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Blocking immune checkpoint programmed cell death receptor 1 (PD-1) or programmed death receptor-ligand 1 (PD-L1) can enhance anti-tumor activity of effector T cells. However, the lack of response in many patients to PD-1/PD-L1 therapy remains a question. Improving the immunosuppressive tumor microenvironment (TME) to enhance the efficacy of immune checkpoint inhibitors has become a promising cancer treatment strategy. We constructed a liposome system (PD-L1/siCXCL12-Lp) of CXCL12 siRNA and anti-PD-L1 peptide with matrix metalloproteinases (MMPs) responsiveness, which combined the TME regulation of siCXCL12 and the immune regulation of anti-PD-L1 peptide. All animal experiments were approved by the Biomedical Ethics Committee of Peking University. The authors found that PD-L1/siCXCL12-Lp directly down-regulated the expression of CXCL12 in vitro (33.8%) and in vivo (15.5%). It also effectively increased the ratio of CD8+/Treg by 20.0%, which helped the anti-PD-L1 peptide to better exert its immune effect. The combination therapy significantly inhibited tumor growth (52.08%) with great safety, which explored a new idea for cancer immunotherapy.
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OBJECTIVE@#The current difficulties in the treatment of tumor include repeated administration and high recurrence rate after tumor resection. In order to reduce the number of doses, avoid side effects of chemotherapeutic drugs, suppress tumor growth and delay tumor recurrence after surgery, a temperature-sensitive in situ gel with paclitaxel microspheres (PTX/M gel) was prepared. PTX/M gel was administered by intratumoral injection once a month.@*METHODS@#First of all, paclitaxel microspheres (PTX/M) were prepared by emulsion solvent evaporation method. A laser particle size distribution analyzer was used to investigate the size, distribution, specific surface area of microspheres. Paclitaxel content was determined by high performance liquid chromatography (HPLC). Then encapsulation efficiency of paclitaxel was calculated and in vitro release characteristics were studied. Secondly, PTX/M gel was prepared by cold dissolution method. The phase transition temperature, elastic modulus, dissolution curve, correlation between dissolution and release were measured. Finally, U87 MG and 4T1 subcutaneous tumor models were established respectively to study the efficacy of PTX/M gel in suppressing tumor growth and delaying tumor recurrence after surgery.@*RESULTS@#The median diameter of the selected PTX/M was (32.24±1.09) μm, the specific surface area was (206.61±10.23) m2/kg, the encapsulation efficiency was 85.29%±1.34%, and the cumulative release percentage of paclitaxel from PTX/M was 33.56%±3.33% in one month. Phase transition temperature of PTX/M gel was 33 °C. The elastic modulus of PTX/M gel at 25 °C and 37 °C were 4.2×103 Pa and 18×103 Pa, respectively. The gel could stay in the body for up to 48 hours. It could be seen from the results of animal experiments that were compared with the saline group and the Taxol group, and the tumor-bearing mice of the PTX/M gel group had the slowest tumor growth (P<0.05). Similarly, in the tumor recurrence experiments, the mice of PTX/M gel group had the latest tumor recurrence after surgery.@*CONCLUSION@#As a local sustained-release preparation, PTX/M gel can effectively suppress tumor growth and delay postoperative recurrence of tumors. It has potential advantages in tumor treatment.
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Animais , Camundongos , Antineoplásicos Fitogênicos , Linhagem Celular Tumoral , Preparações de Ação Retardada , Microesferas , PaclitaxelRESUMO
Objectives: To evaluate the impact of nutritional states on mortality of acute myocardial infarction (AMI) patients by the controlling nutritional (CONUT) score. Methods: We performed a monocentric retrospective cohort study among AMI patients after percutaneous coronary intervention(PCI) and the median follow-up was 36(33, 36 interquartile range) months. The endpoint was all cause of death. Information was obtained by medical records, clinical visit and telephone calls.Patients were divided into three groups:normal(CONUT=0~1, n=304),mild malnutrition (CONUT=2~4, n=476) and moderate-severe malnutrition (CONUT=5~12, n=58) groups.The differences on mortality among groups were compared by Kaplan-Meier survival analysis. Results: 51 patients out of 838 patients died during follow up, 63.7% patients were in the malnutrition state according to the CONUT score.The mortality was 2.6%, 6.3%, and 22.4% in normal, mild malnutrition and moderate-severe malnutrition groups, respectively.The mortality was significantly higher in mild and moderate-severe groups than in normal group (P=0.021, P<0.001, respectively). The Cox proportional hazard analyses revealed that the risk of all cause of death of both mild and moderate-severe groups were significantly higher than in normal group in full-adjusted model (Mild HR[95%CI]:3.473[1.507-8.003] , P=0.003; moderate-severe HR[95%CI]: 10.775[3.958-29.334] , P<0.001). Conclusions: Malnutrition is a common phenomenon in AMI patients treated with PCI and relates to increased risk of all-cause mortality. CONUT score could be used to predict the risk of all-cause mortality in AMI patients undergoing PCI.
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Current researches find that malnutrition is related with prognosis of cardiovascular diseases .Evaluation tool of nutritional status is very important for early identification of malnutrition and active treatment .The present article made a brief review for relationship between malnutrition and cardiovascular diseases and current nutritional evaluation tool.
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Objective: To propose the feasibility of the vortex method of acid dye colorimetry replacing extraction method to determine the content of total alkaloids in plasma of rats after oral administration with Mahuang Decoction. Methods: The contents of total alkaloids in plasma of rats orally administered with Mahuang Decoction extracted by traditional extraction method and vortex method were determined by acid dye colorimetry, and the results were contrasted and analyzed. Results: The extraction method and vortex method had good linear relationship in the range of 4-40 and 4-80 μg/mL with the average recovery rates of 95.63% (RSD = 1.92%) and 111.55% (RSD = 0.26%), respectively. The regression equations established were A = 0.0171 C + 0.2355, r = 0.9855 and A = 0.0068 C + 0.0102, r = 0.9964. The metabolic processes of total alkaloids in rats were both complied with the one-compartment model. The main pharmacokinetic parameters AUC, Cmax, tmax, and t1/2 were 5.30 × 105 min·μg/mL, 57.13 μg/mL, 37.20 min, 6403.78 min and 1.94 × 106 min·μg/mL, 663.20 μg/mL, 361.90 min, 1756.87 min. The Cmax and AUC of vortex method were 11.61 times and 3.66 times compared with those of extraction method. Conclusion: The vortex method is more rapid, accurate, sensitive, simple, stable, safe, and reproducible and has little harm to laboratory assistants, which can extract the total alkaloids in maximum, with the necessity, scientificity, and practicality of replacing traditional extraction method.
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To prepare rivastigmine liposome, rivastigmine was loaded into liposome via ammonium sulfate gradient method. Its pharmacokinetic profile in rats was evaluated after intranasal administration. The size, zeta potential, entrapped efficiency and release of rivastigmine from the liposome in vitro were determined. Plasma concentration of rivastigmine was determined by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS) using antipyrine as internal standard. The pharmacokinetic parameters were calculated by DAS 2.0. The entrapped efficiency of rivastigmine liposome was (33.41 +/- 6.58) %, with the mean diameter of 154-236 nm and zeta potential of (-10.47 +/- 2.41) mV. The release behavior of rivastigmine was fitting the first order equation in vitro. The pharmacokinetic studies indicated that the C(max), T(max) and AUC(0-infinity), of rivastigmine liposome were (1.50 +/- 0.15) mg x L(-1), 15 min and (89.06 +/- 8.30) mg x L(-') x min, respectively. Rivastimine liposome was absorbed rapidly, and could reach a certain concentration in rat plasma after intranasal delivery.