ABSTRACT
With the discovery of lung cancer targets and drug development, targeted therapy has improved the clinical prognosis of non-small cell lung cancer (NSCLC) with driver gene mutations. Immune checkpoint inhibitors (ICIs) have shown good efficacy in driver gene-negative NSCLC. Although some patients with driver gene mutations benefited significantly from the corresponding targeted therapy, they did not respond well to immunotherapy. In most clinical trials and daily practice, patients with NSCLC and driver gene mutations such as EGFR and ALK are excluded or only account for a minority of patients. Applying immunotherapy to patients with driver gene mutations, selecting the best treatment regimens among targeted therapy, chemotherapy, and immunotherapy, and formulating the optimal treatment strategy are crucial to improve the prognosis of patients with advanced NSCLC and driver gene mutations. This paper reviews the characteristics of tumor immune microenvironment with different driver gene mutations and the application of immunotherapy for patients with NSCLC and different driver gene mutations.
ABSTRACT
ObjectiveTo investigate the mechanism of Lycium barbarum polysaccharides （LBP） in promoting the activation of RAW264.7 macrophages. MethodRAW264.7 macrophages were stimulated with LBP at different concentrations （50， 100， 200 mg·L-1）， and those stimulated with lipopolysaccharide （LPS） at 100 μg·L-1 and galactose （Gal） at 100 mg·L-1 as positive controls. After 24 h of LBP stimulation， the cell counting kit-8 （CCK-8） was used to detect the survival rate of RAW264.7 macrophages treated with LBP （0， 50， 100， 200， 400， 800 mg·L-1）. The levels of interleukin-6 （IL-6） and interleukin-12 （IL-12） in cell culture supernatant were detected by enzyme-linked immunosorbent assay （ELISA）. The protein and mRNA expression of p38 mitogen-activated protein kinase （MAPK）， extracellular signal-regulated kinase （ERK）， c-Jun N-terminal kinase （JNK）， and nuclear factor κB （NF-κB） in Toll-like receptor 4 （TLR4）/Toll-like receptor 2 （TLR2）/macrophage galactose-type lectin （MGL） pathway of RAW264.7 macrophages was detected by Real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR） and Western blot. ResultCCK-8 results showed that compared with the results in the blank group， the survival rate of RAW264.7 macrophages decreased in the 400， 800 mg·L-1 LBP groups （P<0.05）. ELISA results showed that compared with the blank group， 50 mg·L-1 LBP could promote the secretion of IL-12 in RAW264.7 macrophages （P<0.01）. Compared with the blank group， 100 mg·L-1 LBP and 200 mg·L-1 LBP could promote the secretion of IL-6 in RAW264.7 macrophages （P<0.05， P<0.01）. Western blot results showed that compared with the blank group， the LBP groups （50， 100， 200 mg·L-1） enhanced protein expression levels of MAPK key molecules （p-p38 MAPK， p-ERK， p-NF-κB， and p-JNK） in TLR4， TLR2， and MGL pathways （P<0.05， P<0.01）. Compared with the model group， the 200 mg·L-1 LBP group could promote the expression level of p-NF-κB protein in RAW264.7 macrophages （P<0.01）. Real-time PCR results showed that compared with the blank group， the LBP groups （50， 100， and 200 mg·L-1） enhanced the mRNA expression levels of MAPK key molecules （p38 MAPK， ERK， NF-κB， and JNK） in TLR4 and TLR2 pathways （P<0.05， P<0.01）. Compared with the model group， the 50 and 200 mg·L-1 LBP groups could promote the mRNA expression levels of JNK and ERK2 in RAW264.7 macrophages （P<0.05， P<0.01）. ConclusionLBP can regulate the activation of RAW264.7 macrophages and participate in the immune response through the TLR2/TLR4/MGL pathway.
ABSTRACT
In recent years,the application of immune checkpoint blockades has brought dramatical revolution to the treatment of malignant tumors,which not only significantly increase the clinical benefits of partial advanced lung cancer,but also gradually change the landscape of available treatment options for patients with local advanced and early-staged lung cancer.But problems of immunotherapy about efficacy and safety follows.It is urgent to find dynamic biomarkers to identify the patients who are most likely to benefit from immunotherapy and to monitor tumor-specific immune responses.Several dynamic biomarkers have been identified,we will review some of lung cancer-related biomarkers,such as PD-L1 、TMB 、ctDNA 、TILs and peripheral blood biomarkers.
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Objective To evaluate the effect of high-level spinal cord injury(SCI)on the expression of mitochondrial voltage-dependent anion channel 2(VDAC2)in rat cardiomyocytes.Methods Forty-eight pathogen-free healthy adult male Sprague-Dawley rats,weighing 200-250 g,were divided into 2 groups(n=24 each)using a random number table:sham operation group(group S)and high-level SCI group(group H).The animals were anesthetized with intraperitoneal chloral hydrate and subjected to SCI using the modified Allen weight-drop method in group H.The spinal cord was only exposed in group S.At 6,12,24 and 48 h after SCI(T1-4),6 rats in each group were randomly selected and sacrificed,and myocardial specimens were collected from the cardiac apex for microscopic examination of the cell morphology(with a transmission electron microscope) and for determination of cell apoptosis(by TUNEL assay),expression of Bax,Bcl-2 and VDAC2 protein and mRNA in cardiomyocytes(by Western blot and real-time polymerase chain reaction,respectively).The apoptosis rate and ratios of Bax/Bcl-2 protein and mRNA were calculated.Results Compared with group S,the apoptosis rate and ratios of Bax/Bcl-2 protein and mRNA were significantly increased at T1-4,the expression of VDAC2 protein and mRNA was significantly down-regulated at T2-4(P<0.05 or 0.01),and the pathologic changes of cardiomyocytes were aggravated in group H.Conclusion The mechanism of myocardial damage is related to down-regulation of mitochondrial VDAC2 expression in cardiomyocytes and promotion of cell apoptosis in rats with high-level SCI.
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Objective To evaluate the effect of high-level spinal cord injury (SCI) on the myocardial energy metabolism in rats.Methods Sixty healthy male Sprague-Dawley rats,weighing 250-300 g,were randomly divided into 2 groups (n=30 each) using a random number table:sham operation (group S) and SCI group.SCI was induced in anesthetized rats by dropping a 10 g weight onto C7 spinal cord from 5 cm height falling freely inside a vertical hollow glass tube.At 6,12,24,48 and 72 h after SCI,6 rats in each group were chosen and arterial blood samples were taken for measurement of serum creatine kinase (CK) and creatine kinase isoenzyme-MB (CK-MB) activities.The rats were then sacrificed and myocardial specimens were obtained for examination of myocardial ultrastructure and for determination of ATP weight ratio,levels of Na+-K+-ATPase,Ca2+-Mg2+-ATPase,non-esterified fatty acids (NEFA) and lactic acid (LD),and expression of peroxisome proliferator-activated receptor alpha (PPARα) mRNA and protein (using fluorescent quantitative PCR and Western blot).Results Compared with group S,the serum CK and CK-MB activities were significantly increased,the ATP weight ratio,activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase and levels of NEFA and LD were decreased,and the expression of PPAR-α mRNA and protein was down-regulated in SCI group.No pathological changes of myocardium were found in group S,and the pathological changes of myocardium were obvious in SCI group.Conclusion High-level SCI can lead to decrease in the myocardial energy metabolism in rats,and down-regulated expression of PPARα is involved in the mechanism.