Impaired tryptophan metabolism by type 2 inflammation in epithelium worsening asthma.

Previous researches indicate that tryptophan metabolism is critical to allergic inflammation and that indoleamine 2,3-dioxygenase 1 (IDO1), as a key enzyme, is known for its immunosuppressive properties. Therefore, we are aimed to explore whether tryptophan metabolism, especially IDO1, influences allergic asthma and clarify specific mechanism. With the analysis of clinical data, exploration in cell experiments, and verifying in HDM-induced asthma mice models, we finally found that in allergic asthma, low level of T1 cytokines along with high level of T2 cytokines inhibited the expression of IDO1 in airway epithelium, hampering the kynurenine pathway in tryptophan metabolism and decreasing the level of intracellular kynurenine (Kyn). As an endogenous ligand of aryl hydrocarbon receptor, Kyn regulated the expression of cystathionine-γ-lyase (CTH). Notably, in asthma models, enhancing either IDO1 or H2S relieved asthma, while inhibiting the activity of CTH exacerbated it. IDO1-Kyn-CTH pathway could be a potential target for treatment for allergic asthma.

Stevens-Johnson syndrome induced by toripalimab in a previously EGFR-TKI-treated advanced lung adenocarcinoma patient harboring EGFR mutations 19 del/T790M/C797S in trans and cis: a case report.

Background: The treatment paradigm for advanced non-small-cell lung cancer (NSCLC) is rapidly changing. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anti-programmed death-1 (PD-1) antibodies have increasingly been incorporated into routine care for nearly all patients with NSCLC. Toripalimab was recently approved as the first-line treatment for advanced non-squamous NSCLC in combination with chemotherapy. Stevens-Johnson syndrome (SJS) is a rare but potentially fatal complication of TKI and anti-PD-1 therapy. We reported a case of SJS after sequential use of EGFR-TKIs and toripalimab in an NSCLC patient with EGFR mutations 19 del/T790M/C797S in trans and cis. Case presentation: A 58-year-old man with stage IV NSCLC received gefitinib because next-generation sequencing (NGS) revealed an EGFR 19del, followed by osimertinib and pemetrexed with the emergence of EGFR T790M. Four EGFR mutations 19 del/T790M/C797S in trans and cis were detected after osimertinib resistance. The combination of toripalimab and docetaxel was administered as a third-line treatment. The patient developed SJS at 21 days, and toripalimab was discontinued. After treatment with methylprednisolone and prednisolone, the skin toxicity of the patient gradually decreased and eventually disappeared. The patient received osimertinib and anlotinib after recovery, and SJS has not recurred. The ongoing treatment is still effective and results in stable disease. Conclusion: We reported the first case of SJS induced by toripalimab in a patient with lung adenocarcinoma harboring multiple EGFR mutations. The TKI treatment after SJS was well tolerated and effective.

Metagenomic next-generation sequencing for the diagnosis of pulmonary aspergillosis in non-neutropenic patients: a retrospective study.

This study aimed to obtain further in-depth information on the value of metagenomic next-generation sequencing (mNGS) for diagnosing pulmonary aspergillosis in non-neutropenic patients. We did a retrospective study, in which 33 non-neutropenic patients were included, of which 12 were patients with pulmonary aspergillosis and 21 were diagnosed with non-pulmonary aspergillosis. Fungi and all other co-pathogens in bronchoalveolar lavage fluid (BALF) (27 cases), blood (6 cases), and/or pleural fluid (1 case) samples were analyzed using mNGS. One of the patients submitted both BALF and blood samples. We analyzed the clinical characteristics, laboratory tests, and radiologic features of pulmonary aspergillosis patients and compared the diagnostic accuracy, including sensitivity, specificity, positive predictive value, and negative predictive value of mNGS with conventional etiological methods and serum (1,3)-ß-D-glucan. We also explored the efficacy of mNGS in detecting mixed infections and co-pathogens. We further reviewed modifications of antimicrobial therapy for patients with pulmonary aspergillosis according to the mNGS results. Finally, we compared the detection of Aspergillus in BALF and blood samples from three patients using mNGS. In non-neutropenic patients, immunocompromised conditions of non-pulmonary aspergillosis were far less prevalent than in patients with pulmonary aspergillosis. More patients with pulmonary aspergillosis received long-term systemic corticosteroids (50% vs. 14.3%, p < 0.05). Additionally, mNGS managed to reach a sensitivity of 91.7% for diagnosing pulmonary aspergillosis, which was significantly higher than that of conventional etiological methods (33.3%) and serum (1,3)-ß-D-glucan (33.3%). In addition, mNGS showed superior performance in discovering co-pathogens (84.6%) of pulmonary aspergillosis; bacteria, bacteria-fungi, and bacteria-PJP-virus were most commonly observed in non-neutropenic patients. Moreover, mNGS results can help guide effective treatments. According to the mNGS results, antimicrobial therapy was altered in 91.7% of patients with pulmonary aspergillosis. The diagnosis of Aspergillus detected in blood samples, which can be used as a supplement to BALF samples, seemed to show a higher specificity than that in BALF samples. mNGS is a useful and effective method for the diagnosis of pulmonary aspergillosis in non-neutropenic patients, detection of co-pathogens, and adjustment of antimicrobial treatment.

Prognostic Analysis of Lung Adenocarcinoma Based on DNA Methylation Regulatory Factor Clustering.

There is a known link between DNA methylation and cancer immunity/immunotherapy; however, the effect of DNA methylation on immunotherapy in lung adenocarcinoma (LUAD) remains to be elucidated. In the current study, we aimed to screen key markers for prognostic analysis of LUAD based on DNA methylation regulatory factor clustering. We classified LUAD using the NMF clustering method, and as a result, we obtained 20 DNA methylation regulatory genes. These 20 regulatory genes were used to determine the pattern of DNA methylation regulation, and patients were grouped for further analysis. The risk score model was analyzed in the TCGA dataset and an external validation set, and the correlation between the risk score and DNA methylation regulatory gene expression was explored. We analyzed the correlation between the prognostic model and immune infiltration and checkpoints. Finally, we analyzed the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions of the prognosis model and established the nomogram model and decision tree model. The survival analyses of ClusterA and ClusterB were significantly different. Survival analysis showed that patients with a high risk score had a poor prognosis. Survival models (tobacco, T, N, M, stage, sex, age, status, and risk score) were abnormally correlated with T cells and macrophages. The higher the risk score associated with smoking was and the higher the stage was, the more severe the LUAD and the more maladjusted the immune system were. Immune infiltration and abnormal expression of immune checkpoint genes in the prognostic model of LUAD were associated with the risk score. The prognostic models were mainly enriched in the cell cycle and DNA replication. Characterization of DNA methylation regulatory patterns is helpful to improve our understanding of the immune microenvironment in LUAD and to guide the development of a more personalized immunotherapy strategy in the future.