KRT5 mutation regulate melanin metabolism through notch signalling pathway between keratinocytes and melanocytes.

Dowling-Degos disease (DDD) is an autosomal dominant hereditary skin disease characterized by acquired reticular hyperpigmentation in flexural sites, and one of its causative genes is KRT5 gene. But the effect of KRT5, expressed only in keratinocytes, on melanocytes is unclear. Other pathogenic genes of DDD include POFUT1, POGLUT1 and PSENEN genes, which is involved in posttranslational modification of Notch receptor. In this study, we aim to determine the ablation of keratinocyte KRT5 affect melanogenesis in melanocyte through Notch signalling pathway. Here we found that KRT5 downregulation decreased the expression of the Notch ligand in keratinocytes and Notch1 intracellular domain in melanocytes, by establishing two cell models of ablation of KRT5 in keratinocytes based on CRISPR/Cas9 site-directed mutation and lentivirus-mediated shRNA. Treatment of melanocytes with Notch inhibitors had same effects with ablation of KRT5 on increase of TYR and decrease of Fascin1. Activation of Notch signalling reverses the effect of ablation of KRT5 on melanogenesis. Immunohistochemistry of DDD lesions with KRT5 gene mutation confirmed changes in the expression of relevant molecules in Notch signalling. Our research elucidates molecular mechanism of KRT5-Notch signalling pathway in the regulation of melanocytes by keratinocytes, and preliminary reveal the mechanism of DDD pigment abnormality caused by KRT5 mutation. These findings identify potential therapeutic targets of the Notch signalling pathway for the treatment of skin pigment disorders.

Expression of lncRNA FGD5-AS1 correlates with poor prognosis in melanoma patients.

BACKGROUND: Growing evidence demonstrates that long non-coding RNAs (lncRNAs) play an important role in cancer origination and progression. A novel identified lncRNA, FGD5 antisense RNA 1 (FGD5-AS1), was reported to be overexpressed in several tumors. The present study aimed to investigate the expression of FGD5-AS1 in melanoma and its associations with clinical prognosis in melanoma patients. METHODS: The expression levels of FGD5-AS1 in 188 pairs of melanoma specimens and matched non-tumor specimens were determined using a real-time polymerase chain reaction. A chi-squared test was performed to determine the relationship between FGD5-AS1 levels and clinicopathological features. The overall survival rates of melanoma patients based on the expression of FGD5-AS1 were calculated by the Kaplan-Meier method with a log-rank test. Finally, univariate and multivariate assays were carried out to determine whether FGD5-AS1 was a prognostic factor in melanoma patients. RESULTS: We observed that FGD5-AS1 in melanoma specimens was distinctly up-regulated compared to adjacent non-tumor specimens (p < 0.01). In malignant cases, higher expression of FGD5-AS1 was prominently associated with tumor thickness (p = 0.024) and advanced tumor stage (p = 0.039). The data from our clinical study revealed that patients with high FGD5-AS1 expression had a distinctly shorter overall survival (p = 0.0034) and disease-free survival (p < 0.0001) than those with low FGD5-AS1 expression. Multivariate analysis demonstrated that high FGD5-AS1 expression may serve as a potential independent prognostic factor in melanoma. CONCLUSIONS: FGD5-AS1 may act as a prognostic predictor and a possible drug-target for melanoma patients.

Crystal structure of 2-chloro-1-(6-fluoro-3,4-di-hydro-2H-chromen-2-yl)ethanone.

In the title mol-ecule, C11H10ClFO2, the benzene ring, the F atom and the O atom of the di-hydro-pyran ring are essentially coplanar, with an r.m.s. deviation of 0.007 Å. The di-hydro-pyran ring is in a half-chair conformation. In the crystal, mol-ecules are linked by pairs of weak C-H⋯π hydrogen bonds, forming inversion dimers.

Patchy alopecia areata sparing gray hairs: a case series.

Alopecia areata is an unpredictable, non-scarring hair loss condition. Patchy alopecia areata sparing gray hairs is rare. Here we present 4 cases with patchy non-scarring hair loss, which attacked pigmented hairs only and spared gray hairs. It should be differentiated from vitiligo, colocalization of vitiligo and alopecia areata, and depigmented hair regrowth after alopecia areata.

Inflammatory loop involving Staphylococcus aureus, IL-36γ, and cathepsin S drives immunity disorders in familial acne inversa keratinocytes.

Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an essential event in AI, the interaction between bacteria and keratinocytes in AI pathophysiology remains unclear. In this study, the NCSTN gene was suppressed using short hairpin RNA in HaCaT cells. Using RNA sequencing, real-time polymerase chain reaction, and western blotting, the expression of IL-36 cytokines was analyzed. The impact of Staphylococcus aureus on AI keratinocyte inflammation and underlying regulatory molecules was investigated by exposing the HaCaT cells to S. aureus. By stimulating NCSTN knockdown HaCaT cells with IFN-γ, the expression and regulatory mechanism of Cathepsin S (Cat S), an IL-36γ cleavage and activating protease, were investigated. After NCSTN knockdown, the IL-36α expression increased, and the IL-36Ra expression was downregulated. NCSTN/MEK/ERK impairment-induced Krüppel-like factor 4 (KLF4) up-regulation in concert with S. aureus-induced nuclear factor kappa B elevation acts synergistically to promote IL-36γ production with the subsequent IL-8 activation in HaCaT cells. NCSTN/MEK/ERK impairment was also observed in familial AI lesions. IFN-γ-induced Cat S in keratinocytes was enhanced after NCSTN knockdown. The expression of IFN-II pathway molecules was significantly upregulated in both NCSTN knockdown HaCaT cells and familial AI lesions. The Cat S expression was significantly elevated in the patient's AI lesions. Our findings suggested a synergistic relationship between S. aureus and NCSTN/MAPK/KLF4 axis in IL-36γ-induced familial AI keratinocytes.

2-(4-Bromo-1H-indol-3-yl)acetonitrile.

In the title compound, C(10)H(7)BrN(2), the non-H atoms, except the N atom of the acetonitrile group and the C atom bonded to it, lie in the least-squares plane defined by the atoms of the indole ring system (r.m.s deviation = 0.019 Å), with the N and C atom of the cyano group displaced by 2.278 (1) and 1.289 (1) Å, respectively, out of that plane. In the crystal, N-H⋯N hydrogen bonds link the mol-ecules into a C(7) chain along [100].

Acquired latent tuberculosis infection in psoriasis patients treated with etanercept in the People's Republic of China.

BACKGROUND: TNF-α plays a key role in host defense against mycobacterial infection, and patients receiving TNF-α blocker treatment have increased susceptibility to tuberculosis disease. In the People's Republic of China, an intermediate tuberculosis-burden country, the latent tuberculosis infection (LTBI) risk in patients with psoriasis who are treated with etanercept, the safest kind of TNF-α blocker, is unknown. OBJECTIVES: This study reports the LTBI risk in patients with psoriasis after etanercept treatment and aims to answer the question of how often rescreening for LTBI should be done in order to reduce active tuberculosis infection of patients and further reduce the incidence of active tuberculosis disease. PATIENTS AND METHODS: This retrospective review evaluated patients with moderate-to-severe chronic plaque psoriasis between 2009 and 2013. All patients were excluded tuberculosis infection and received etanercept 25 mg twice weekly, then the patients were checked for LTBI 3 months after etanercept treatment to observe the incidence of LTBI and assess the need for rescreening for LTBI every 3 months. RESULTS: We retrospectively analyzed 192 patients with psoriasis with moderate-to-severe chronic plaque whose tuberculin skin test and chest X-rays were negative and who received etanercept 25 mg twice weekly. Eighteen of them were excluded because they received less than 3 months of etanercept therapy. After treatment with etanercept, four patients were found to have LTBI. CONCLUSION: In this study, the incidence of LTBI after 3 months was four in 192 (2.1%), which is higher than the annual incidence of LTBI in the People's Republic of China (0.72%), so LTBI could be expected to occur within 3 months in psoriasis patients on etanercept. Periodic screening for LTBI in the therapy course, as well as before initiating treatment, is necessary in those patients who use a TNF-α blocker. We recommend rescreening for LTBI every 3 months.

A novel missense KIT mutation causing piebaldism in one Chinese family associated with café-au-lait macules and intertriginous freckling.

Piebaldism is a rare autosomal dominant genodermatosis, manifesting as congenital and stable depigmentation of the skin and white forelock. It has been found to be associated with mutations in the KIT or SLUG genes. We report a Chinese piebaldism family including a 28-year-old woman and her 3-year-old son with characteristics of white patches and forelock associated with numerous brown macules and patches. Genomic DNA samples of the proband and her son were extracted from their peripheral blood. One hundred unrelated healthy individuals were used as controls. All coding regions of KIT, SLUG, and NF1 genes were amplified by polymerase chain reaction using exon flanking intronic primers and Sanger sequencings were performed. DNA sequencing revealed heterozygous missense c.2431T>G mutation in exon 17 of the KIT gene in the proband and the affected son. No potentially pathogenic variant was identified in SLUG or NF1 genes. The nucleotide substitution was not found in 100 unrelated control individuals. This study reveals a novel KIT mutation in piebaldism, and it further supports that café-au-lait macules and intertriginous freckling of piebaldism are parts of pigmented anomaly in piebaldism, which does not necessarily represent coexistence of neurofibromatosis type 1 (NF1).