Host metabolome predicts the severity and onset of acute toxicities induced by CAR T-cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B-cell lymphoma. However, widespread use is deterred by the development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), that induce significant morbidity and require close monitoring. Identification of host biochemical signatures that predict the severity and time-to-onset of CRS and ICANS may assist patient stratification to enable timely mitigation strategies. Here, we report pretreatment host metabolites that are associated with CRS and ICANS induced by axicabtagene ciloleucel or tisagenlecleucel therapy. Both untargeted metabolomics analysis and validation using targeted assays revealed a significant association between the abundance of specific pretreatment biochemical entities and an increased risk and/or onset of clinically significant CRS (q < .1) and ICANS (q < .25). Higher pretreatment levels of plasma glucose and lower levels of cholesterol and glutamate were associated with a faster onset of CRS. In contrast, low baseline levels of the amino acids proline and glycine and the secondary bile acid isoursodeoxycholate were significantly correlated with clinically significant CRS. Lower concentration of the amino acid hydroxyproline was associated with higher grade and faster onset of ICANS, whereas low glutamine was negatively correlated with faster development of ICANS. Overall, our data indicate that the pretreatment host metabolome has biomarker potential in determining the risk of clinically significant CRS and ICANS, and may be useful in risk stratification of patients before anti-CD19 CAR T-cell therapy.

Design, synthesis, and evaluation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based novel dual kinase inhibitors of CK2 and GSK3ß.

Casein kinase 2 (CK2) and glycogen synthase kinase-3beta (GSK3ß) are responsible for the phosphorylation of a tumor suppressor protein (PTEN) in a cooperative manner which causes its deactivation. Thus, it is essential to inhibit both kinases simultaneously to prevent PTEN deactivation more efficiently. In this study, we have designed a novel lead from Hit15 which was identified in silico as a dual kinase inhibitor against CK2 and GSK3ß through our previous study. The dataset of structural analogs of the lead was designed and confirmed by pharmacophore mapping and molecular docking. The screened analogs were considered further and a series of "tetrahydrobenzo[d]thiazoles" were synthesized. Compound 1g has shown highest dual kinase inhibitory activity at a concentration of 1.9 µM against CK2 and 0.67 µM against GSK3ß. Our results suggest that the presence of a carboxyl group at the meta position of the phenyl ring plays a vital role in dual kinase inhibition.

Protective effect of methanolic extract of Garcinia indica fruits in 6-OHDA rat model of Parkinson's disease.

CONTEXT: Several studies have reported that antioxidants play an important role in Parkinson's disease (PD). Garcinia indica extract is a natural antioxidant, the present study was undertaken to evaluate the neuroprotective effect of methanolic extract of Garcinia indica (GIM) against 6-hydroxydopamine (6-OHDA) neurotoxicity for striatal dopaminergic neurons in the rat. MATERIALS AND METHODS: Thirty adult Wistar rats were randomly divided into five groups namely control, 6-OHDA model, and GIM (100, 200, and 400 mg/kg body weight suspended in one ml of 0.1% carboxymethyl cellulose). The treatment was started three days before surgery and continued for next 14 days. The surgery was done on third day in all groups for administration of 6-OHDA into the right striatum and right substantia nigra, whereas control group injected with 6-OHDA vehicle. Various behavior and biochemical tests (Apomorphine-induced rotational behavior, Stepping test, Initiation time, Postural balance test, and Disengage time) were used to evaluate the neuroprotective effect of GIM. One-way analysis of variance (ANOVA) followed by Dunnett's test was used to compare inter-group differences. P<0.05 was considered as statistically significant. RESULTS: GIM had significant (P<0.05, P<0.01) preventive effect in biochemical tests, i.e., dopamine and its metabolites measurement and in various behavior tests, i.e., apomorphine-induced rotational behavior, stepping test, initiation time, postural balance test, and disengage time as compared to 6-OHDA-treated rats. CONCLUSIONS: Our results demonstrated that GIM acted as an effective neuroprotective agent for striatal dopaminergic neurons in 6-OHDA lesioned rat model of PD.