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Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.
Assuntos
Humanos , Neoplasias/patologia , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Objective:To investigate the effect of lncRNA UCA1 on the radiosensitivity of in vitro cultured glioma cell lines SHG-44, U87 and U251 by regulating the miR-873-5p expression. Methods:The survival of glioma cells SHG-44, U87 and U251 treated with different radiation intensities (0, 2, 4, 6 and 8 Gy) was detected by colony formation assay. The expression levels of UCA1 in glioma cells SHG-44, U87 and U251 were measured by qRT-PCR. The radiation-resistant glioma cells U87 and U251 were selected for subsequent study. After silencing UCA1 expression and/or over-expressing miR-873-5p, the cell survival rate was detected by colony formation assay, and the cell apoptosis rate was determined by flow cytometry. The dual luciferase reporter gene assay and qRT-PCR were employed to verify the targeting relationship between UCA1 and miR-873-5p.Results:UCA1 was up-regulated in the radiation-resistant U87 and U251 cells. Silencing UCA1 or over-expressing miR-873-5p inhibited the survival of U87 and U251 cells, and promoted the cell apoptosis induced by radiation exposure. miR-873-5p was a target gene of UCA1, and UCA1 negatively regulated the expression of miR-873-5p. The inhibition of miR-873-5p could reverse the effect of silencing UCA1 on the radiosensitivity of glioma cells. Silencing UCA1 increased the inhibitory effect of radiation on the glioma cell U251 xenografts.Conclusion:Silencing UCA1 inhibits the survival of glioma cells and promotes the cell apoptosis by up-regulating the expression of miR-873-5p, thereby increasing the radiosensitivity of glioma cells.
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Objective@#To develop the Chinese version of anterior skull base questionnaire(ASBQ) and to verify its application in patients with anterior and middle skull base tumors.@*Methods@#The following steps were finished including getting the permission from the author of the original English scale, translating and back-translating, tentative test, discussing the consequence and cultural debugging. From October 2016 to December 2018, 51 patients with skull base tumors from Xuanwu Hospital and China-Japan Friendship Hospital were enrolled as an experimental group, aged from 24 to 70 years old, with 19 males and 32 females, which included 27 patients with anterior skull base tumor and 24 patients with middle skull base tumor. From December 2016 to January 2018, 46 healthy volunteers were selected as a control group, aged from 18 to 36 years old, including 26 females and 20 males. The subjects in the test group and the control group were rigorously tested with official manuscripts and judged whether the manuscript was applicable. The SPSS 22.0 statistical software was used to analyze the data of the test group, the anterior skull base group, the middle skull base group and the control group to evaluate the performance of the scale.@*Results@#Both the rate of the recovery and efficiency in experimental group, anterior skull base group and middle skull base group were 100%, with the average time of completion of (8.7±3.2), (11.2±4.0) and (7.3±2.1) min, respectively in each group. The r value of test-retest reliability was 0.96, 0.99 and 0.97 in experimental group, anterior skull base group and middle skull base group, with the split-half reliability coefficient of 0.91, 0.90 and 0.96, with the entire scale Cronbach′s coefficient of 0.91, 0.95 and 0.93, respectively. The content validity and the construct validity of the scale were good enough, and the criteria validity was-0.483,-0.509 and -0.489 in experimental group, anterior skull base group and middle skull base group. The scale could well distinguish the difference of the quality of life between the preoperative and postoperative patients in experimental group and the middle skull base group. The difference of the quality of life in anterior skull base group was not found between preoperative and postoperative patients.@*Conclusion@#The Chinese version of ASBQ has good reliability and validity, which is suitable for a wide range of Chinese patients with anterior and middle skull base tumors to assess their quality of life.
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OBJECTIVE To investigate the effect of the treatment of allergic rhinitis on the quality of life of patients with bronchial asthma.METHODS Fifty-three patients with moderate-severe allergic rhinitis and mildmoderate asthma were included in this study and all of them had not yet received treatment for allergic rhinitis.There were 20 males and 33 females with an age ranged from 18 to 76 years.They had been treated with Salmeterol/Fluticasone propionate(seretide) 50/100 μg twice a day and combined with Ventolin if needed.On this basis,they were treated with loratadinel0 mg and Fluticasone proplonate nasal spray 200 micrograms once daily for 12 weeks.The visual analog scale,the asthma control test and Juniper's asthma quality of life questionnaire were recorded before and after treatment.RESULTS After treatment of allergic rhinitis,the rate of full asthma control was 28％,the rate of partial asthma control was 63％,and the rate of uncontrolled asthma was 9％.There was a significant improvement in asthma control after treatment of allergic rhinitis(P＜0.05).The scores after treatment were higher than that before treatment in all dimensions of asthma quality of life questionnaire(P＜0.01).CONCLUSION Allergic rhinitis and bronchial asthma are two closely related diseases,treatment of allergic rhinitis is benefit to bronchial asthma control and can improve the quality of life of the patients.
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<p><b>OBJECTIVE</b>To explore the upstream signal transduction mechanism responsible for the decrease of the ratio of the two glucocorticoid receptor (GR) subunits (GRα and GRβ) in nasal polyp in vitro.</p><p><b>METHODS</b>The GRα/GRβ decrease cell model was established by lipopolysaccharide (LPS)-induced human nasal epithelia (HNE) of nasal polyp in vitro. Changes in the protein and mRNA expression of GRα, GRβ and the key enzymes in the p38MAPK, ERK and JNK signal pathways were measured, respectively, before and after being induced with different doses of LPS and specific inhibitors of p38MAPK, JNK and ERK. SPSS 16.0 software (Analysis of variance, ANOVA) was used to analyze the data.</p><p><b>RESULTS</b>With the LPS induction, the GRα/GRβ ratio declined in both a time-dependent manner and a concentration-dependent manner in HNE, which demonstrated the successful establishment of a GRα/GRβ decrease model in vitro. After cultured HNE were induced with the same set of LPS, the p38MAPK, ERK and JNK signal pathways were also activated. The mRNA expression of p38MAPK and JNK in each LPS-induced group (17.14 ± 1.50, 22.34 ± 2.78, 30.12 ± 1.07; 2.51 ± 0.13, 3.79 ± 0.67, 4.41 ± 0.83; 25.62 ± 1.77, 31.33 ± 1.97, 37.25 ± 2.46) was significantly higher than that (7.39 ± 0.31, 2.04 ± 0.34, 2.38 ± 0.35) in the control group (χ² value was 15.347, 18.331, 14.671, all P < 0.01). Either a specific inhibitor (SB203580) of the p38MAPK pathway or a specific inhibitor (SP600125) of the JNK pathway increased the GRα/GRβ ratio at the meantime of inhibiting their pathways. SB203580 exhibited a much stronger increase effect on GRα/GRβ ratio than SP600125. The specific inhibitors (PD98059) of ERK had no influence on the expression of GR isoforms.</p><p><b>CONCLUSIONS</b>The above results demonstrated that the decrease of GRα/GRβ ratio in HNE induced by LPS in vitro is mediated through the p38MAPK and JNK signal pathways. It is possible to improve the treatment effect of GC resistance in nasal polyp by targeting these specific signal pathways.</p>