Objective To investigate the effect of external abdominal aorta compression on circulation during anesthetic induction in elderly patients. Methods A prospective randomized controlled trial was conducted. Patients with age of 60-75 years old, requiring a general anesthesia for non-abdominal surgery, and with Ⅱ-Ⅲ class of American Society of Anesthesiologists (ASA) physical status classification, and admitted to General Hospital of Chinese People's Armed Police Forces from January to April in 2017 were enrolled. They were divided into abdominal aorta pressure group and control group according to random number method, with 20 patients in each group. In both groups, anesthesia was induced with midazolam, propofol, fentanyl and cisatracurium, and was maintained with propofol, remifentanil and cisatracurium. After successful intubation, the anesthesia machine was changed into mechanical ventilation. The patients in abdominal aorta pressure group were given abdominal aorta pressure 1 minute after induction of general anesthesia with midazolam till 5 minutes after intubation. The mean arterial pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO2) were observed before anesthesia induction, immediately after anesthesia induction, immediately after intubation, 5 minutes and 10 minutes after intubation, respectively. The incidence of hypotension or bradycardia, and usage of ephedrine or atropine were recorded. Results There were no significant differences in MAP [mmHg (1 mmHg = 0.133 kPa): 83.6±4.7 vs. 82.9±4.7], HR (bpm: 67.3±5.9 vs. 65.9±5.7) and SpO2 (0.962±0.007 vs. 0.960±0.009) before anesthesia induction between abdominal aorta pressure group and control group (all P > 0.05). Immediately after anesthesia induction, the MAP and HR in control group were significantly decreased as compared with those before anesthesia induction [MAP (mmHg): 70.0±8.7 vs. 82.9±4.7, HR (bpm): 60.7±6.7 vs. 65.9±5.7, both P < 0.05], and they were also significantly lower than those of abdominal aorta pressure group [MAP (mmHg): 83.1±3.9, HR (bpm): 66.8±4.9, both P < 0.05]. Immediately after intubation, the MAP and HR in control group were significantly increased as compared with those immediately after anesthesia induction [MAP (mmHg): 78.9±7.9 vs. 70.0±8.7, HR (bpm): 67.3±2.7 vs. 60.7±6.7, both P < 0.05], but the changes in MAP and HR in abdominal aorta pressure group were not obvious. During the anesthesia induction period, there was no statistical difference in SpO2 change between the two groups. During induction of anesthesia, no adverse reaction was found in the abdominal aorta pressure group, but 4 patients with hypotension and 2 patients with bradycardia were found in the control group. Two patients with hypotension were treated with ephedrine, and 2 patients with bradycardia were treated with atropine. Conclusion Anesthesia induction of elderly patients with abdominal aorta pressure can help maintain hemodynamic stability.

PD-1 and CTLA-4 antibodies offer great hope for cancer immunotherapy. However, many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient immune activation. The combination of checkpoint blockers has been proposed to increase the response rates. Besides, antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration problems. In this study, we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting LAG-3. As a result, C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR (MHC-II). Additionally, C25 could significantly stimulate CD8 T cell activation in human PBMCs. The results also demonstrated that C25 could inhibit tumor growth of CT26, B16 and B16-OVA bearing mice, and the infiltration of CD8 T cells was significantly increased while FOXP3 Tregs significantly decreased in the tumor site. Furthermore, the secretion of IFN- by CD8 T cells in spleen, draining lymph nodes and especially in the tumors was promoted. Simultaneously, we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide, and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects CD8 T cells but not direct killing. In conclusion, cyclic peptide C25 provides a rationale for targeting the immune checkpoint, by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity, and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.

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.

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