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Hepatic fibrosis （HF） is a pathological process of abnormal repair of liver tissue structure caused by chronic liver injury， and its pathogenesis has not been fully clarified. Related studies have shown that programmed cell death may be associated with the onset of HF， and traditional Chinese medicine （TCM） has a significant effect in regulating programmed cell death to intervene against HF. This article reviews the main mechanism of the influence of programmed cell death on HF and discusses the possible mechanism of TCM regulation of programmed cell death in improving HF， which provides new ideas for TCM prevention and treatment of HF.
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@#Objective To construct a yeast two-hybrid recombinant bait plasmid of human programmed cell death ligand 1(PD-L1)immunoglobulin variable region(IgV)domain gene,detect its expression in yeast and detect the cytotoxicity and self-activation of PD-L1 IgV protein as well as the interaction between PD-L1 IgV and human thioredoxin(hTrx).Methods Human PD-L1 was analyzed by bioinformatics method,and primers were designed to amplify PD-L1 IgV domain based on the coding region of PD-L1 gene registered in NCBI GenBank database. PCR amplification was carried out with pENTERPD-L1 plasmid as template,and then cloned into yeast two-hybrid bait vector pGBKT7. The recombinant bait plasmid and pGBKT7 empty vector were transformed into Y2HGold yeast cells respectively,and the PD-L1 IgV gene and its expression were detected by PCR and Western blot;Meanwhile,the protein toxicity and self-activation of PD-L1 IgV were detected,and the interaction between PD-L1 IgV and hTrx was detected by drip plate method.Results The bioinformatics analysis results of PD-L1 were consistent with related reports. The recombinant bait plasmid pGBKT7-PD-L1 IgV was correctly constructed,and Y2HGold positive clone was obtained,in which PD-L1 IgV was stably expressed. The empty vector pGBKT7 and recombinant bait plasmid pGBKT7-PD-L1 IgV grew well on SD/-Trp and SD/-Trp/X-α-Gal plates with the same colony size and number and white colony,but they did not grow on SD/-Trp/X-α-Gal/AbA plates,which indicated that PD-L1 IgV protein had no toxicity and no self-activation effect on yeast. The results of drip plates test showed that all experimental groups grew well on SD/-Trp/-Leu plate,while only positive control group grew on SD/-Trp/-Leu/X-α-Gal/AbA plate and showed blue color,which indicated that bait protein PD-L1 IgV and hTrx did not self-activate,and there was no interaction between them.Conclusion Recombinant human PD-L1 IgV bait plasmid was successfully constructed. PD-L1 IgV protein showed no toxicity and self-activation effect on yeast cells,and there was no interaction between PD-L1 IgV and hTrx. Subsequently,hTrx can be used to construct a peptide aptamer library,from which peptide aptamers that specifically bind to PD-L1 IgV can be screened.
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Introducción:La inmunoterapia con pembrolizumab ha mejorado el pronóstico del cáncer de pulmón metastásico. En el presente caso se presenta la supervivencia extendidad y evolución de un paciente específico.Caso clínico:Hombre de 66 años, fumador. Diagnosticado de masa pulmonar en lóbulo infe-rior izquierdo de dimensiones 9 x 8 cm, con metástasis supra e infratentoriales intraaxiliares. Taller diagnóstico: Establecida como neoplasia de pulmón en estadio IVc, se comprobó el estado de PDL1 que positivo en un 80 % de la muestra de masa pulmonar. Debuta con me-tástasis cerebrales.Evolución: Se inció inmunoterapia con Pembrolizumab, el cual se mantubo hasta la presencia de un efecto secundario atribuido al pembrolizumab, cumpliendo 30meses de supervivencia hasta el cierre de esta observación no se reportó la muerte del paciente.Conclusiones:En el presente reporte, la determinación del biomarcador histológico PDL1 po-sitivo en cáncer de pulmón ayudo a prescribir un tratamiento con inmunoterpia dirigida, lo que demostró aumentar la supervivencia más allá que el tratamiento convencional con quimiote-rapia
Introduction: Immunotherapy with pembrolizumab has improved the prognosis of metastatic lung cancer. A specific patient's extended survival and evolution is presented in the present case.Clinical case: 66-year-old man, smoker. Diagnosed with a lung mass in the left lower lobe measuring 9 x 8 cm, with supra and infratentorial intra-axial metastases.Diagnostic workshop: To establisha stage IVc lung neoplasm, 80% of the lung mass sample was confirmed to be positive for PDL1.Evolution: Immunotherapy was started with Pembrolizumab, which was maintained until the presence of a side effect attributed to pembrolizumab, completing 30 months of survival until the closure of this observation, the patient's death was not reported.Conclusions: In the present report, the determination of the positive histological biomarker PDL1 in lung cancer helped prescribe treatment with targeted immunotherapy, which was shown to increase survival beyond conventional treatment with chemotherapy
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Humans , Male , Aged , Immunotherapy , Lung Neoplasms , Lung DiseasesABSTRACT
Objective:To investigate the value of serum soluble programmed cell death protein 1 (sPD-1), soluble B7 homolog 5 (sB7-H5) and trefoil factor 2 (TFF2) in evaluating the severity of disease and the risk of death in patients with acute pancreatitis (AP).Methods:A prospective research method was adopted. Three hundred and twenty-eight patients with AP (AP group) from February 2020 to February 2021 in Xiangyang Central Hospital were selected, including 124 patients with mild AP (MAP), 106 patients with moderately severe AP (MSAP) and 98 patients with severe AP (SAP). The serum levels of sPD-1, sB7-H5 and TFF2 were measured by enzyme-linked immunosorbent assay and compared with 60 healthy people (healthy control group). The patients with AP were followed up for 90 d, 284 patients survived and 44 died. The amylase, C-reactive protein (CRP), procalcitonin (PCT), acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ), sequential organ failure assessment (SOFA), modified CT severity index (MCTSI), sPD-1, sB7-H5 and TFF2 were compared between the two groups. Pearson method was used for correlation analysis. Multivariate Logistic regression was used to analyze the independent risk factors of death in patients with AP. The efficacy of sPD-1, sB7-H5 and TFF2 in predicting the death in patients with AP was evaluated using the receiver operating characteristics (ROC) curve.Results:The sPD-1, sB7-H5 and TFF2 in AP group were significantly higher than those in healthy control group: (177.99 ± 17.81) ng/L vs. (50.20 ± 10.81) ng/L, (2.69 ± 0.72) μg/L vs. (1.40 ± 0.35) μg/L and (569.97 ± 38.91) μg/L vs. (94.59 ± 11.98) μg/L, and there were statistical differences ( P<0.01). The amylase, sPD-1, sB7-H5 and TFF2 in patients with MSAP and SAP were significantly higher than those in patients with MAP: (639.36 ± 91.67) and (835.24 ± 109.30) U/L vs. (575.24 ± 89.78) U/L, (180.13 ± 20.61) and (221.17 ± 15.70) ng/L vs. (142.03 ± 16.76) ng/L, (2.85 ± 0.74) and (3.34 ± 0.82) μg/L vs. (2.05 ± 0.52) μg/L, (539.66 ± 36.58) and (763.55 ± 40.08) μg/L vs. (442.90 ± 35.79) μg/L, the indexes in patients with SAP were significantly higher than those in patients with MSAP, and there were statistical differences ( P<0.01). Pearson correlation analysis result showed that sPD-1 was positively correlated with sB7-H5 and TFF2 in patients with AP ( r = 0.552 and 0.641, P<0.01), and the sB7-H5 was positively correlated with TFF2 ( r = 0.610, P<0.01). The amylase, CRP, PCT, APACHE Ⅱ, SOFA, MCTSI, sPD-1, sB7-H5 and TFF2 in the dead patients were significantly higher than those in the living patients: (1 098 ± 105) U/L vs. (641 ± 93) U/L, (235.60 ± 40.17) mg/L vs. (118.04 ± 32.90) mg/L, (4.32 ± 0.52) μg/L vs. (3.14 ± 0.44) μg/L, (19.39 ± 3.14) scores vs. (11.18 ± 2.53) scores, (12.13 ± 2.78) scores vs. (7.40 ± 2.15) scores, (7.12 ± 1.73) scores vs. (4.31 ± 1.52) scores, (222.23 ± 22.30) ng/L vs. (171.14 ± 18.50) ng/L, (3.37 ± 0.89) μg/L vs. (2.59 ± 0.59) μg/L and (629.27 ± 39.63) μg/L vs. (560.78 ± 30.45) μg/L, and there were statistical differences ( P<0.01). Multivariate Logistic regression analysis result showed that CRP, PCT, APACHE Ⅱ, SOFA, sPD-1, sB7-H5 and TFF2 were independent risk factors death of in patients with AP ( OR = 1.339, 1.416, 1.285, 1.327, 1.092, 1.171 and 1.080; 95% CI 1.145 to 1.566, 1.146 to 1.751, 1.132 to 1.460, 1.150 to 1.531, 1.024 to 1.164, 1.072 to 1.280 and 1.031 to 1.131; P<0.01). The ROC curve analysis result showed that the area under the curve of sPD-1, sB7-H5 and TFF2 combined detection to predict the death in patients with AP was larger than that of sPD-1, sB7-H5, and TFF2 alone detection (0.870 vs. 0.771, 0.734 and 0.685). Conclusions:The increase of serum sPD-1, sB7-H5 and TFF2 levels in patients with AP is related to the severity of disease of patients with AP. The combined detection of the indexes can assist in evaluating the risk of death in patients with AP.
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@#We reported three cases of stageⅢ/N2 non-small cell lung cancer (NSCLC) treated with neoadjuvant immunotherapy and stereotactic body radiation therapy (SBRT) in our hospital, including 2 males and 1 female with a mean age of 65.7 years. The patients received two doses of the programmed cell death protein-1 inhibitor toripalimab after 1 week of SBRT. Thereafter, surgery was planned 4-6 weeks after the second dose. One patient achieved pathologic complete response, one achieved major pathologic response (MPR), and one did not achieve MPR with 20% residual tumor. There were few side effects of toripalimab combined with SBRT as a neoadjuvant treatment, and the treatment did not cause a delay of surgery.
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@#Objective Establish quality control methods for critical quality attribute of bispecific antibody against programmed cell death protein 1(PD-1)/cytotoxic T-lymphocyte-associated protein 4(CTLA-4).Methods The biological activity of PD-1 target was determined by reporter gene assay,and the competitive binding activity of CTLA-4 target was determined by flow cytometry;The antibody molecular size variants were controlled by reducing/non-reducing capillary electrophoresis-sodium dodecyl sulfonate(CE-SDS) and size exclusion chromatography-high performance liquid chromatography(SEC-HPLC);Charge heterogeneity was determined by imaging capillary isoelectric focusing electrophoresis(iCIEF);Bispecific anti-PD-1/CTLA-4 antibody was identified by peptide map analysis;Glycosylation was analysed by high performance liquid chromatography(HPLC)Results The concentration for 50% of maximal effect(EC_(50)) of PD-1target was(6.91±0.78) nmol/L,and the relative biological potency to the reference was(103.50±13.08)% with the RSD of 12.64%;The EC_(50) of CTLA-4 target activity was(0.35±0.28) nmol/L,and the relative biological potency was(99.30±9.15)% with the RSD of 8.32%.The percentage of peak area of light chain and heavy chain of reducing CE-SDS was(98.86±0.02)%.The main peak area percentage of non-reducing CE-SDS was(93.07±0.13)%,fragment percentage was(4.44±0.13)%,and polymer percentage was(2.49±0.15)%.The peak area percentage of SEC-HPLC monomer and polymer were(97.20±0.01)% and(2.68±0.01)%,respectively.The area percentage of peak A group,peak B group,peak C group and peak D group were(38.43±0.54)%,(43.26±0.32)%,(11.31±0.14)% and(7.00±0.17)%,respectively.Peptide mapping showed the specific spectrum of the bispecific anti-PD-1/CTLA-4 antibody,which could be adopted for identification test.The highest proportion of glycotype was GOF,with a content of(41.06±0.11)%,There were three types of glycan containing sialic acid,namely G2F+G1F-NANA,G2F-NANA and G2F-2NANA,with the content of(12.44±0.12)%,(12.00±0.05)% and(5.37±0.05)%,respectively.The total content of glycan containing sialic acid was(29.80±0.20)%.Conclusion The critical quality attributes of bispecific anti-PD-1/CTLA-4 antibody were studied and the corresponding quality control methods were established to ensure its safety,effectiveness and quality control,which provides a reference for the quality control methods and strategies of this type of monoclonal antibody products.
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@#Objective To investigate the influence of immunotherapy by antibiotic(ATB) combined with programmed cell death protein 1(PD1) on curative effect of hepatocellular carcinoma in mice.Methods H_(22) tumor-bearing male BALB/c mouse model was established.Eight model mice were injected i.p.with anti-PD1,250 μg for each,and administered intragastrically with ceftriaxone sodium(100 mg/kg) plus lincomycin hydrochloride(200 mg/kg),using eight normal mice administered intragastrically with normal saline(0.2 mL for each) as control.The anticancer effect of ATB combined with PD1 was evaluated by tumor size,hematoxylin-eo sin(HE) staining of tumor tissue and spleen index.The secretion levels of IL-2,IL-10 and IFN_γ in sera of mice were determined by ELISA,while the proportions of CD3~+ and CD8~+ T cells in mouse lymphocytes by flow cytometry,and the expression levels of CD3 and CD8 in mouse tumor tissue by immunohistochemistry(IHC) method.Results The therapy by ATB combined with anti-PD 1 showed significantly inhibitory effect on tumor growth,which increased the proportions of CD3~+ and CD8~+ T cells in T lymphocytes,up-regulated the secretion levels of IL-2,IL-10 and IFN_γ,and regulated the immune function of T cells by up-regulating the expression levels of CD3 and CD8 in tumor tissue to continuously activate the immune system and suppress the tumor.Conclusion Narrow-spectrum ATB may promote the effect of anti-PD 1 immunotherapy on tumors by improving immune function.
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@#Objective To prepare bispecific antibody targeting cluster of differentiation 73(CD73) and programmed cell death-ligand 1(PD-L1),and evaluate its binding ability and killing ability in vitro.Methods Using genetic engineering method,PD-L1 single-chain fragment variable(scFv) was inserted into the hinge region of CD73 monoclonal antibody to construct anti-CD73/PD-L1 bispecific antibody(BS-21),which was screened by CHO GS expression system to obtain highly expressed cell line.After purified by Protein A and molecular sieve,the purity of antibody was detected by size exclusion chromatography-high performance liquid chromatography(SEC-HPLC),the binding ability of antibody in vitro was detected by flow cytometry,and the killing ability in vitro was detected by using peripheral blood mononuclear cell(PBMC) to kill Calu 1 lung cancer cells in vitro.Results High-yield cell lines were obtained by pressure screening.A bispecific antibody BS-21 with a purity of 99.6% was obtained by purification,which bound to CD73 and PD-L1 molecules simultaneously.Compared with anti CD73 and anti PD-L1 groups,BS-21 group significantly increased the killing rate of immune cells to Calu 1 tumor cells(F=30.36,each P<0.001).Conclusion Bispecific antibody BS-21 reduced the immunosuppressive effect of CD73 and PD-Ll on immune cells simultaneously,and showed good anti-tumor function.
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Objective:To investigate the relationship between KRAS gene mutation, programmed death receptor ligand 1 (PD-L1) expression and prognosis of first-line concurrent chemoradiotherapy in patients with locally advanced non-small cell lung cancer.Methods:The clinical data of 50 patients with locally advanced non-small cell lung cancer who were admitted to Nanping First Hospital from January 2018 to December 2021 were retrospectively analyzed. All patients were treated with first-line concurrent chemoradiotherapy. Tissue samples of patients were obtained and paraffin embedded before treatment. Real-time fluorescence quantitative polymerase chain reaction was used to detect the type of KRAS gene mutation in tissues before treatment, and the expression of PD-L1 was determined by immunohistochemistry (the percentage of positive cells in tumor cells ≥1% was positive), and the relationship between KRAS gene status, PD-L1 expression and clinical characteristics and short-term efficacy of patients was analyzed. Patients were followed up for 1 year, and progression-free survival (PFS) curves were plotted by Kaplan-Meier method, and log-rank test was used for comparison. Univariate and multivariate Cox proportional hazards models were used to analyze the influencing factors of PFS.Results:Among the 50 patients, 11 (22.00%) were KRAS mutant, and 36 (72.00%) were PD-L1 positive. Among the 11 patients with KRAS mutation, there were 2 cases of codon 13 mutation and 9 cases of codon 12 mutation in exon 2. The objective response rate (ORR) and clinical control rate (DCR) were 76.00% (38/50) and 86.00% (43/50). There were no significant differences in patients' age, pathological type, TNM stage, ORR and DCR between KRAS mutant group and KRAS wild type group (all P > 0.05). The proportions of male patients [72.73% (8/11) vs. 38.46% (15/39)], patients with smoking history [90.91% (10/11) vs. 20.51% (8/39)] and patients with PD-L1 positive expression [100.00% (11/11) vs. 64.10% (25/39)] in KRAS mutant group were higher than those in KRAS wild type group (all P < 0.05). There were no significant differences in patients' age, pathological type, gender, smoking history, TNM stage, ORR and DCR between PD-L1 positive group and PD-L1 negative group (all P > 0.05). The median PFS time of patients in KRAS mutant group and wild type group was 8.75 and 11.32 months, and the difference in PFS between the two groups was statistically significant ( P = 0.039). The median PFS time of patients with PD-L1 positive and negative was 10.19 and 11.16 months, and there was no statistical significance in PFS between the two ( P = 0.116). Multivariate Cox regression analysis showed that KRAS gene mutation was an independent risk factor for PFS in patients with locally advanced NSCLC after first-line concurrent chemoradiotherapy ( HR = 1.449, 95% CI 1.071-1.196, P = 0.017). PD-L1 expression, smoking history and gender were not independent influencing factors for PFS (all P > 0.05). Conclusions:KRAS gene status is closely related to the prognosis of patients with locally advanced non-small cell lung cancer treated with first-line concurrent chemoradiotherapy, while PD-L1 expression is not.
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Objective:To investigate the factors influencing the prognosis of hepatitis B-related hepatocellular carcinoma treated with programmed death receptor 1 (PD-1) inhibitors, and to construct a prognostic nomogram model for these patients and evaluate its clinical significances.Methods:The clinical data of 121 patients with hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors at the First Affiliated Hospital of Xinxiang Medical College from July 2018 to July 2021 were retrospectively analyzed. Follow-up was performed from the beginning of PD-1 inhibitor use, and the Kaplan-Meier method was used to analyze the overall survival of patients. The variables screened by the univariate Cox proportional hazards model analysis and variables clinically believed to be related to the prognosis were included in the multivariate Cox proportional hazards model for overall survival, and the stepwise regression method was used to screen the independent factors influencing overall survival. Based on the independent influencing factors of overall survival, R 3.5.1 software was used to construct a prognostic nomogram model for overall survival of hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors. Calibration curve was used to the consistency of model prediction and practice. The Harrell consistency index and receiver operating characteristic (ROC) curve (with imaging diagnosis as the gold standard) were used to analyze the efficacy of model in predicting the 1-year and 2-year overall survival rates.Results:The median follow-up time of 121 patients was 12.40 months, and the median overall survival time was 14.30 months, with overall survival rates of 82.60% and 62.30% at 6 and 12 months. Multivariate Cox regression analysis showed that albumin (ALB) ( HR = 0.946, 95% CI 0.901-0.992), international normalized ratio (INR) ( HR = 32.034, 95% CI 5.046-203.362), aspartate aminotransferase (AST) ( HR = 1.010, 95% CI 1.007-1.012) were independent influencing factors for overall survival of patients. According to the three factors, a prognostic nomogram model for hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors was constructed. The slope of the calibration curve of the model predicting 1-year and 2-year overall survival rates was close to 1. The Harrell consistency index of the nomogram model was 0.809 (95% CI 0.760-0.858). ROC curve analysis showed that the area under the curve (AUC) of the nomogram model predicting 1-year and 2-year overall survival rates of patients was 0.794 (95% CI 0.744-0.887, P < 0.001) and 0.791 (95% CI 0.708-0.860, P = 0.002). Conclusions:ALB, INR and AST are the influencing factors of prognosis of hepatitis B-related hepatocellular carcinoma patients treated with PD-1 inhibitors, and the nomogram model constructed based on prognostic influencing factors has a good effect on predicting the 1-year and 2-year overall survival rates of patients, which can be used to screen the population suitable for immunotherapy and is conducive to the clinical formulation of individualized and precise treatment plans.
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Klebsiella pneumoniae can cause a variety of infectious diseases, especially in immunocompromised population. The emergence of multidrug-resistant hypervirulent Klebsiella pneumoniae has greatly limited the choice of treatment for Klebsiella pneumoniae infection, and the exploration of new treatment strategies is imminent. In the process of infection, there is a complex interaction between the programmed cell death of host cells and the invasion of Klebsiella pneumoniae. This paper mainly reviewed the research progress in several mechanisms of programmed cell death such as pyroptosis, apoptosis, necroptosis and autophagy caused by Klebsiella pneumoniae.
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Programmed cell death receptor 1 (PD-1)/PD-1 ligand (PD-L1) maintains immune tolerance of normal tissues and mediates immune escape of tumors. For autoimmune thyroiditis, thyroid follicular epithelial cells inhibit the damage of T cells by up-regulating PD-L1 expression. With the application of immune checkpoint inhibitors (ICIs) in the field of cancer therapy, the incidence of immune-related thyroid disorders caused by ICIs has increased. Thyroid function should be monitored during and after ICIs treatment to promptly diagnose primary and (or) secondary thyroid disorders. The PD-1/PD-L1 signaling directly stimulates thyroid cancer cells, and exerts inhibitory effects on tumor-infiltrating immune cells. Combination of ICIs targeting PD-1/PD-L1 with chemo-radiotherapy or targeted therapy is a promising therapeutic strategy in the treatment of refractory thyroid cancers.
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Objective:To assess the prognostic value of pretreatment 18F-FDG PET/CT metabolic parameters in patients with metastatic malignant melanoma treated with anti-programmed cell death-1 (PD1) immunotherapy. Methods:A retrospective analysis of 29 patients (15 males, 14 females, age (59.1±13.0) years) with pathologically diagnosed metastatic malignant melanoma in Nanjing Drum Tower Hospital between June 2017 and October 2020 was conducted. Anti-PD1 immunotherapy were performed in all patients after 18F-FDG PET/CT imaging. 18F-FDG PET/CT parameters including SUV max, bone marrow-to-liver SUV max ratio (BLR), spleen-to-liver SUV max ratio (SLR) were obtained. Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) of primary lesions were measured automatically using the thresholds of 40%SUV max. The median value of each PET parameter was regarded as the threshold value and was used to divide patients into 2 groups (≥ and < the median value, respectively). Kaplan-Meier survival curve and Cox proportional risk model were used to analyze the overall survival (OS) differences between groups. Results:The median follow-up time was 15.0 months and 13 patients died. The median OS was 26.0(95% CI: 20.4-31.6) months. The median SUV max, TMTV, TLG, BLR and SLR were 6.2, 8.2 cm 3, 38.6 g, 0.82 and 0.84 respectively. Kaplan-Meier method and log-rank test showed that differences of OS between SUV max≥6.2 and <6.2 groups, TLG≥38.6 g and <38.6 g groups, BLR≥0.82 and <0.82 groups, SLR≥0.84 and <0.84 groups were not significant ( χ2 values: 0.01-0.35, P values: 0.061-0.929), while patients with TMTV≥8.2 cm 3 suffered from poorer OS compared with those with TMTV<8.2 cm 3 ( χ2=5.90, P=0.015). Cox multivariate analysis showed that TMTV (hazard risk ( HR)=6.347, 95% CI: 1.039-38.789) was a significant predictor of OS ( P=0.045). Conclusion:18F-FDG PET/CT parameter TMTV is the independent predictive factor of OS in metastatic melanoma treated with anti-PD1 immunotherapy.
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@#Objective To explore the short-term efficacy and safety of pembrolizumab combined with chemotherapy in the neoadjuvant treatment of non-small cell lung cancer. Methods The clinical data of 11 male patients with non-small cell lung cancer who underwent pembrolizumab combined with neoadjuvant chemotherapy in the Department of Thoracic Surgery, the First Affiliated Hospital of Xi'an Jiaotong University from December 2019 to June 2021 were retrospectively analyzed. The average age of the patients was 52.0-79.0 (62.0±6.9) years. The imaging data and pathological changes before and after neoadjuvant treatment were compared, and adverse reactions during neoadjuvant treatment were recorded. Objective remission rate (ORR) and main pathological remission rate (MPR) and pathological complete remission rate (pCR) were the main observation endpoints. Results After preoperative neoadjuvant therapy with pembrolizumab combined with platinum or paclitaxel, all patients successfully underwent thoracoscopic radical resection of lung cancer. The ORR was 72.7%, and the MPR was 81.8%. Among them, 45.5% of patients achieved pCR. The main adverse reactions were hypoalbuminemia, decreased appetite and nausea. The mortality rate within 30 days after surgery was 0, and no tumor metastasis was observed. Conclusion Pembrolizumab combined with neoadjuvant chemotherapy is safe and feasible to treat non-small cell lung cancer, and the short-term efficacy is beneficial.
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Objective@#To investigate the mechanism of vascular endothelial growth factor(VEGF) inducing tolerogenic dendritic cells(DCs) in oral squamous cell carcinoma (OSCC).@*Methods@#The DCs were divided into four groups: Control group (DC), VEGF group (VEGF added into DC), Co-culture group (DC co-cultured with SCC7) and Anti-VEGF group (anti-VEGF antibody added into DC co-cultured with SCC7). Flow cytometry (FCM) was used to detect DC surface markers. To detect the effect of DC on proliferation activity of T lymphocyte, the experiment included five groups: Nc group (T lymphocyte), Control group (T lymphocyte added into DC), VEGF group (T lymphocyte + DC + VEGF), Co-culture group (T lymphocyte + DC + supernatant of SCC7) and Anti-VEGF group (T lymphocyte + DC + supernatant of SCC7 + anti-VEGF antibody). Subsequently, the mixed lymphocyte reaction(MLR) was conducted. The expression levels of indole-2, 3-doxygenase(IDO)and programmed cell death 1 ligand 1(PD-L1)in DC were detected by western blot, real time PCR and FCM respectively. For the cytotoxic lymphocyte (CTL) assay, SCC7 cells and CTLs were mixed and CTL-mediated SCC7 cells cytotoxicity was tested. The experiment included four groups: Control group (T lymphocyte + DC), IDO inhibition group (T lymphocyte + DC + IDO inhibitor), Anti-PD-L1 antibody group (T lymphocyte + DC + anti-PD-L1 antibody) and Combination group (T lymphocyte + DC + IDO inhibitor + anti-PD-L1 antibody). The SCC7 tumor-bearing mice treated with IDO inhibitor and the anti-PD-L1 antibody were sacrificed and the tumor inhibition rate and the spleen index were determined. @*Results@#Compared with Control group, exogenous VEGF or SCC7 co-culture inhibited the relative number of DC expressing CD11C, CD80, CD86, CD40 and MHC Ⅱ. The positive DCs were increased in the Anti-VEGF group compared with VEGF or Co-culture group. In VEGF or Co-culture group, the number of T cells stimulated by SCC7-pulsed DCs was decreased compared with Control group. However, the ability of Anti-VEGF group to induce T cell proliferation was significantly increased compared with VEGF or Co-culture group. Significantly increased expression of IDO and PD-L1 were observed in VEGF and Co-culture group. However, this was partially reversed by addition of anti-VEGF antibody into the co-culture system. Compared with Control group, the expressions of CD11C and CD86 in DC in both the IDO inhibition group and Anti-PD-L1 antibody group were increased, and were significantly higher in the Combination group compared with the single drug groups. The similar results were exhibited in MLR and CTL assay. In vivo, the results revealed that the tumors obtained from the mice in three experimental groups were smaller than those in the control group. Furthermore, the tumor volume of the Combination group was the smallest. The spleen index of each group was calculated and the results showed the spleen index of the three experimental groups was significantly higher than that of Control group.@*Conclusion@#VEGF in OSCC micro-environment inhibits the maturation and function of DC that are transformed into tolerogenic DC by high expression of IDO and PD-L1.
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With the development of small-molecule immunotherapy drugs, its combination with the programmed cell death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) antibodies would provide a new opportunity for cancer treatment. Therefore, targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity and considered as the next generation of tumor immunotherapy. In the present study, we investigated the anti-tumor role of salvianolic acid B (SAB) by regulating the PD-L1 level in tumors. Changes of total PD-L1 and membrane PD-L1 levels were determined by Western blot, flow cytometry and PD-1/PD-L1 interaction assays. The expression of mRNA level of PD-L1 was detected by real-time PCR. The cytotoxicity of activated peripheral blood mononuclear cell (PBMC) cells toward co-cultured tumor cells was measured by cell impedance assay and crystal violet experiment. Surface plasma resonance technique was used to analyze the direct interaction between SAB and ubiquitin carboxyl-terminal hydrolase 2 (USP2). The antitumor effect of SAB in vivo was examined by C57BL/6 mice bearing MC38 xenograft tumor (all animal experiments were conducted in accordance with the Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences). Western blot and flow cytometry assay showed that SAB can significantly downregulate the abundance of PD-L1 in RKO and PC3 cells in dose- and time-dependent manner. PD-1/PD-L1 binding assay revealed that SAB reduces the binding of tumor cells to recombinant PD-1 protein. Mechanism studies revealed that SAB can bind directly to USP2 protein and inhibit its activity, thus promote the ubiquitin-proteasome pathway degradation of PD-L1 proteins. In addition, Cell impedance and crystal violet staining indicated that SAB enhances the killing activity of co-cultured PBMC cells toward tumor cells. MC38 tumor transplanted mouse experiments revealed that SAB treatment displayed significant suppression in the growth of MC38 tumor xenografts in C57BL/6 mice with an inhibition rate of 63.2% at 20 mg·kg-1. Our results demonstrate that SAB exerts its anti-tumor activity by direct binding and inhibiting the activity of USP2 and reducing the PD-L1 level. Our study provides an important material basis and scientific basis for the potential application of SAB in tumor immunotherapy drug targeting USP2-PD-L1 axis.
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Silicosis is a common occupational disease caused by long-term inhalation of large amounts of free SiO2 dust and deposition in lung tissues, characterized by the formation of silicon nodules and diffuse fibrosis of lung tissues. Silicosis is one of the most common and serious occupational diseases in China, and its treatment imposes a huge economic burden on individuals and the country. The formation mechanism of silicosis is very complex, and no early screening indicators, effective drugs, and treatment methods are available yet. The current diagnosis of silicosis is based on occupational history and chest radiography findings, and it is irreversible once pulmonary fibrosis develops. Moreover, as silicosis is a continuously progressive disease, even if silicosis patients stop exposure to free SiO2 dust, their pulmonary fibrosis will continue to develop and deteriorate. Programmed cell death (autophagy, apoptosis, ferroptosis, etc.) is a key factor involved in the development of silicosis. This article summarized the important roles of programmed cell death, including autophagy, apoptosis, and ferroptosis, in silicotic fibrosis, and concluded that regulating different programmed cell death and related signaling pathways through effective means may delay the process of silicosis fibrosis, providing new ideas and clues for exploring potential mechanisms of silicosis formation and formulating prevention and treatment strategies.
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Pyroptosis belongs to the programmed cell death of inflammatory cells, which is regulated by GSDMD (Caspase-1,-4,-5-11) and GSDME (Caspase-3, granzyme). Multiple regulatory pathways of pyroptosis are abnormally expressed in gastric cancer cells, indicating that pyroptosis is closely related to gastric cancer and has the potential to become a new target for gastric cancer treatment. Combined with current mainstream treatments such as chemotherapy and immunotherapy, it may improve clinical treatment effect of gastric cancer. This article reviews the molecular mechanism of pyroptosis, the related research on gastric cancer and pyroptosis, and the related research on pyroptosis and gastric cancer treatment to explore the possibility of pyroptosis as a new target for gastric cancer, and to provide new research ideas for gastric cancer treatment.
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Objective:To observe the dynamic changes of soluble programmed cell death protein 1 (sPD-1) and cellular immunity and humoral immunity in patients with sepsis and septic shock, and to explore the relationship between sPD-1 and immunosuppression in sepsis.Methods:This study was a prospective cohort study. Patients with sepsis and septic shock admitted to the ICU of General Hospital of Ningxia Medical University from June 2018 to December 2018 were included as the study subjects, ordinary postoperative patients admitted to the ICU during the same period were included as the non-sepsis group, and healthy volunteers matched in age and sex were included as healthy controls. The sPD-1, lymphocyte count, serum immunoglobulin and lymphocyte subsets of peripheral blood on the first, third and seventh days after admission to the ICU were detected. The changes of sPD-1 and various immune indices in each group were compared, and the correlation between the indices was analyzed. For healthy controls and non-sepsis patients, only blood samples were tested on the day of inclusion.Results:A total of 90 patients [58 males and 32 females, aged (58.36±17.46) years] were included in this study, including 29 cases of sepsis, 31 cases of septic shock, 15 cases of non-sepsis, and 15 volunteers were recruited as healthy control group. The 28-day fatality rate of patients in the sepsis and septic shock groups was 28.3%. On the first day of ICU admission, the sPD-1 concentration were significantly higher in the septic shock group and sepsis group than those in the non-sepsis group and healthy control group [512.64 (216.85, 1039.41) pg/mL vs. 261.90 (191.96, 421.99) pg/mL vs. 191.56 (151.26, 232.66) pg/mL vs. 200.51 (162.14, 241.26) pg/mL, all P<0.05]. The sPD-1 concentration in the septic shock group was significantly higher than that in the sepsis group, and this phenomenon persisted for at least one week ( P<0.05). The lymphocyte count on the first day in the sepsis and septic shock groups were significantly lower than those in the healthy control and non-sepsis groups (all P<0.05), and the lymphocyte count in the septic shock group remained lower levels until the seventh day of ICU admission (all P<0.05). The percentage of lymphocytes and total T lymphocytes in the sepsis and septic shock groups were significantly lower than those in the healthy control and non-sepsis groups (all P<0.05), while the percentage of total B lymphocytes did not differ between groups (all P>0.05). The percentage of CD8+ T lymphocytes on the seventh day of ICU admission in the septic shock group was still significantly lower than that in the sepsis group [(18.36±2.23)% vs. (28.28±2.97)%, P<0.05]. The levels of serum immunoglobulin IgG and IgM were significantly lower in the sepsis and septic shock group than those in the healthy control and non-sepsis groups (all P<0.05), and the IgG and IgM in the sepsis and septic shock groups returned to normal on the seventh day of ICU admission. The area under the ROC curve was used to evaluate the predictive value of sPD-1 on poor prognosis, and the results showed that sPD-1 on the seventh day of ICU had a good predictive value for 28-day prognosis in patients with sepsis and septic shock, and the best cut-off value was 286.52 pg/mL, with a sensitivity of 100.00% and specificity of 56.25%. Conclusions:Immunosuppression occurs in patients with sepsis and septic shock in the early stage, and the duration of immunosuppression in patients with septic shock is prolonged, but humoral immunosuppression plays a major defense in the early stage, and cellular immunosuppression is dominant in the later stage.
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Objective:To investigate the efficacy of programmed cell death-1 (PD-1) inhibitor combined with immunochemotherapy in the treatment of refractory primary mediastinal large B-cell lymphoma (PMBCL).Methods:The clinical data of 2 refractory PMBCL patients who were achieving remission after applying PD-1 inhibitor combined with immunochemotherapy in Qilu Hospital of Shandong University (Qingdao) in July 2019 and January 2020 were retrospectively analyzed, and the relevant literature was reviewed.Results:The two patients were initially treated with CDOPE and R-CDOPE regimens, respectively, but the disease did not reach remission state. Later, they were adjusted to PD-1 inhibitor combined with immunochemotherapy to achieve remission. Radiotherapy and autologous hematopoietic stem cell transplantation were used as consolidation treatment, and maintenance therapy with PD-1 inhibitors was effective and had a good safety profile.Conclusions:For refractory PMBCL patients, PD-1 inhibitor combined with immunochemotherapy may have good efficacy.