Multiple antigen specific cell therapy(Hengrui Yuanzheng Bio-Technology Co., Ltd.)

A group of 5-methylsalicylaldehyde thiosemicarbazone derivatives (HMTs) bearing different lipophilic and steric substituents attached at the 3-position of cresol ring were synthesized and investigated as mushroom tyrosinase (TYR) inhibitors. The ability of HMTs to inhibit the diphenolase activity of TYR was evaluated with L-DOPA as substrate by determining IC₅₀ values in relation to their structure modifications. HMTs displayed distinct inhibitory competencies towards TYR activity with IC₅₀ values in the range of 1.02-143.56 μM. A close correlation between their inhibition potency and both lipophilicity and molecular size was observed. The inhibitory effect of the hydroxyethyl-containing derivatives was much higher than the hydroxyethyl-free ones overall. Among them, HMT-NBO exhibited the most potent effect with IC₅₀ of 5.85 μM, which was nearly 25-fold and 3.8-fold lower than its parent HMT-NBE and the control kojic acid, respectively. The hydroxyethyl clearly benefited the improvement of the inhibitory competences and acted as a regulating group of lipophilicity of the inhibitors. The kinetic analyses showed that HMTs were reversible and mixed type inhibitors against mushroom TYR. The inhibition mechanism was studied by means of fluorescence spectroscopy, FT-IR, ESI-MS and molecular docking analysis. The results indicated that the observed inhibitory effect of HMTs was accomplished by acting on the amino acid residues rather than by chelating the centre copper ions of TYR. Each of HMTs can insert the hydrophobic pocket and interact with the residues of TYR through Van der Waals forces and hydrogen bonds, with additional electrostatic interactions for HMT-NEE and HMT-NEO further strengthening the affinity. Meanwhile, the inhibitors were observed to bind with L-DOPA or/and L-DOPAquinone forming 1:1 stoichiometric complexes, probably exerting indirect inhibition against TYR activity.

Background & Aims: The prognosis of hepatocellular carcinoma (HCC) remains poor and available treatment options are limited. This retrospective study evaluated the efficacy of Multiple Antigen Stimulating Cell Therapy (MASCT) as an adjuvant therapy for the treatment of HCC after curative treatment. Methods: Patients who underwent HCC curative treatments were classified into two groups: the MASCT group, in which patients received MASCT treatment after curative treatment (n = 47), and the control group, in which patients did not receive any treatment after curative treatment (n = 99). Patients who received ≥ 5 courses of MASCT treatment before recurrence or death (n = 26) were further stratified into a subgroup (multiple-course MASCT group) for analysis. The primary endpoint was overall survival (OS). The secondary endpoints were disease-free survival (DFS) and safety. Results: Kaplan-Meier analysis showed no statistically significant difference in OS between the MASCT group and the control group (P = 0.132), nor in DFS (P = 0.310) (median: 36.17 vs. 24.27 months). However, when comparing the multiple-course MASCT treated group to the control group, Kaplan-Meier analysis showed a significant difference in OS (P = 0.011), but not in DFS (P = 0.104) (median: 47.10 vs. 24.27 months). The overall incidences of treatment-related adverse events in the MASCT group and control group were 14.89% (7/47) and 19.19% (19/99), respectively. No MASCT treatment-related serious adverse events were reported. Conclusions: Although the MASCT group was not associated with significantly longer OS or DFS, the multiple-course MASCT group showed significantly improved overall survival after curative treatment, and the treatment procedures were well-tolerated. Multiple-course MASCT may therefore provide another choice for patients with HCC after curative treatment.