Advances in treatment of immune-related adverse reactions and hyperprogressive diseases associated with antitumor immunotherapy with PD-1/PD-L1 monoclonal antibody drugs / 中国药理学与毒理学杂志

There have been breakthroughs in the development and clinical application of immuno-therapeutic agents in recent years.As the clinical targets of second-generation immune checkpoint inhibitors(ICIs),programmed death-1(PD-1)and its ligand(programmed death-ligand 1,PD-L1)have become one of the hot spots in drug discovery.The Food and Drug Administration of the USA and National Medical Products Administration in China have approved a variety of PD-1/PD-L1 monoclonal antibody drugs(such as nivolumab,pembrolizumab and atezolizumab),which are marketed for the treatment of small-cell lung cancer,rectal cancer,colon cancer,and melanoma,among other diseases.However,in the clinical application of PD-1/PD-L1 monoclonal antibody drugs,it is found that they can cause different degrees of immune-related adverse reactions in the lung,liver,kidney,gastrointestinal system,endocrine system and skin,and even the emergence of hyperprogressive disease.Effective monitoring and management of clinical applications of PD-1/PD-L1 monoclonal antibody drugs and rational use of some drugs can improve the immunotherapy process and reduce the effects of adverse reactions and hyperprogressive diseases in patients under immunotherapy.

Clinical study of Acupoint Pressing Therapy of Zang and Fu for the children with functional constipation and food retention of heat patterns / 国际中医中药杂志

Objective:To observe the clinical efficacy, safety and recurrence rate of Acupoint Pressing Therapy of Zang and Fu in the treatment of children with functional constipation.Methods:A total of 120 children with functional constipation form the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine from January 2020 to June 2021, were divided into two groups randomly, 80 in observation group and 40 in control group. Both groups were treated with routin therpy. The observation group was treated with Acupoint pressing therapy of Zang and Fu, and the control group was treated with Xiaoerhuashi syrup. Both groups were treated for 2 weeks. Before and after treatment, TCM syndromes were scored, daily defecation and spontaneous defecation response were recorded, and the efficacy was evaluated. The patients were followed up for 4 weeks and the recurrence was recorded.Results:Seventh and 14th day after treatment, the effective rates of TCM syndrome efficacy in the observation group were 87.5% (70/80) and 92.5% (74/80), and 62.5% (25/40) and 80.0% (32/40) in the control group. The scores of main symptoms, secondary syndromes and total scores of TCM syndromes in the observation group were significantly lower than those in the control group ( P<0.01 or P<0.05) at 7th day ( t values were 2.90, 2.77 and 3.93) and 14th day ( t values were 4.24, 5.95 and 6.27) after treatment. The effective rates of the observation group was 83.8% (67/80) and that of the control group was 65.0% (26/40). The difference between the two groups was statistically significant ( χ2=5.38, P=0.020). In the follow-up, the recurrence rate of the observation group was 9.5% (7/74) and that of the control group was 18.8% (6/32). There was no significant difference between two groups ( χ2=1.79, P=0.181). Conclusion:Acupoint Pressing Therapy of Zang and Fu has the advantages of curative effect, low recurrence rate and safety in the treatment of children's functional constipation.

The classification and clinicopathological analysis of hepatocellular adenoma based on immunohisto-chemistry / 中华肝胆外科杂志

Objective The subtypes of hepatocellular adenoma (HCA) were classified by immuno-histochemical study, and the clinicopathological characteristics of each subtype were analyzed. Methods From December 2003 to March 2018, 31 cases with HCA were retrieved from the archive files of the Depart-ment of Pathology, Peking Union Medical College Hospital, including 16 male patients and 15 female patients. The age ranged from 16 to 63 years. Hematoxylin and eosin ( HE) and immunohistochemical staining were performed with HCA samples. The subtypes were classified by immunohistochemical staining, and the clinicopathological characteristics of each subtype were analyzed. Results The HCA patients had no obvious and specific clinical symptoms, and most of them were diagnosed during the routine health checkup. All of the 31 patients were treated with surgery, and the complete resection was achieved in 26 cases. The adenomas were mainly in the right lobe of the liver (51. 6% , 16/31), and the solitary adenoma accounted for 54. 8% (17/31). 8 HCA were classified as H-HCA, 14 as I-HCA, 7 as β-HCA, and 2 as U-HCA by immunohistochemistry. H-HCA was characterized histologically by marked steatosis and lobulated contours, lacking L-FABP staining. I-HCA exhibited inflammatory infiltrate, telangiectasia, thickened arteries, more or less obvious ductular reaction, with the positive L-FABP/SAA/CRP staining. β-HCA all showed fibrous capsules, some of adenomas exhibited pseudoglandular structure and nodules in nodule. A strong homogeneous cytoplasmic overexpression of GS and nuclear β-catenin were observed in all β-HCA cases. The staining of SAA/CRP/GS was lacking in the U-HCA. Conclusions HCA is rare and difficult to diagnose in clinic. Final diagnosis relies on histological features, and immunohistochemical examinations need to be used for subtyping classification. Each of the four subtypes has characteristic pathological features.

The influence of the toll-like receptor-4 signaling pathway on IFN-γ and PDGF-AB expressions in the synthesis and secretion of pulmonary artery smooth muscle cells of COPD rats / 实用医学杂志

Objective To study the function of the toll-like receptor-4 (TLR-4) signaling pathway in the synthesis and secretion of pulmonary artery smooth muscle cells of rats with COPD. Methods The primary pulmonary artery smooth muscle cells (PASMCs) of rats with COPD were digested, separated and purified. Then they were randomly divided into control group, LPS group, TLR4 inhibitor group (TAK242) and LPS + TLR4 inhibitor group. RT-PCR, Western blot were used to detect the expression level of TLR-4 and NF-κB among groups. The levels of IFN-γ and PDGF-AB in supernatant with PASMCs in each group were detected by ELISA. Results LPS increased the expression of TLR-4、 NF-κB and the levels of IFN-γ and PDGF-AB. The expression of TLR4, NF-κB and the levels of IFN-γ and PDGF-AB were significantly reduced after inhibiting the expression of TLR4(P < 0.05). Conclusion TLR-4 signaling pathway involved in the inflammatory response and pulmonary vascular remodeling which increased the synthesis and secretion of IFN-γ and PDGF-AB in PASMCs. It provides a theoretical approach for the early intervention of clinical with COPD.

The dose-effect relationship of folic acid on human umbilical vein endothelial cells in vitro / 天津医药

Objective To investigate the protective effects of folic acid on the oxidative damage that ox-LDL (oxi?dized low-density lipoprotein receptor 1) render to human umbilical vein endothelial cells (HUVEC). Methods HUVECs were injured by ox-LDL (120 mg/L) for 24 h while they were incubated with various concentration of folic acid (0,15, 60, 150, 225, 300, 375 nmol/L). Then HUVECs were cultured in media contains same concentration of folic acid but without ox-LDL for 72 hours. Finally, HUVECs were harvested after 24, 48, 72 and 96 h. The morphological changes were observed us?ing inverted microscope and cell viability were examined by MTT. Results Various concentrations of folic acid (0,15, 50, 100, 200 and 500 nmol/L) has no obvious promotion or inhibition effect in growth of normal HUVEC (P>0.05). However, compared with the ox-FA-def group, 150, 225, 300 and 375 nmol/L of folic acid promoted proliferation of HUVECs with 96 and 120 hours of incubations (P < 0.05). Folic acid of 60, 150, 225, 300 and 375 nmol/L promoted the proliferation of HUVECs with 72 h and 96 hours of incubation (P<0.05). Conclusion High dose folic acid can reduce the ox-LDL oxida?tive damage on HUVEC in a concentration dependent manner.

Polymeric nanoparticles with therapeutic gene for gene therapy: I. Preparation and in vivo gene transfer study / 生物医学工程学杂志

VEGF nanoparticle (VEGF-NP) was prepared by a multi-emulsification technique using a biodegradable poly-dl-lactic-co-glycolic (PLGA) as matrix material. The nanoparticles were characterized for size, VEGF loading capacity, and in vitro release. VEGF-NP and naked VEGF plasmid were intramuscularly injected into the ischemia site of the rabbit chronic hindlimb ischemia model and the efficiency of VEGF-NP as gene delivery carrier for gene therapy in animal model was evaluated. Gene therapuetic effect was assessed evaluated by RT-PCR, immunohistochemistry and angiography assay. The average size of VEGF-NP was around 300 nm. The encapsulation efficiency of VEGF was above 96%. Loading amount of VEGF in the nanoparticles was about 4%. In vitro, nanoparticles maintained sustained-release of VEGF for two weeks. Two weeks post gene injection the capillary density in VEGF-NP group (81.22 per mm2) was significantly higher than that in control group (29.54 mm2). RT-PCR results showed greatly higher VEGF expression in VEGF-NP group (31.79au * mm) than that in naked VEGF group (9.15 au * mm). As a carrier system for gene therapy in animal model, VEGF-NP is much better than naked DNA plasmid. The results demonstrate great possibility of using NP carrier in human gene therapy.

Generation of recombinant human tissue factor pathway inhibitor in E. coli / 生物医学工程学杂志

Tissue factor pathway inhibitor (TFPI) is one of the major physiological inhibitors of the human blood coagulation cascade and may have great potential in the prevention and therapy of diseases caused by thrombus formation. In this study, recombinant human tissue factor was generated in E. coli containing a recombinant vector constructed by inserting TFPI cDNA into pGEX-2T vector. The generated recombinant TFPI (rTFPI) could be simply purified with glutathione-agarose affinity method and maintained its biological function in terms of inhibition of tissue factor and factor Xa.