Objective To evaluate the effectiveness of three neurological assessments in experimental autoim?mune encephalomyelitis. Methods Thirty-two female C57BL/6 mice (18-20g) were randomly divided into normal group (n=15) and immune group (n=17). Immune group were induced subcutaneously in the flank by emulsion consisted of MOG33-35 and complete Freund’s adjuvant. Mice were assessed by two investigators for 35 days after immunization in a blinded manner using Kono’s 5-point criterion, Weaver’s 15-point criterion and improved 15-point criterion. Based on H&E staining, we analyzed the accuracy, sensibility and dependency of three assessments. Results 35-day clini?cal-score plots revealed that the fluctuation of symptoms was more obvious in improved 15-point criterion compared with the other two criteria. 15-point criterion and improved 15-point criterion are more accurate than 5-point criterion in atypical-onset EAE. 15-point criterion and improved 15-point criterion could detect the neurological deficits much earli?er than 5-point criterion (P<0.001). Neurological scores assessed by improved 15-point were well correlated with the pathological findings during the peak and remission stage. Conclusion Improved 15-point criterion is better neurological score system than Kono’s 5-point criterion and Weaver’s 15-point criterion because of its accurate assessment of the neurological deficits in experimental autoimmune encephalomyelitis.

OBJECTIVE: To study the mechanism and clinical significance of specific immunotherapy (SIT) on the expression changes of GM-CSF and IL-5 in the tissue samples of recurrent nasal polyps. METHOD: Perennial allergic rhinitis patients with recurrent nasal polyps were randomly divided into 2 groups. The experimental group of 19 patients was treated by SIT and standardized treatment (glucocorticoid nasal spray) , and the control group of 17 patients was only treated by standardized treatment (glucocorticoid nasal spray). We measured the expression levels of GM-CSF and IL-5 in the tissue samples of the nasal polyps by ELISA, and compared the results obtained before treatment with expression levels detected at 6 months and 1 year after the treatment. RESULT: The expression of GM-CSF and IL-5 in the recurrent nasal polyps reduced significantly (P < 0.05) in both groups after 6 months and 1 year post-treatment compared with pre-treatment, and the expression of GM-CSF and IL-5 in the experimental group was much lower than that of the control group. CONCLUSION SIT decreases the expression of GM-CSF and IL-5 and reduces the inflammatory reaction in the tissue samples of recurrent nasal polyps.
Enzyme-Linked Immunosorbent Assay ; Granulocyte-Macrophage Colony-Stimulating Factor ; metabolism ; Humans ; Immunotherapy ; Inflammation ; drug therapy ; Interleukin-5 ; metabolism ; Nasal Mucosa ; pathology ; Nasal Polyps ; drug therapy ; metabolism ; Rhinitis, Allergic, Perennial ; drug therapy ; metabolism

Objective: To evaluate the efficacy and safety of portal vein stenting combined with 125I particle strand implantation followed by drug-eluting beads transarterial chemoembolization (DEB-TACE) and molecular-targeted therapy for the treatment of stageⅢa liv-er cancer lacking a blood supply. Methods: A retrospective analysis of 11 patients who had stageⅢa liver cancer lacking a blood sup-ply combined with portal vein tumor thrombosis (PVTT) was conducted from October 2016 to October 2018. All the patients under-went portal vein stenting combined with 125I particle strand implantation, DEB-TACE, and comprehensive treatment containing molecu-lar-targeted drugs. During the follow-up period, all patients were evaluated for stent patency after the implantation and tumor re-sponse after DEB-TACE treatment. The liver function and blood routine changes before and 1 month after the surgery were completed, and the complications were summarized. Results: All 11 patients were judged as stageⅢa liver cancer based on the Chinese staging criteria (2017), Child-Pugh classification grade A and B. The imaging findings indicated that these tumors were hypovascular. The maxi-mum diameter of these lesions was (8.4±4.1) (2.8-14.1) cm, and all patients had PVTT. Among them, there were 4 cases of Cheng's typeⅡand 7 cases of typeⅢ: 6 cases of main PVTT≥50% and 1 case of PVTT<50%. All patients underwent portal vein stenting com-bined with 125I particle strand implantation, DEB-TACE, and comprehensive treatment containing molecular-targeted drugs. Three and 6 months after stent implantation, the patency rate was 100%; 3 months after DEB-TACE treatment, complete response was achieved in 4 (36.4%) patients, partial response was achieved in 5 (45.5%) patients, and stable disease was achieved in 2 (18.2%) patients. No patients exhibited progressive disease. Therefore, the objective response rate was 81.8% and disease control rate was 100%. As for the liver and kidney function and blood routine tests, there were no significant differences between baseline and 1 month after the sur- gery. In addition, no patient had any serious complication during the perioperative period. Conclusions: For patients with stageⅢa liv-er cancer lacking a blood supply and PVTT, a comprehensive treatment strategy including portal vein stenting combined with 125I parti-cle strand implantation, DEB-TACE, and molecular-targeted therapy can restore portal vein blood flow and maintain mid-and long-term stent patency, while effectively killing tumors and controlling tumor growth, which is a safe and effective treatment strategy.

Effective supervision of the clinical research management department can guarantee and improve the quality of the investigator initiated trials(IIT). The authors analyzed relevant clinical research regulations and literature and summarized the current situation of risk-based IIT project process quality management. On such basis, they determined the risk-based IIT project process quality management method in combination with the previous research of the research group.From 2021 to 2022, this method was used to implement process quality management for 353 IIT projects in Shanghai′s tertiary hospitals. More than 3 000 risk points were identified through centralized supervision, and then on-site supervision was carried out to correct the problems found. As proven by the results, the method could find existing problems in time and define the risk level of the project, and also formulate an individualized risk supervision plan accordingly, so as to effectively ensure the data reliability and scientific results. It is suggested that the clinical research management department implement risk based management for the whole process of IIT projects, increase funding and staffing, and implement hierarchical management for the projects by research types, so as to promote the sustainable development of IITs.

Adventitia ; Atherosclerosis/genetics* ; Cell Communication ; Humans ; Hyperhomocysteinemia/genetics* ; Sequence Analysis, RNA

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of K _d = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.