI, 41.3%-59.1%) were newly diagnosed by rheumatologists. Consequently, the prevalence of undiagnosed PsA among psoriasis patients was 5.2% (95% CI, 4.4%-6.2%). CONCLUSION: The prevalence of PsA in the Chinese population with psoriasis is about 10.4%, which is almost double that of previous reports in the Chinese population, but lower than that in Caucasians.

Measurement properties of the patient global assessment numerical rating scale in moderate-to-severe psoriasis.

BACKGROUND: Patient global assessment (PtGA) has been recommended as one of the core domains in psoriasis clinical trials. Among multiple versions of PtGA, the single-question, 11-point PtGA numeric rating scale (NRS) remains to be validated in patients with plaque psoriasis. OBJECTIVES: To evaluate the psychometric characteristics of an 11-point PtGA NRS for disease severity in patients with moderate-to-severe plaque psoriasis. METHODS: Data were analysed from 759 patients with moderate-to-severe psoriasis in the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), a prospective, multicentre and observational registry assessing the comparative effectiveness and safety of biologics (adalimumab, ustekinumab, secukinumab or ixekizumab), conventional systemic therapies (acitretin or methotrexate) and phototherapy. RESULTS: The test-retest reliability of the PtGA NRS showed good agreement (intraclass correlation coefficient range 0.79-0.83). No floor or ceiling effects of PtGA NRS were observed. The PtGA NRS was significantly correlated with the Psoriasis Area and Severity Index (PASI), static Physician Global Assessment (sPGA), body surface area, Dermatology Quality of Life Index (DLQI) and Hospital Anxiety and Depression Scale. Relatively large correlations of PtGA NRS with PASI and the DLQI 'symptoms and feelings' domain (all correlations ≥ 0.4 except at baseline) supported convergent validity. The presence of psoriatic arthritis or joint symptoms had no significant association with the PtGA NRS. In multivariate regression analyses, the PtGA NRS at baseline was predicted by age, lesion extent, lesion intensity, patients' symptoms and feelings, and impact on work or school. The PtGA NRS displayed known-groups validity with the PASI, sPGA and DLQI score bands. The PtGA NRS was responsive to change in PASI and DLQI after treatment. Anchor- and distribution-based approaches supported -3 as the minimal important difference for PtGA NRS. An absolute PtGA NRS ≤ 2 during follow-up was concordant with the state of minimal disease activity based on a 90% reduction in PASI (PASI 90) or PASI 90 plus a DLQI of 0/1. Sensitivity analysis using subgroup comparison and multiple imputation model yielded consistent conclusions. CONCLUSIONS: The PtGA NRS showed good reliability, validity and responsiveness in patients with psoriasis, and was feasible in clinical trials and daily practice.

New insights into inflammatory memory of epidermal stem cells.

Inflammatory memory, as one form of innate immune memory, has a wide range of manifestations, and its occurrence is related to cell epigenetic modification or metabolic transformation. When re-encountering similar stimuli, executing cells with inflammatory memory function show enhanced or tolerated inflammatory response. Studies have identified that not only hematopoietic stem cells and fibroblasts have immune memory effects, but also stem cells from various barrier epithelial tissues generate and maintain inflammatory memory. Epidermal stem cells, especially hair follicle stem cells, play an essential role in wound healing, immune-related skin diseases, and skin cancer development. In recent years, it has been found that epidermal stem cells from hair follicle can remember the inflammatory response and implement a more rapid response to subsequent stimuli. This review updates the advances of inflammatory memory and focuses on its mechanisms in epidermal stem cells. We are finally looking forward to further research on inflammatory memory, which will allow for the development of precise strategies to manipulate host responses to infection, injury, and inflammatory skin disease.

Inorganic hollow mesoporous spheres-based delivery for antimicrobial agents.

Microorganisms coexist with human beings and have formed a complex relationship with us. However, the abnormal spread of pathogens can cause infectious diseases thus demands antibacterial agents. Currently available antimicrobials, such as silver ions, antimicrobial peptides and antibiotics, have diverse concerns in chemical stability, biocompatibility, or triggering drug resistance. The "encapsulate-and-deliver" strategy can protect antimicrobials against decomposing, so to avoid large dose release induced resistance and achieve the controlled release. Considering loading capacity, engineering feasibility, and economic viability, inorganic hollow mesoporous spheres (iHMSs) represent one kind of promising and suitable candidates for real-life antimicrobial applications. Here we reviewed the recent research progress of iHMSs-based antimicrobial delivery. We summarized the synthesis of iHMSs and the drug loading method of various antimicrobials, and discussed the future applications. To prevent and mitigate the spread of an infective disease, multilateral coordination at the national level is required. Moreover, developing effective and practicable antimicrobials is the key to enhancing our capability to eliminate pathogenic microbes. We believe that our conclusion will be beneficial for researches on the antimicrobial delivery in both lab and mass production phases.

Secondary Generalized Cutaneous Mucinosis Developed During Etanercept Treatment in a Patient with Psoriasis.

Cutaneous mucinosis is a rare disease that manifests as an excessive accumulation of mucin in the skin that forms waxy papules or plaques. We report a case of a 44-year-old male psoriatic patient who developed generalized cutaneous mucinosis after 11 months of biological treatment. The patient had a history of psoriasis for 20 years and had been treated with narrow-band UVB phototherapy, methotrexate, or acitretin intermittently. He was started on etanercept after he was diagnosed with psoriatic arthritis, and 11 months later, he complained of swelling in his extremities and myxoid cysts on his fingers. Etanercept was then discontinued due to loss of efficacy and widespread skin lesions. However, the lesions subsided spontaneously after 6 months without specific systemic treatment.

First case report of complete paternal isodisomy of chromosome 10 harbouring a novel variant in COL17A1 that causes junctional epidermolysis bullosa intermediate.

BACKGROUND: Uniparental disomy (UPD) is a condition in which both chromosomes are inherited from the same parent, except for imprinting disorders. Uniparental isodisomy (UPiD) may result in a homozygous variant contributing to an autosomal recessive disorder in the offspring of a heterozygous carrier. Junctional epidermolysis bullosa intermediate (JEB intermediate) is an autosomal recessive inherited disease that is associated with a series of gene variants, including those of COL17A1. CASE PRESENTATION: We report the first case of complete paternal UPiD of chromosome 10 harbouring a novel homozygous variant in COL17A1: c.1880(exon23)delG (p.G627Afs*56). This variant led to the clinical phenotype of junctional epidermolysis bullosa intermediate in a 5-year-old child. Trio-whole exome sequencing (Trio-WES) and in silico data analysis were used for variant identification, Sanger sequencing was performed for variant validation, and pathological examination was performed as the gold standard for phenotype confirmation. CONCLUSIONS: We recommend the use of WES as a first-tier test for the diagnosis of epidermolysis bullosa, especially for paediatric patients. Moreover, UPD events should be detected and analysed routinely through WES data in the future.

Assessment of four screening tools and retrieval of key questions to detect undiagnosed psoriatic arthritis in Chinese patients with psoriasis: A multicenter study.

Several screening tools have been developed to facilitate early diagnosis of psoriatic arthritis (PsA); however, their performance varied greatly across different studies. In this study, we validated and compared the performance of four screening tools in detecting undiagnosed PsA Chinese patients with psoriasis, and determined the key questions and their weights. The four screening tools were the Early Arthritis for Psoriatic Patients (EARP) questionnaire, Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire, Psoriasis and Arthritis Screening Questionnaire (PASQ), and Psoriasis Epidemiology Screening Tool (PEST). The receiver-operator curve (ROC) with area under curve (AUC) was used to determine sensitivity, specificity, and accuracy. Least absolute shrinkage and selection operator and logistic regression were utilized to retrieve key questions, and a nomogram was utilized to visualize their weights. Of 482 psoriasis patients from dermatology clinics, 77 were newly diagnosed with PsA. Another 68 patients with newly diagnosed PsA from rheumatology clinics were incorporated in the analysis. ROC analysis indicated that the optimal cut-off values for EARP, PASE, PASQ, and PEST were 3, 40, 7, and 3, with corresponding sensitivities of 91.4%, 88.6%, 86.2%, and 88.5%, and specificities of 88.6%, 75.2%, 80.2%, and 83.6%, respectively. The AUC of EARP (0.925) was higher than those of PASE (0.885), PASQ (0.905), and PEST (0.827). However, none of them were sufficiently sensitive to identify pure axial PsA (sensitivities of EARP, PASQ, and PASE were 25.0%, 36.8%, and 42.1%, respectively). Twelve key questions were retrieved from these four tools to establish a nomogram with a high discrimination (C-index = 0.993) and a good calibration (mean absolute error = 0.014). In conclusion, to screen undiagnosed PsA, EARP has slightly better balanced sensitivity and specificity, and higher accuracy. The retrieval of key questions and nomogram signify the necessity of attributing different scores to differently weighted questions when developing a new screening tool to make it function more efficiently.

MicroRNA-146a Deficiency Delays Wound Healing in Normal and Diabetic Mice.

Objective: MiRNAs are important regulators of inflammation and wound healing. However, the mechanisms through which miRNAs regulate wound healing under normal and diabetic conditions are poorly understood. We aimed to determine the effects of miR-146a on the pathogenesis of wound healing in normal and streptozotocin (STZ)-induced diabetic mice. Approach: Wild-type (WT) and miR-146a knockout (KO) mice were induced to develop diabetes with STZ. Next, skin and corneal wounds were produced and measured. Percent wound closure and histology were evaluated. Inflammation at wound sites was analyzed using flow cytometry, reverse-transcription PCR, and western blot. Results: Healing of wounded skin was significantly delayed in miR-146a KO compared with WT mice. However, corneal epithelial wound healing did not differ significantly in the mice with normal blood glucose, whereas corneal and skin wound healing was significantly delayed in KO mice with diabetes. Neutrophil infiltration increased in skin wounds of KO compared with normal mice. The potential mechanisms were associated with dysregulated interleukin 1ß, tumor necrosis factor alpha (TNF-α), IRAK1 (interleukin-1 receptor-associated kinase 1), TRAF6 (TNF receptor-associated factor 6), and nuclear factor kappa B (NF-κB) signaling induced by miR-146a KO. Innovation: Skin wound healing was delayed in miR-146a KO mice and enhanced inflammatory responses were mediated by the NF-κB signaling pathway. Conclusions: Deficiency in miR-146a delayed skin wound healing by enhancing inflammatory responses in normal and diabetic mice. Therefore, miR-146a may be a potential target for modulation to accelerate skin wound healing.

An Update Review of Biosimilars of Adalimumab in Psoriasis - Bioequivalence and Interchangeability.

Biologic drugs have revolutionized the treatment of psoriasis and other rheumatological diseases. In recent years, many biosimilar agents that are highly similar in structure and function to their originator products have been developed, including the tumor necrosis factor-alpha antagonist adalimumab. The considerably lower cost of these products has greatly cut the economic burden of the patients and increased the accessibility of biologic therapies worldwide. The US Food and Drug Administration and/or the European Medicines Agency have approved eight biosimilars of adalimumab (ABP 501/BI 695501/SB5/GP2017/FKB327/MSB11022/PF-06410293/CT-P17) for the treatment of psoriasis, and others are under review. Given that these agents showed pharmacokinetic, efficacy, safety, and immunogenicity profiles comparable to those of the originator, adalimumab biosimilars were licensed for all indications approved for reference adalimumab based on extrapolation; however, some of the equivalence studies were only conducted in one or two disease populations. This review discusses the bioequivalence of adalimumab biosimilars as demonstrated by various clinical trials, the extrapolation of indications, guidance and policies of the EU and US on interchangeability (nonmedical switching/automatic substitution) between biosimilars and originators, and the real-life practices of switching from reference adalimumab to the respective biosimilars. Further data from real-world studies and post-marketing analyses are needed better to address the efficacy and safety of the transition strategy.

miR-19a/b and miR-20a Promote Wound Healing by Regulating the Inflammatory Response of Keratinocytes.

Persistent and impaired inflammation impedes tissue healing and is a characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. In this study, we show that in human wound-edge keratinocytes, the expressions of microRNA (miR)-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, are upregulated during wound repair. However, their levels are lower in chronic ulcers than in acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines and cytokines by keratinocytes. Thus, miR-19a/b and miR-20a being crucial regulators of wound inflammation, the lack thereof may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.

Vulvar myeloid sarcoma as the presenting symptom of acute myeloid leukemia: a case report and literature review of Chinese patients, 1999-2018.

BACKGROUND: Myeloid sarcoma (MS), which represents a rare malignancy that comprises of myeloid blasts occurring at extra-medullary sites, closely correlates with the onset and relapse of acute myeloid leukemia (AML) and other hemopoietic neoplasm. Female genital system is an uncommon location of MS, with the vulvar MS being even rarer that only eight cases have been reported in English-written literature. CASE PRESENTATION: A 47-year-old woman presented with chronic ulceration on her vulva for one and a half month. Microscopic examination of incisional biopsy revealed dermal infiltration of myeloid precursor cells, which were positive for MPO, lysozyme, CD43, CD68, CD38 and CD117. Bone marrow flowcytometric analysis showed myeloblast count of 74%, which expressed CD13, CD33, CD117 and HLA-DR. A diagnosis of AML (M2 type) was made and vulvar MS was the earliest symptom. The patient achieved complete remission after chemotherapy with no evidence of recurrence in a 27-month follow-up. We reviewed the literature and identified 54 cases of Chinese patients with gynecological MS between 1999 and 2018, and discovered that in Chinese population, MS most frequently involved uterine cervix followed by the ovary and vulva, and ovarian MS onset much earlier than other sites. Remarkably, vulvar MS exhibited a high rate of concurrent AML and secondary myeloid leukemia within a short time of its occurrence. Despite its limited distribution, MS should be tackled aggressively with chemotherapy followed by allogeneic hematopoietic stem cell transplantation if the appropriate donor is available. CONCLUSIONS: Female genital MS, especially vulvar MS, should be included in the differential diagnosis of gynecological neoplasm, which will facilitate its early diagnosis and prompt management.

Effects of recombinant human parathyroid hormone (1-34)on cell proliferation, chemokine expression and the Hedgehog pathway in keratinocytes.

Psoriasis is an autoimmune disease involving the excessive proliferation of keratinocytes mediated by T­cells. Parathyroid hormone (PTH) has been identified as an essential factor in the treatment of psoriasis. In the present study, the mechanism underlying the effect of recombinant human parathyroid hormone (rhPTH) (1­34) in keratinocytes was investigated. The effects of rhPTH (1­34) on cell proliferation, cell cycle, and the secretion and expression of C­X­C motif chemokine 11 (CXCL11) and components of the Hedgehog signaling pathway were examined in HaCaT cells by MTT assay, flow cytometric analysis, ELISA and gene chip analysis. The data showed that rhPTH (1­34) significantly inhibited keratinocyte proliferation at concentrations >8x10­7 mol/l. rhPTH (1­34) induced G1 phase arrest of the cell cycle in the keratinocytes. The secretion of CXCL11 in tumor necrosis factor (TNF)­α­induced keratinocytes was downregulated by rhPTH (1­34) in a dose­dependent manner, compared with that in keratinocytes treated with TNF­α alone. It was also found that rhPTH (1­34) inhibited the expression of CXCL11 in the HaCaT cells. rhPTH (1­34) also affected the Hedgehog signaling pathway specifically by regulating the expression of associated genes. In conclusion, these data suggested that rhPTH (1­34) inhibited cell proliferation, and the secretion and expression of CXCL11 in HaCaTs. rhPTH (1­34) also altered the expression of associated genes in the Hedgehog pathway. Therefore, rhPTH (1­34) can be considered as a novel therapeutic agent for the treatment of psoriasis.

Norwegian scabies in a patient treated with Tripterygium glycoside for rheumatoid arthritis.

We report an 80-year-old male patient with severe rheumatoid arthritis who was treated with tripterygium glycoside, an immunosuppressive agent made from the extract of a Chinese medicinal herb called Tripterygium wilfordii Hook F. The patient had no apparent skin lesions before the treatment, but he developed aggressive hyperkeratotic lesions with rapid progression after using tripterygium glycoside. He was repeatedly diagnosed with eczema, but treatment failed to achieve efficacy. Interestingly, a microscopic examination of the lesions revealed numerous scabies mites and eggs. Thus, we confirmed the diagnosis of Norwegian scabies infection. Treated with crotamiton 10% cream and 10% sulfur ointment for one month, the patient's clinical symptoms disappeared.

Norwegian scabies in a patient treated with Tripterygium glycoside for rheumatoid arthritis

Abstract: We report an 80-year-old male patient with severe rheumatoid arthritis who was treated with tripterygium glycoside, an immunosuppressive agent made from the extract of a Chinese medicinal herb called Tripterygium wilfordii Hook F. The patient had no apparent skin lesions before the treatment, but he developed aggressive hyperkeratotic lesions with rapid progression after using tripterygium glycoside. He was repeatedly diagnosed with eczema, but treatment failed to achieve efficacy. Interestingly, a microscopic examination of the lesions revealed numerous scabies mites and eggs. Thus, we confirmed the diagnosis of Norwegian scabies infection. Treated with crotamiton 10% cream and 10% sulfur ointment for one month, the patient's clinical symptoms disappeared.

An Essential Role of Maspin in Embryogenesis and Tumor Suppression.

Maspin (SerpinB5) is an epithelial-specific tumor suppressor gene product that displays context-dependent cellular functions. Maspin-deficient mouse models created to date have not definitively established maspin functions critical for cancer suppression. In this study, we generated a mouse strain in which exon 4 of the Maspin gene was deleted, confirming its essential role in development but also enabling a breeding scheme to bypass embryonic lethality. Phenotypic characterization of this viable strain established that maspin deficiency was associated with a reduction in maximum body weight and a variety of context-dependent epithelial abnormalities. Specifically, maspin-deficient mice exhibited pulmonary adenocarcinoma, myoepithelial hyperplasia of the mammary gland, hyperplasia of luminal cells of dorsolateral and anterior prostate, and atrophy of luminal cells of ventral prostate and stratum spinosum of epidermis. These cancer phenotypes were accompanied by increased inflammatory stroma. These mice also displayed the autoimmune disorder alopecia aerate. Overall, our findings defined context-specific tumor suppressor roles for maspin in a clinically relevant model to study maspin functions in cancer and other pathologies. Cancer Res; 77(4); 886-96. ©2017 AACR.

miRNA miR-17-92 cluster is differentially regulated in the imiqumod-treated skin but is not required for imiqumod-induced psoriasis-like dermatitis in mice.

MicroRNAs (miRNAs) play very important roles in the control of immune cell and keratinocyte development and function and are implicated in skin inflammatory diseases, including psoriasis. miRNA miR-17-92 was reported to promote the differentiation of Th1 and Th1 cells and to regulate cell proliferation and apoptosis. Here we showed that imiquimod (IMQ) differentially regulates the expression of miR-17-92 cluster in the mouse skin, upregulating miR-17 and miR-19 families and downregulating miR-92. To investigate whether miR-17-92 cluster is functionally involved in the psoriasis, we have generated three mutant mice with specific deletion or overexpression of miR-17-92 cluster in keratinocytes, or with deletion of miR-17-92 cluster in T cells. Interestingly, deletion or overexpression of miR-17-92 cluster in keratinocytes, or deletion of miR-17-92 in T cells did not significantly affect IMQ-induced psoriasis-like dermatitis development in the mutant mice compared with wild-type littermates. Thus, miRNA miR-17-92 cluster may not be a key factor regulating imiqumod-induced psoriasis-like dermatitis.