GSDMD suppresses keratinocyte differentiation by inhibiting FLG expression and attenuating KCTD6-mediated HDAC1 degradation in atopic dermatitis.

Background: Recent studies have shown that activated pyroptosis in atopic dermatitis (AD) switches inflammatory processes and causes abnormal cornification and epidermal barrier dysfunction. Little research has focused on the interaction mechanism between pyroptosis-related genes and human keratinocyte differentiation. Methods: The AD dataset from the Gene Expression Omnibus (GEO) was used to identify differently expressed pyroptosis-related genes (DEPRGs). Hub genes were identified and an enrichment analysis was performed to select epithelial development-related genes. Lesions of AD patients were detected via immunohistochemistry (IHC) to verify the hub gene. Human keratinocytes cell lines, gasdermin D (GSDMD) overexpression, Caspase1 siRNA, Histone Deacetylase1 (HDAC1) siRNA, and HDAC1 overexpression vectors were used for gain-and-loss-of-function experiments. Regulation of cornification protein was determined by qPCR, western blot (WB), immunofluorescence (IF), dual-luciferase reporter assay, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP). Results: A total of 27 DEPRGs were identified between either atopic dermatitis non-lesional skin (ANL) and healthy control (HC) or atopic dermatitis lesional skin (AL) and HC. The enrichment analysis showed that these DEPRGs were primarily enriched in the inflammatory response and keratinocytes differentiation. Of the 10 hub genes identified via the protein-protein interaction network, only GSDMD was statistically and negatively associated with the expression of epithelial tight junction core genes. Furthermore, GSDMD was upregulated in AD lesions and inhibited human keratinocyte differentiation by reducing filaggrin (FLG) expression. Mechanistically, GSDMD activated by Caspase1 reduced FLG expression via HDAC1. HDAC1 decreased FLG expression by reducing histone acetylation at the FLG promoter. In addition, GSDMD blocked the interaction of Potassium Channel Tetramerization Domain Containing 6 (KCTD6) and HDAC1 to prohibit HDAC1 degradation. Conclusion: This study revealed that GSDMD was upregulated in AD lesions and that GSDMD regulated keratinocytes via epigenetic modification, which might provide potential therapeutic targets for AD.

Case report: B7-H3 CAR-T therapy partially controls tumor growth in a basal cell carcinoma patient.

B7-H3 is over-expressed in multiple types of solid tumors, making it an ideal target for chimeric antigen receptor (CAR)-T therapy. Here, we first report a case of multiple basal cell carcinoma (BCC) patient treated with humanized monoclonal anti-B7-H3 CAR-T cells through direct intratumoral injection. After three dose-escalated injections, the lesion in the abdomen decreased by 40% in volume, shrank from bulging to flat, but was not eradicated completely. The large lesion in the forehead became dry from original ulcer and bleeding. The adverse events observed were itching, myalgia, and redness. Immunohistochemistry analysis demonstrated that B7-H3-positive tumor cells and B7-H3 expression intensity were reduced after injections of CAR-T cells. The number of infiltrating CD3 T cells increased significantly but mainly located outside the tumor region. Subsequently, high levels of TGF-ß in the tumor area were observed, suggesting that solid tumor microenvironment may hinder the infiltration and effect of CAR-T cells. In summary, in this particular case report, intratumoral injection of B7-H3 CAR-T cells partially controls tumor growth in the BCC patient with minor adverse events. The efficacy and safety of B7-H3 CAR-T therapy need to be further investigated with a larger cohort of patients. Although only one clinical case is reported here, the anti-B7-H3 CAR-T cell therapy should be considered as a treatment option for solid tumors in the future. This clinical trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) with registration number ChiCTR2100044386.

Keratoacanthoma centrifugum marginatum: An unusual case.

Keratoacanthoma centrifugum marginatum (KCM) of the skin is a rare variant of cutaneous keratoacantoma. KCM was first reported in 1962 andpresents with progressive peripheral expansion , no spontaneous clearing and a bank-shaped outer wall with concurrent central healing. Treatment options include topical and systemic therapies.Surgical intervention is the preferred therapy for solitary KCM. We report on surgery and photodynamic therapy delivered sequentially to treat a giant facial Keratoacanthoma centrifugum marginatum patient. It was safe and effective .

Metastatic Patterns and Prognosis of de novo Metastatic Nasopharyngeal Carcinoma in the United States.

OBJECTIVE: To evaluate the distant metastatic patterns and prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in de novo metastatic nasopharyngeal carcinoma (mNPC) using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Patients with de novo mNPC who had been diagnosed between 2004 and 2016 were identified from the SEER database. Kaplan-Meier analysis was used to calculate OS and CSS. Log-rank tests were employed to measure survival variation among subgroups. Individual predictors of CSS and OS were examined using Cox proportional-hazards regression models in patients with de novo mNPC. RESULTS: We evaluated 224 patients with de novo mNPC who matched our inclusion criteria. Three-year CSS and OS for the whole cohort was 29.8% and 27.9%, respectively. Univariate analysis indicated that CSS and OS were influenced by age, histology, radiotherapy, chemotherapy, and liver metastasis. Neither the number of metastatic sites nor their specific location in bone, lungs, distant lymph nodes or brain significantly affected CSS or OS. The aforementioned independent prognosticators continued to significantly influence survival following multivariate analysis. Taking distant metastasis without liver involvement as a reference, liver metastasis was associated significantly with shorter OS at a hazard ratio (HR) of 1.581 (P = .021) and CSS at a HR of 1.643 (P = .016). Older age, keratinizing squamous cell carcinoma, no chemotherapy, and no radiotherapy were also prognosticators for poor OS (P < .05). Similar results were documented for CSS (P < .05). CONCLUSION: For patients with de novo mNPC, liver metastasis is an independent prognosticator for inferior CSS and OS. LEVEL OF EVIDENCE: 3a Laryngoscope, 131:E1130-E1138, 2021.

Racial/ethnic disparities in penile squamous cell carcinoma incidences, clinical characteristics, and outcomes: A population-based study, 2004-2016.

PURPOSE: This study assessed the impact of race/ethnicity on penile squamous cell carcinoma (PSCC) incidence rates, clinical characteristics, and outcomes. MATERIALS AND METHODS: Surveillance, Epidemiology and End Results data from 2004 to 2016 was used for this study. We evaluated racial/ethnic differences in clinical characteristics using χ2 tests. Overall survival (OS) and PSCC-specific survival (PSCC-SS) were estimated using the Kaplan-Meier method, and differences were determined using the log-rank test. Cox regression models were performed to assess independent predictors for PSCC patient survival. RESULTS: A total of 2,720 PSCC patients were included for incidence analysis, and 2,438 patients were identified for the χ2 testing and survival analyses.The overall incidence of PSCC during 2004 to 2016 was 0.30 per 100,000. Only non-Hispanic white (NHW) patients had a statistically significant increase in age-adjusted incidence rates (annual percent change = 2.26, 95% confidence interval [CI]: 0.78-3.76; P = 0.01). In univariate analysis, race/ethnicity was an independent prognostic factor for OS and PSCC-SS. After adjusting for age, marital status, income, grade, TNM (tumor, node, metastasis) stage, and treatment strategies, non-Hispanic black patients still had a statistically significant hazard ratio of 1.35 (95% CI: 1.08-1.68; P = 0.007) for OS, and a hazard ratio of 1.36 (95% CI: 1.01-1.82; P = 0.045) for PSCC-SS compared to NHW. CONCLUSION: NHW patients had a statistically significant increase in age-adjusted incidence rate during the period 2004 to 2016. Race/ethnicity is an independent prognostic factor for OS and PSCC-SS, and non-Hispanic black were proven to have unfavorable OS and PSCC-SS compared with NHW.

Patterns and Prognostic Value of Lymph Node Metastasis on Distant Metastasis and Survival in Nasopharyngeal Carcinoma: A Surveillance, Epidemiology, and End Results Study, 2006-2015.

This study was conducted to identify factors associated with lymph node (LN) metastasis in nasopharyngeal carcinoma (NPC) patients, analyze node distribution patterns, and explore the prognostic value of the LN metastasis level for survival. We included 2994 patients with primary NPC diagnosed between 2006 and 2015 with information in the Surveillance, Epidemiology, and End Results (SEER) database. Patients' demographic and clinicopathologic features were compared according to LN status using chi-squared tests. The 5-year overall survival (OS) and cancer-specific survival (CSS) rates were calculated by the Kaplan-Meier method, and the differences were estimated by log-rank tests. Multivariate Cox proportional hazard models were used to evaluate independent risk factors for OS and CSS. Logistic regression was used to evaluate the risk of each LN metastasis category for distant metastasis. There were 695 patients in the N0 stage and 2299 with LN metastasis (classified as stage N1, N2, or N3). The overall incidence of LN metastasis was 76.8%. Sex and T stage were not associated with LN metastasis. Older patients had a significantly worse 5-year OS and CSS than younger patients. In terms of histologic type, keratinizing squamous cell carcinoma had the lowest 5-year OS and CSS at 48.2% and 53.8%, respectively. The most common nodal involvement level was II (65.9%), followed by III (29.1%), V (25.6%), I (17.6%), IV (15.7%), and retropharynx (13.5%). The skip metastasis rate was 5.7% (130/2299). Patients with only level II metastasis (classified as level 2) was the most common category, accounting for 30%. Compared to level 2, patients with only level I (classified as level 1) had an OR of 2.101 (95% CI: 1.090-4.047, P=0.027) for distant metastasis, patients with simultaneous levels II, III, IV, and V (classified as levels 2345) had the highest OR of 4.064 (95% CI: 2.155-7.666, P < 0.001) for distant metastasis, and level 24 had an OR of 3.003 (95% CI: 1.074-8.395, P=0.036) for distant metastasis. In survival analysis, levels 235 had a significant HR of 1.708 (95% CI: 1.089-2.678, P=0.020) for CSS compared to level 2 after adjustment for age, sex, race, histology, TNM (tumor, node, and metastasis) stage, and treatment.

TRAF4 Promotes Fibroblast Proliferation in Keloids by Destabilizing p53 via Interacting with the Deubiquitinase USP10.

Keloids represent one extreme of aberrant dermal wound healing. One of the important characteristics of keloids is uncontrolled fibroblasts proliferation. However, the mechanism of excessive proliferation of fibroblasts in keloids remains elusive. In this study, we demonstrated that TRAF4 was highly expressed in keloid fibroblasts and promoted fibroproliferation. We investigated the underlying molecular mechanism and found that TRAF4 suppressed the p53 pathway independent of its E3 ubiquitin ligase activity. Specifically, TRAF4 interacted with the deubiquitinase USP10 and blocked the access of p53 to USP10, resulting in p53 destabilization. Knockdown of p53 rescued cell proliferation in TRAF4-knockdown keloid fibroblasts, suggesting that the regulation of proliferation by TRAF4 in keloids relied on p53. Furthermore, in keloid patient samples, TRAF4 expression was inversely correlated with p53-p21 signaling activity. These findings help to elucidate the mechanisms underlying keloid development and indicate that blocking TRAF4 could represent a potential strategy for keloid therapy in the future.

Secondary syphilis presenting as erythema multiforme in a HIV-positive homosexual man: a case report and literature review.

Early syphilis can rarely cause erythema multiforme-type eruptions as well as triggering erythema multiforme (EM). EM-like lesions in secondary syphilis are characterized by clinical features of EM and laboratory tests consistent with secondary syphilis and the skin histology shows predominantly a plasma cell infiltrate with the presence of treponemes. When EM is triggered by early syphilis, the skin histology shows mixed inflammatory cells usually in the absence of treponemes in the skin lesion. There may also be mixed histology with the presence of treponemes in the absence of a plasma cell infiltrate and vice versa. We describe a case of secondary syphilis presenting as EM with bullae and histology showing EM features without a plasma cell infiltrate but positive for Treponema pallidum by immunohistochemical staining. The patient was also coinfected with cytomegalovirus, human immunodeficiency virus, and anal warts. The EM eruptions resolved with treatment for secondary syphilis with benzathine penicillin G.

TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4 Therapy in Metastatic Melanoma.

TP53 has been proved to be associated with cytotoxic T-cell induced apoptosis, however, the association between TP53 and the benefit of immunotherapy in melanoma has not been studied. In the present study, we examined the relationship between TP53 mutation and response to CTLA-4 blockade in metastatic melanoma by analyzing the data from one public cohort consisting of 110 patients with metastatic melanoma. The sequencing, mRNA and survival data of 368 patients with skin melanoma from The Cancer Genome Atlas (TCGA) was used to explore the underlying mechanism. TP53 mutation was associated with significant poorer progression-free survival (HR, 2.25; 95% CI, 1.15-4.37; P = 0.014), poorer overall survival (HR, 2.05; 95% CI, 1.02-4.13; P = 0.040) and trend of poorer response (OR, 0.20; 95% CI, 0.02-1.62; P = 0.131). The correlations were significant in multivariate analysis including lactate dehydrogenase, tumor mutational burden and tumor stage (P < 0.05). In TCGA, no association was observed between TP53 mutation and survival (P = 0.55). The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type. Our findings suggest that TP53 mutation is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade.