ABSTRACT
Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients. Here, we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells, especially myeloid derived suppressor cells (MDSCs) and CD8+ T cells. Then, peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique, and its mutant peptide VS3 was obtained by molecular docking based mutation. Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition, and elicit anti-tumor activity in vivo. The peptide DVS3-Pal was further designed by d-amino acid substitution and fatty acid modification, which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8+ T cell function and decreasing MDSCs infiltration. This is the first study to develop peptides to block VISTA/PSGL-1 interaction, which could act as promising candidates for cancer immunotherapy.
ABSTRACT
The protein tyrosine phosphatase Src homology phosphotyrosyl phosphatase 2 (SHP2) is implicated in various cancers, and targeting SHP2 has become a promising therapeutic approach. We herein described a robust cross-validation high-throughput screening protocol that combined the fluorescence-based enzyme assay and the conformation-dependent thermal shift assay for the discovery of SHP2 inhibitors. The established method can effectively exclude the false positive SHP2 inhibitors with fluorescence interference and was also successfully employed to identify new protein tyrosine phosphatase domain of SHP2 (SHP2-PTP) and allosteric inhibitors. Of note, this protocol showed potential for identifying SHP2 inhibitors against cancer-associated SHP2 mutation SHP2-E76A. After initial screening of our in-house compound library (∼2300 compounds), we identified 4 new SHP2-PTP inhibitors (0.17% hit rate) and 28 novel allosteric SHP2 inhibitors (1.22% hit rate), of which SYK-85 and WS-635 effectively inhibited SHP2-PTP (SYK-85: IC
ABSTRACT
Tryptophan 2,3-dioxygnease 2 (TDO2) is specific for metabolizing tryptophan to kynurenine (KYN), which plays a critical role in mediating immune escape of cancer. Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers, its tumor-promoting role in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we observed that TDO2 was overexpressed in ESCC tissues and correlated significantly with lymph node metastasis, advanced clinical stage, and unfavorable prognosis. Functional experiments showed that TDO2 promoted tumor cell proliferation, migration, and colony formation, which could be prevented by inhibition of TDO2 and aryl hydrocarbon receptor (AHR). Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model, tumor burden of C57BL/6 mice with ESCC induced by 4-NQO, enhance the expression of phosphorylated AKT, with subsequent phosphorylation of GSK3
ABSTRACT
To investigate the role of prokineticin (PROK) 1 and prokineticin-receptor (PROKR) 1 in the pathogenesis of endometriosis and its clinical signifaicance. Methods: Quantitative real-time PCR (qPCR) and Western bloting were used to detect the expression of PROK 1 and PROKR 1 in eutopic and ectopic endometrium of endometriosis (n=22) and normal control endometrium (n=18). Endometrial stromal cells were isolated and cultured in 6 normal controls. The expression of PROK 1 mRNA was detected by qPCR after treated with estradiol (E2) or TNF-α. Results: PROK 1 and PROKR 1 mRNA were expressed in eutopic and ectopic endometrium of endometriosis and normal control endometrium, and the expression level gradually declined (P<0.05). The expression of PROKR-1 protein in eutopic and ectopic endometrium of endometriosis and normal control endometrium gradually declined (P<0.05). The expression of PROK-1 protein in normal control endometrial cells and eutopic endometrium cell was higher in secretory phase than in proliferative phase (P<0. 05). E2 did not change the expression of PROK 1, whereas TNF-α up-regulated the expression of PROK 1. Conclusion: PROK-1 and its receptors are involved in the pathogenesis and development of endometriosis. TNF-α can promote angiogenesis via up-regulating the expression of PROK 1.
Subject(s)
Female , Humans , Endometriosis , Endometrium , Gastrointestinal Hormones , Metabolism , RNA, Messenger , Receptors, G-Protein-Coupled , Metabolism , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived , MetabolismABSTRACT
Objective To improvethe control of infection source by improving the continuous quality of sputum disposal management. Methods PDCA method based on the management of tuberculosis sputum disposal of the hospital quality improvement. The cross-sectional survey of tuberculosis ward in 32 cases of hospital patients, as control group.PDCA first round of "sputum cup distribution and use of work flow" for quality improvement,the reason leading the work flow of workers to nurse led work flow,the improved cross-sectional survey in 36 cases of hospital patients as experimental group 1.Aiming at the problem of low utilization rate of special sputum cup in the improvement of the first round of PDCA,the improvement of the sputum cup was carried out,On this basis, the "special sputum disposal Cup" was designed to obtain the national patent authorization. After the second round of improvement, the cross-sectional investigation in 35 patients in the hospital,as the experimental group 2.Results After two rounds of PDCA improvement,experimental group 2 groups compared with control,bedside sputum cup configuration was not in place rate decreased from 53.1% (17/32)to 0,the difference was statistically significant(Χ2=24.916,P<0.05);configuration after the sputum cup unused rate from 53.1%(17/32)down to 8.6%(3/35),the difference was statistically significant(Χ2=15.846,P<0.05).Conclusion PDCA method can improve the quality of management standard sputum disposal. Ward sputum cup ration is standardized sputum disinfection ward-based nurse intervention and leading sputum cup release, ward can improve the sputum cup ration, improved sputum containers (sputum cup) can improve patient compliance standard of spitting.
ABSTRACT
Objective To investigate the clinical value of tissue and blood long noncoding RNA(lncRNA) detection in the patients with hepatocellular cancer(HCC).Methods The HCC tissue sample,blood sample, suspected HCC puncture sample and blood sample from the persons undergoing healthy physical examination were selected for conducting the study.The six lncRNAs which were more than 5-fold expression amount were picked out in the 338 transcripts with abnormal high expression.The expression amount of lncRNA AK057037 in HCC tissue and serm tissue was detected by using the real time quantitative polymerase chain reaction and in situ hybridization.Then the results were statistically analyzed.Results The six lncRNAs were highly ex-pressed in the tissues and blood of the liver cancer,and the difference was statistically significant(P<0.05). Compared with healthy people,the relative expression of AK057037 in the tissues and blood of the liver cancer increased significantly,and the relative expression level in tumor and paracancerous tissues was statistically significant(P<0.05).As the tumor progresses,the relative expression of AK057037 was further enhanced. There was a higher relative expression in advanced liver cancer especially,and the difference was statistically significant(P<0.05).The results of the receiver operating characteristic curve showed that the area under curve of AK057037 was 0.834(95% CI 0.705-0.918)in the blood specimen,and its diagnostic efficiency was better than that of commonly used nucleic acid marker miR-29a.Conclusion lncRNA AK057037 is highly ex-pressed in HCC sample and blood,and can be used for clinical detection of HCC.
ABSTRACT
Objective To explore the effect of psychological nursing on anxiety and depression and quality of life of patients with multi drug resistant pulmonary tuberculosis.Methods 58 patients with multi -drug resistant pulmonary tuberculosis were randomly divided into observation group and control group,29 cases in each group.The control group received routine nursing care,the observation group received psychological nursing on the basis of the control group.Before and after psychological nursing intervention,the self rating anxiety scale(SAS)and depression self rating scale(SDS),health survey(SF -36)score were observed,and the clinical curative effect and compliance of the two groups were observed.Results After psychological nursing intervention,the SAS and SDS scores of the observation group[(36.83 ±7.61)points and (40.07 ±5.49)points]were significantly lower than the control group [(44.07 ±9.16)points and (43.90 ±7.91)points],the differences were statistically significant(t =3.27,2.14,all P <0.05).The SF -36 scores showed that after psychological nursing intervention,the physiological function(PF), physiological functions(RP),general health(GH),vitality(VT),social function(SF),role emotional(RE),mental health(MH),the seven dimensions scores of the observation group were significantly higher than those in the control group,the differences were statistically significant(t =7.18,10.22,8.85,12.71,12.04,9.68,4.79,all P <0.05). The compliance of the observation group was 93.10%,which of the control group was 72.41%,the difference was significant(χ2 =4.35,P <0.05).The total effective rate of the observation group was 86.21%,which of the control group was 62.07%,the difference was statistically significant(χ2 =4.41,P <0.05).Conclusion The psychological nursing intervention can improve the anxiety and depression of patients with multi -drug resistant tuberculosis, improve the quality of life of patients,improve the treatment compliance of patients,and improve the clinical efficacy.