Construction of an immune-related prognostic model and potential drugs screening for esophageal cancer based on bioinformatics analyses and network pharmacology.

BACKGROUND: Esophageal cancer (ESCA) is a highly invasive malignant tumor with poor prognosis. This study aimed to discover a generalized and high-sensitivity immune prognostic signature that could stratify ESCA patients and predict their overall survival, and to discover potential therapeutic drugs by the connectivity map. METHODS: The key gene modules significantly related to clinical traits (survival time and state) of ESCA patients were selected by weighted gene coexpression network analysis (WCGNA), then the univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a 15-immune-related gene prognostic signature. RESULTS: The immune-related risk model was related to clinical and pathologic factors and remained an effective independent prognostic factor. Enrichment analyses revealed that the differentially expressed genes (DEGs) of the high- and low-risk groups were associated with tumor cell proliferation and immune mechanisms. Based on the gathered data, a small molecule drug named perphenazine (PPZ) was elected. The pharmacological analysis indicates that PPZ could help in adjuvant therapy of ESCA through regulation of metabolic process and cellular proliferation, enhancement of immunologic functions, and inhibition of inflammatory reactions. Furthermore, molecular docking was performed to explore and verify the PPZ-core target interactions. CONCLUSION: We succeed in structuring the immune-related prognostic model, which could be used to distinguish and predict patients' survival outcome, and screening a small molecule drug named PPZ. Prospective studies also are needed to further validate its analytical accuracy for estimating prognoses and confirm the potential use of PPZ for treating ESCA.

Implications of obstructive sleep apnea in lung adenocarcinoma: A valuable omission in cancer prognosis and immunotherapy.

Lung adenocarcinoma (LUAD) is a highly invasive malignant tumor with poor prognosis, and there is growing evidence that obstructive sleep apnea (OSA) could significantly promotes the risk of LUAD. In order to improve the treatment outcomes of patients with LUAD and OSA, we aim to screen OSA-related genes that may potentially affect LUAD and to discover a high sensitivity prognostic signature that can stratify LUAD/OSA patients and to further accurately identify LUAD patients who might respond to immunotherapy. Molecular subtypes classified by the prognostic signature did not belong to any previously reported subtypes of LUAD. The tumor microenvironment (TME), mutation, and so on, were significantly distinct between patients within different risk groups or clusters. Combined with gene set variation analysis (GSVA) and drug susceptibility analysis, patients in the low-risk group (The vast majority of patients belonging to cluster2 by molecular subtyping) were not suitable for immunotherapy due to T-cell exhaustion caused by long-term inflammatory response; the question of how to reverse T-cell exhaustion may be a primary consideration. Cluster3 patients had the highest benefit from immunotherapy, and although cluster1 patients had the worst prognosis, they were more sensitive to traditional chemotherapeutic drugs. Animal experiments showed that chronic intermittent hypoxia (CIH) could not only significantly promote the tumor growth of LUAD, but also increase the expression levels of risk genes. This risk model may contribute greatly to the evaluation of prognosis, molecular characteristics, and treatment modalities of LUAD/OSA, and could be further translated into clinical applications to ameliorate the treatment dilemmas.

Effects of dechlorane plus on oxidative stress, inflammatory response, and cell apoptosis in Cyprinus carpio.

The levels of the chlorinated organic compound Dechlorane Plus (DP) are increasing in aquatic ecosystems. To investigate the adverse effects of DP on aquatic animals, common carp (Cyprinus carpio) were subjected to three different DP concentrations (30 µg L-1, 60 µg L-1, and 120 µg L-1) for 1 d, 15 d, and 30 d. Histology and the hepatic and cerebral expression levels of several key antioxidant, detoxification, and apoptotic factors were then examined. Histopathological inspections showed that the liver and brain were severely damaged in carp exposed to 60 µg L-1 and 120 µg L-1 DP. Relative to the controls, the superoxide dismutase and glutathione activity levels and the malondialdehyde content were also changed in livers and brains exposed to DP. Besides, significant alterations in the expression levels of the inflammatory cytokines IL-1ß, IL-6, and IL-10 were observed in the livers of carp subjected to DP. Relative to the control, the brains of DP-exposed carp presented with significantly upregulated IL-1ß and IL-6 in carp treated with 120 µg L-1 DP for 30 d. The transcription levels of hepatic cyp2b4, cyp1b1, and cyp3a138 were all increased compared with the untreated at all DP exposure concentrations. The aforementioned results suggest that DP exposure perturbs fish metabolism and causes liver injury by inhibiting antioxidant enzyme activity, increasing lipid peroxidation, promoting inflammation, and inducing cell apoptosis. This information and the analytical methodology used to acquire it may form the basis for future ecological risk assessments on DP and related xenobiotics in aquatic animals.

Effects of dechlorane plus on intestinal barrier function and intestinal microbiota of Cyprinus carpio L.

Dechlorane Plus (DP) is a typical polychlorinated flame retardant that has been emerged in chemical products. Due to its accumulation and amplification effect, the toxicity of DP has become a widespread environmental safety issue. However, whether DP can affect the intestinal tract of teleost fish remains largely unclear. To understand its effects on the intestinal barrier, morphological characteristics and intestinal microbiome of common carp, different concentrations (30, 60 and 120 µg/L) of DP were exposed to common carps for 4 weeks. The results indicated that DP evidently shortened the intestinal folds and damaged the intestinal epithelium layer. In addition, the mRNA expression levels of occludin, claudin-2 and zonula occludens-1 (ZO-1) were significantly decreased with increasing DP concentrations. Furthermore, the relative abundance of some microbiota species were also changed significantly. Our study first demonstrated that DP could cause damage to the intestinal epithelium and destroy the intestinal barrier and increase the relative abundance of pathogenic bacteria, thereby increasing the probability of contact between intestinal epithelium and pathogenic bacteria, which in turn lead to an increased susceptibility to various diseases and poor health. In summary, our findings reveal that chronic DP exposure can have a harmful effect on the intestinal flora balance and is potentially linked to human disease.