ABSTRACT
The challenge to improve the clinical efficacy and enlarge the population that benefits from immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) is significant. Based on whole-exosome sequencing analysis of biopsies from NSCLC patients before anti-programmed cell death protein-2 (PD-1) treatment, we identified NLRP4 mutations in the responders with a longer progression-free survival (PFS). Knockdown of NLRP4 in mouse Lewis lung cancer cell line enhanced interferon (IFN)-α/ß production through the cGAS-STING-IRF3/IRF7 axis and promoted the accumulation of intratumoral CD8+ T cells, leading to tumor growth retardation in vivo and a synergistic effect with anti-PD-ligand 1 therapy. This was consistent with clinical observations that more tumor-infiltrating CD8+ T cells and elevated peripheral IFN-α before receiving nivolumab treatment were associated with a longer PFS in NSCLC patients. Our study highlights the roles of tumor-intrinsic NLRP4 in remodeling the immune contextures in the tumor microenvironment, making regional type I IFN beneficial for ICI treatment.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , B7-H1 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/therapeutic use , Interferon Type I/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/genetics , Animals , CD8-Positive T-Lymphocytes/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Cell Line, Tumor , Female , Humans , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lymphocytes, Tumor-Infiltrating/drug effects , Macrophages/drug effects , Male , Mice , Middle Aged , Mutation , Progression-Free Survival , Signal Transduction/drug effects , Treatment Outcome , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunologyABSTRACT
The pressure sensor with high sensitivity and a broad pressure sensing range is highly desired for flexible electronics. Here, a high-performance pressure sensor based on a hybrid structure was facilely fabricated using the glass template method, which consists of polyurethane (PU) mesodomes embedded with gradient-distributed silver nanowire (AgNW). Such a novel hybrid architecture enables the as-prepared PU/AgNW pressure sensor to have high sensitivity as well as a wide detection range. Moreover, the obtained PU/AgNW pressure sensors have a fast response time (20 ms), good cycling stability, and excellent flexibility. The pressure sensor, benefiting from its outstanding comprehensive sensing performance, can be used for expression recognition and human activity monitoring, showing tremendous application potential in wearable devices. The proposed architecture and developed methodology in this work is promising for future flexible electronic applications.
ABSTRACT
OBJECTIVE: To study the association between serum neuron-specific enolase (NSE) and the extent of brain damage and the outcome after acute traumatic brain injury (TBI). METHODS: The release patterns of serum NSE in 78 patients after acute TBI were analyzed by using the enzyme linked immunosorbent assay. The levels of NSE were compared with Glasgow coma scale, the category of brain injury and the outcome after 6 months of injury. RESULTS: There were different NSE values in patients with minor (12.96 microg/L+/-2.39 microg/L), moderate (23.44 microg/L+/-5.33 microg/L) and severe brain injury (42.68 microg/L+/-4.57 microg/L). After severe TBI, the concentration of NSE in patients with epidural hematomas was 13.38 microg/L+/-4.01 microg/L, 24.03 microg/L+/-2.85 microg/L in brain contusion without surgical intervention group, 55.20 microg/L+/-6.35 microg/L in brain contusion with surgical intervention group, and 83.85 microg/L+/-15.82 microg/L in diffuse brain swelling group. There were close correlations between NSE values and Glasgow coma scale (r=-0.608, P<0.01) and the extent of brain injury (r=0.75, P<0.01). Patients with poor outcome had significantly higher initial and peak NSE values than those with good outcome (66.40 microg/L+/-9.46 microg/L, 94.24 microg/L+/-13.75 microg/L vs 32.16 microg/L+/-4.21 microg/L, 34.08 microg/L+/-4.40 microg/L, P<0.01, respectively). Initial NSE values were negatively related to the outcome (r=-0.501, P<0.01). Most patients with poor outcomes had persisting or secondary elevated NSE values. CONCLUSIONS: Serum NSE is one of the valuable neurobiochemical markers for assessment of the severity of brain injury and outcome prediction.
