Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.

The tumor-suppressor gene tumor protein p53 (TP53) is one of the most commonly mutated genes in human lung cancer, and TP53 mutations are associated with a worsened prognosis and causes resistance to cancer therapy. RNA sequencing and TP53 mutation data were downloaded to determine specific TP53-associated signature based on differentially expressed genes between patients with lung squamous cell carcinoma (LUSC) with wild type (TP53 ^WT) and mutated (TP53^MUT) TP53. We investigated the predictive value of this signature on the immune microenvironment, tumor mutational burden (TMB), and likelihood of response to immunotherapy and chemotherapy. In total, 1,556 differentially expressed genes were identified based on TP53 mutation status. Three genes (KLK6, MUC22 and CSN1S1) identified by univariate and multivariate Cox regression analyses, comprised the prognostic signature which was an independent and specific prognostic marker of overall survival in patients with LUSC. A nomogram was also established to validate this signature for clinical use. Moreover, the high-risk group was characterized by increased infiltration of monocytes and macrophages M1, and decreased T cells CD8 and T cells follicular helper. High-risk group exhibited a higher TMB, and was much more sensitive to immunotherapy and chemotherapy. KLK6 and CSN1S1 expression and the prognostic prediction values were further validated in clinical samples. The derived TP53-associated signature is a specific and independent prognostic biomarker for LUSC patients, and could provide potential prognostic biomarker or therapeutic targets for the development of novel immunotherapies and chemotherapies.

Hypomagnesemia is commonly seen but frequently overlooked in critically ill patients in intensive care unit (ICU). However, the strength and consistency of the effect of hypomagnesemia on outcomes in critically ill patients remain controversial. In this report, we performed a systematic review and meta-analysis to evaluate the association of serum magnesium level with prognosis of critically ill patients upon admission to the ICU. A comprehensive search for clinical trials was performed, and 10 studies comprising 1,122 cases and 630 controls were finally selected for analysis. The patients with hypomagnesemia had higher mortality rate (risk ratio [RR] 1.76; 95% confidence interval [CI] 1.54–2.00; P <0.00001), more frequently had sepsis (RR 2.04; 95% CI 1.21–3.42; P = 0.0007) and more frequent need for ventilatory support (RR 1.36; 95% CI 1.21 to 1.53; P <0.00001). Length of ICU stay was also higher in the hypomagnesemia group (RR 1.85; 95% CI 0.43– 3.26; P = 0.01). Collectively, our data indicated that hypomagnesemia appears associated with greater risk of mortality, sepsis, mechanical ventilation, and the length of ICU stay in patients admitted to ICU. The role of magnesium therapy for improving outcomes in critically ill patients is needed to further study.

Lung cancer is the most common cause of cancer deaths worldwide, and lung adenocarcinoma (LUAD) is the most common histological subtype. However, the prognostic and predictive outcomes differ because of this cancer type heterogeneity. LUAD subtypes were identified on the basis of the immunogenomic profiling of 29 immune signatures. We named three LUAD subtypes: Immunity High, Immunity Medium, and Immunity Low. The Immunity High subtype was characterized by immune activation, e.g., increased immune scores, elevated stromal scores and the highest infiltration of CD8⁺ T cells, and decreased tumor purities. Activated expressions of human leukocyte antigen (HLA) genes, immune checkpoint molecules, and T helper 1 (Th1)/interferon-gamma (IFNγ) gene signature were also observed in the Immunity High subtype. N ⁶-methyladenosine (m⁶A) RNA methylation, associated with cancer initiation and progression, was reduced in the Immunity High subtype. Functional and signaling pathway enrichment analysis further showed that differentially expressed genes between the Immunity High subtype and the other subtypes mainly participated in immune response and some cancer-associated pathways. In addition, the Immunity High subtype exhibited more sensitivity to immunotherapy and chemotherapy. Finally, candidate compounds that aimed at LUAD subtype differentiation were identified. Comprehensively characterizing the LUAD subtypes based on immune signatures may help to provide potential strategies for LUAD treatment.

BACKGROUND:WeChat is a convenient and popular social medium, and it seems to be an appropriate platform for education and management of patients. This study sought to identify usefulness in clinical control of cough-variant asthma (CVA). MATERIAL AND...