Evaluation of Efficacy and Prognosis Analysis of Stage III-IV SMARCA4-deficient Non-small Cell Lung Cancer Treated by PD-1 Immune Checkpoint Inhibitors plus Chemotherapy and Chemotherapy / 中国肺癌杂志

BACKGROUND@#The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC.@*METHODS@#46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC.@*RESULTS@#Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC.@*CONCLUSIONS@#Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.

Effects of herbal cake separated moxibustion on Tim-4 and ubiquitination of PD-1 in rabbits with immunosuppression / 中国针灸

OBJECTIVE@#To observe the effects of herbal cake separated moxibustion on macrophage effector molecule T-cell immunoglobulin and mucin-domain containing-4 (Tim-4) and ubiquitination of programmed cell death protein 1 (PD-1) in rabbits with immunosuppression, and to explore the possible mechanism on herbal cake separated moxibustion in improving immunosuppression.@*METHODS@#Thirty-two big-ear white rabbits were randomly divided into a normal group, a model group, a moxa stick moxibustion group and a herbal cake separated moxibustion group, 8 rabbits in each group. Except the normal group, the immunosuppression model was established by intraperitoneal injection of cyclophosphamide of60 mg/kg in the other 3 groups. "Shenque" (CV 8), "Shenshu" (BL 23), "Zusanli" (ST 36), etc. were selected in both the moxa stick moxibustion group and the herbal cake separated moxibustion group. Moxa stick moxibustion was applied in the moxa stick moxibustion group, one cone at each acupoint; herbal cake separated moxibustion was applied in the herbal cake separated moxibustion group, 5 cones at each acupoint. The intervention was given once every other day for 10 times in both groups. Leukocyte content in peripheral blood was detected by blood cell analyzer; the positive expression of PD-1 in CD+4 T lymphocytes, CD+8T lymphocytes and CD+68 macrophages in peripheral blood was measured by flow cytometry, the serum levels of interleukin 2 (IL-2), CD8, CD68 and Tim-4 were detected by ELISA, and the expression of Tim-4 and F-box only protein 38 (FBXO38) in the liver and spleen tissues was measured by immunohistochemistry.@*RESULTS@#Compared with the normal group, in the model group, white blood cell count (WBC) and percentage of neutrophils (NEU%) were decreased while percentage of lymphocyte (LYM%) was increased (P<0.01) in peripheral blood; the positive expression rates of PD-1 in CD+4 T lymphocytes, CD+8T lymphocytes and CD+68 macrophages in peripheral blood were increased (P<0.01); the serum levels of IL-2, CD68 and Tim-4 were increased (P<0.01), the serum level of CD8 was decreased (P<0.01); the average optical density (AOD) of Tim-4 in the liver tissue and FBXO38 in the liver and spleen tissues was increased (P<0.01). Compared with the model group, in the moxa stick moxibustion group and the herbal cake separated moxibustion group, WBC and NEU% were increased (P<0.01); the positive expression rates of PD-1 in CD+4 T lymphocytes, CD+8T lymphocytes and CD+68 macrophages in peripheral blood were decreased (P<0.01); the serum levels of IL-2, CD68 and Tim-4 were decreased (P<0.01), the serum levels of CD8 were increased (P<0.01); the AOD of Tim-4 and FBXO38 in the liver tissue and FBXO38 in the spleen tissue was decreased (P<0.01, P<0.05). Compared with the moxa stick moxibustion group, in the herbal cake separated moxibustion group, the positive expression rate of PD-1 in CD+68 macrophages in peripheral blood was increased (P<0.05); serum level of Tim-4 was increased (P<0.01); AOD of Tim-4 in the liver tissue was decreased (P<0.05).@*CONCLUSION@#Herbal cake separated moxibustion can improve immunosuppression by regulating the expression of macrophage effector molecule Tim-4 and the FBXO38 mediated ubiquitination of PD-1, Tim-4 may be one of the specific indexes of immunomodulation involving with herbal cake separated moxibustion.

Association of circulating levels of soluble PD-1, PD-1 gene polymorphisms with HBV infection and HBV infection-associated hepatocellular carcinoma / 中华预防医学杂志

Objective: To investigate the association of circulating sPD-1 level and PD-1 gene polymorphisms with HBV infection and HBV infection-associated hepatocellular carcinoma. Methods: A case-control study was conducted. A total of 237 chronic HBV infection cases and 138 HBV infection-associated hepatocellular carcinoma in the Department of Infectious Diseases of the First Hospital of Shanxi Medical University from 2018 to 2021 were selected as the case group. About 250 individuals who visited a hospital physical examination center for routine physical examination during the same period were selected as the control group. Plasma sPD-1 levels were measured by using an ELISA kit and genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The association of sPD-1 levels and PD-1 polymorphisms with HBV infection as well as HBV infection-associated hepatocellular carcinoma was analyzed by using logistic regression models after adjusting for age, sex, alcohol consumption, smoking, ALT and AST levels. The sPD-1 level and PD-1 polymorphisms were independent variables, and HBV infection was the dependent variable. Results: The age of 237 chronic HBV infections, 138 HBV infection-related liver cancer case subjects and 250 control subjects in the study was (49.1±10.8), (51.9±12.7) and (50.7±11.9) years, respectively. Multivariate logistic regression model analysis showed that with a 1 pg/ml increase in sPD-1 level, the OR (95%CI) values for the risk of incident HBV infection cases and HBV hepatocellular carcinoma cases were 1.92 (1.68-2.19) and 2.02 (1.69-2.40). For rs2227981, compared with the CC genotype, the TT genotype had a lower risk of HBV infection and liver cancer associated with HBV infection, with OR (95%CI) values of 0.45 (0.22-0.91) and 0.35 (0.14-0.91). For rs2227982, compared with the CC genotype, the CT and TT genotypes also had a lower risk of HBV infection [OR (95%CI) values of 0.72 (0.53-0.97) and 0.57 (0.35-0.93)] and HBV infection-related liver cancer [OR (95%CI) values of 0.64 (0.45-0.92) and 0.52 (0.29-0.93)]. Conclusions: Plasma sPD-1 levels and PD-1 gene polymorphisms are associated with HBV infection and HBV infection-associated hepatocellular carcinoma.

Expert Consensus on Tumor Mutational Burden for Immunotherapy in Lung Cancer / 中国肺癌杂志

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in the world. Immune checkpoint inhibitors (ICIs), including programmed cell death 1 (PD-1) antibody, programmed cell death ligand 1 (PD-L1) antibody, and cytotoxic T lymphocyte associated protein 4 (CTLA-4) antibody. It has brought significant survival benefits to some patients with advanced lung cancer and changed the treatment pattern of advanced lung cancer. Previous studies have shown that the objective response rate of PD-1/PD-L1 antibody in advanced non-small cell lung cancer (NSCLC) is only about 20%. So reliable biomarkers are urgently needed to screen out the potential benefit population of ICIs and improve the clinical response rate. Tumor mutational burden (TMB) is an emerging biomarker of immunotherapy in addition to PD-L1 expression. There is little correlation between PD-L1 expression and TMB in lung cancer. It is estimated that TMB can expand the benefit population of immunotherapy. However, in clinical practice, the detection of TMB, the determination of cut-off value and the clinical guidance strategy are still not standardized. This consensus will give guiding suggestions on the detection and application scenarios of TMB, so as to promote the standardization of TMB application for immunotherapy in lung cancer.
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PD-1 expression, mRNA level and cytotoxicity changes in CD19CAR-T cells / 中华血液学杂志

Objective: To observe the changes of PD-1 expression, mRNA level and cytotoxic activity of CD19 CAR-T cells during the culture process of CAR-T cells. Methods: The peripheral blood T cells of 6 lymphoma patients with high expression of PD-1 and 6 healthy volunteers were the source of CAR-T cells. The expression of PD-1 was analyzed by flow cytometry. The mRNA level of PD-1 was analyzed by PCR. The cell proliferation was analyzed by CCK-8 assay. The cytotoxicity was analyzed by LDH assay. Results: ①The transfection efficiency of high PD-1 expression T cells and healthy volunteer T cells were as the same (P>0.05) . ②The cell proliferation capacity of CD19 CAR-T cells from high PD-1 expression T cells or healthy volunteer T cells, with or without PD-1 inhibitor were as the same (P>0.05) . ③The cytotoxicity to lymphoma cells of high PD-1 expression T cells and CAR-T cells were lower than that of these two T cells combined with PD-1 inhibitor and the CAR-T cells from healthy volunteer T cells (P<0.001) . There was no difference of the cytotoxicity between the CAR-T cells from high PD-1 expression T cells combined with PD-1 inhibitor and the CAR-T cells from healthy volunteer (P>0.05) . ④There was no difference of the expression of PD-1 in all CAR-T cell groups during the culture process (P>0.05) . There was no difference of mRNA level of PD-1 in all groups during the culture process (P>0.05) . ⑤The PD-1 expression of CAR-T cells increased by the time of culture after contacting with lymphoma cells (P<0.001) . The PD-1 inhibitors could antagonize this effect. There was no difference of mRNA level of PD-1 in all groups after contacting with lymphoma cells (P>0.05) . Conclusion: The PD-1 expression of CAR-T cells from high PD-1 expression T cells increased by the time of culture after contacting with lymphoma cells. However, the mRNA level of PD-1 of all groups did not change, even if PD-1 inhibitor was applied.

Phenotypic Characteristics of PD-1 and CTLA-4 Expression in Symptomatic Acute Hepatitis A

BACKGROUND/AIMS: The immunoregulatory molecules programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with the dysfunction of antiviral effector T-cells, which leads to T-cell exhaustion and persistent viral infection in patients with chronic hepatitis C and chronic hepatitis B. Little is known about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A (AHA). METHODS: Peripheral blood mononuclear cells were isolated from seven patients with AHA and from six patients with nonviral acute toxic hepatitis (ATH) during the symptomatic and convalescent phases of the respective diseases; five healthy subjects acted as controls. The expression of PD-1 and CTLA-4 on T-cells was measured by flow cytometry. RESULTS: PD-1 and CTLA-4 expression during the symptomatic phase was significantly higher in the T-cells of AHA patients than in those of ATH patients or healthy controls (PD-1: 18.3% vs 3.7% vs 1.6%, respectively, p<0.05; CTLA-4: 23.5% vs 6.1% vs 5.9%, respectively, p<0.05). The levels of both molecules decreased dramatically during the convalescent phase of AHA, whereas a similar pattern was not seen in ATH. CONCLUSIONS: Our findings are consistent with a viral-protective effect of PD-1 and CTLA-4 as inhibitory molecules that suppress cytotoxic T-cells and thereby prevent the destruction of virus-infected hepatocytes in AHA.

Acarbose versus trans-chalcone: comparing the effect of two glycosidase inhibitors on obese mice

Objective Acarbose and trans-chalcone are glucosidase inhibitors whose beneficial effects have been demonstrated in diabetes. The present study aimed at investigating their potential effects in obesity.Materials and methods NMRI male mice (n = 48) were subjected to a high fat diet for four weeks, which induced an initial state of obesity. One control group was given normal rodent diet. Obese animals were then switched to normal rodent diet, and divided to four groups (n = 12 in each): untreated, sham (receiving grape seed oil), and experimental groups receiving acarbose and trans-chalcone (12 mg/kg) during eight weeks. Body weight, blood glucose and other biochemical parameters including triglycerides (TG), cholesterol, HDL, AST, and ALT were measured, as well as leptin, adiponectin, TNF-α, and total antioxidant capacity (TAC). Histological studies were performed on adipose cells and liver tissue samples.Results All factors were affected in a positive manner by acarbose, save for body weight, blood sugar and leptin levels, on which acarbose effects, although observable, were not statistically significant. Grape seed oil, used as a solvent for trans-chalcone was found to possess significant effect on TG and TAC, and had beneficial effects on other factors including liver enzymes and cholesterol. Trans-chalcone effects were significant on HDL, leptin and ALT. All compounds seemed to be able to affect fat deposition in liver tissue, and decrease the size of adipose tissue cells to some extent.Conclusion In conclusion, the tested compounds were able to affect lipid accumulation in tissues and influence adipokines, which may result in an enhanced state with regard to inflammation and oxidative stress. Arch Endocrinol Metab. 2015;59(3):202-9.

Frecuencia del polimorfismo PD-1.3 del gen del receptor de muerte celular programada 1 (PD-1) y su asociación con diabetes tipo 1 / Frequency of polymorphism PD-1.3 of programmed cell death 1 (PD-1) and their association with type 1 diabetes

Background: The programmed cell death 1 (PDCD-1) immune-receptor is a key element in the negative regulation of peripheral tolerance in T cells. The gene has several polymorphisms and can be associated with susceptibility to autoimmune diseases. Aim: To analyze the frequency and distribution of PD-1.3 polymorphism of PDCD-1 gene and explore its possible contribution as a susceptibility gene for type 1 diabetes (T1D). Patients and Methods: We analyzed 248 cases with T1D with recent diagnosis and 160 control children under 15 years of Santiago. Genetic polymorphism in PD-1 gene variant for PD-1.3 (rs 11568821) was analyzed by polymerase chain reaction and restriction fragment length polymorphism. Comparison of genotype, allele frequency and consistency with respect to Hardy-Weinberg were analyzed using X2 tests and Fisher exact test. Results: There was a very low frequency of the genotype A/A, both in T1D patients and in controls (< 2 percent). The A/G genotype was more common in diabetic patients than in controls (41.6 and 18.8 percent respectively, p < 0.04). G/G genotype was more common in controls than in patients (79.4 and 56.8 percent respectively, p < 0.02). T1D patients carrying genotype G/G had a higher frequency of anti-GAD65 and anti-A-2 antibodies (81 and 67 percent respectively). Conclusions: The distribution of PD-1.3 genotype frequencies are similar to that reported elsewhere. Possibly, this genetic variant (rs 11568821) does not have an important marker role in Chilean T1D patients.