Genetic variants of cell cycle pathway genes are associated with head and neck squamous cell carcinoma in the Chinese population.

Genetic alterations in the cell cycle pathway are common in head and neck squamous cell carcinoma (HNSCC). We identified four novel HNSCC susceptibility loci (CDKN1C rs452338, CDK4 rs2072052, E2F2 rs3820028 and E2F2 rs2075993) through a two-stage matched case-control study. There was a combined effect among the four single nucleotide polymorphisms (SNPs), as the number of risk genotypes increased, the risk of HNSCC displayed an increasing trend (Ptrend < 0.001). And there were multiplicative interactions between rs452338 and rs2072052, rs2072052 and rs3820028, rs2072052 and rs2075993. Functional bioinformatics analysis and dual-luciferase reporter assay revealed that E2F2 rs2075993 T>C reduced the stability of E2F2 3'-UTR secondary structure and affected the binding of E2F2 to miR-940, which was up-regulated in HNSCC tumor tissues (P = 2.9e-8) and was correlated with poor overall survival of HNSCC (HR = 1.39, 95% CI = 1.02-1.90). In vitro assays, we discovered that the expression of miR-940 was regulated by METTL3, and miR-940 promoted the proliferation, migration and invasion, and inhibited the senescence and autophagy of tumor cells. In terms of mechanism, compared with rs2075993 allele T, we found that the protective variant rs2075993 allele C interfered with the translational inhibition of E2F2 by miR-940, resulting in increased expression of E2F2 protein, which further reduced the proliferation, migration, invasion, and increased the senescence of tumor cells.

Association of Atopic Dermatitis with Depression and Suicide: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Atopic dermatitis (AD) has long been hypothesized to be associated with risk of depression and suicide, but the causal relationship between them is still unclear. OBJECTIVE: To evaluate the causality between AD, depression, and suicide using a Mendelian randomization (MR) approach. METHOD: We extracted summary-level data for AD, major depression, and suicidal ideation or attempt from published, nonoverlapping genome-wide association studies (GWAS). Inverse variance-weighted (IVW) analysis was used as the primary analysis. Alternate methods, including weighted median, MR Egger, MR pleiotropy residual sum and outlier, weighted mode, and leave-out analysis, were performed to assess pleiotropy. RESULTS: 13 SNPs (13,287 cases and 41,345 controls) were selected as instrumental variables (IVs). The IVW analysis indicated a statistically significant but small causal effect of AD on major depression (OR = 1.027, 95% CI 1.004-1.050; p = 0.020). No significant evidence was observed for a causal effect of AD on suicide. No significant effect of pleiotropy was found. CONCLUSION: AD has a significant but small effect on major depression, but not on suicide.

New Biologics for the Treatment of Atopic Dermatitis: Analysis of Efficacy, Safety, and Paradoxical Atopic Dermatitis Acceleration.

Atopic dermatitis (AD) is a chronic, inflammatory skin disease with an eczematous rash and itching. Due to undesired adverse effects of traditional systemic treatment, there is still an unmet need for safe and effective long-term therapy for refractory AD. As our understanding of the pathogenesis underlying AD grows, novel treatments targeting specific molecules have been developed. Here, we discuss the efficacy and safety profiles of these drugs in recent clinical trials. Among their adverse effects, of particular note is AD acceleration. Although there is still debate about whether certain adverse reactions can be said to be paradoxical adverse events (PAEs), a wide range of PAEs have been reported during biological treatment for chronic immune-mediated diseases. Close surveillance of novel biologics is crucial to detect new undescribed paradoxical reactions and to shed light on the convoluted pathogenesis of AD.