Relationship between subtype-specific minimal residual disease level and long-term prognosis in children with acute lymphoblastic leukemia.

Minimal residual disease (MRD) based risk stratification criteria for specific genetic subtypes remained unclear in childhood acute lymphoblastic leukemia (ALL). Among 723 children with newly diagnosed ALL treated with the Chinese Children Leukemia Group CCLG-2008 protocol, MRD was assessed at time point 1 (TP1, at the end of induction) and TP2 (before consolidation treatment) and the MRD levels significantly differed in patients with different fusion genes or immunophenotypes (P all < 0.001). Moreover, the prognostic impact of MRD varied by distinct molecular subtypes. We stratified patients in each molecular subtype into two MRD groups based on the results. For patients carrying BCR::ABL1 or KMT2A rearrangements, we classified patients with MRD < 10-2 at both TP1 and TP2 as the low MRD group and the others as the high MRD group. ETV6::RUNX1+ patients with TP1 MRD < 10-3 and TP2 MRD-negative were classified as the low MRD group and the others as the high MRD group. For T-ALL, We defined children with TP1 MRD ≥ 10-3 as the high MRD group and the others as the low MRD group. The 10-year relapse-free survival of low MRD group was significantly better than that of high MRD group. We verified the prognostic impact of the subtype-specific MRD-based stratification in patients treated with the BCH-ALL2003 protocol. In conclusion, the subtype-specific MRD risk stratification may contribute to the precise treatment of childhood ALL.

Theoretical Insights into the Cotransport Mechanism of GSH with Anticancer Drugs by MRP1.

The multidrug resistance protein MRP1 is an ATP binding cassette (ABC) transporter that confers resistance to many anticancer drugs and regulates redox homeostasis, inflammation, and hormone secretion. MRP1 actively transports compounds across cell membranes, and the presence of glutathione (GSH) is required in many cases. However, the process of MRP1-mediated substrate transportation has been poorly understood. With extensive molecular dynamics simulations, we have found a sandwich-like structure which is generated by GSH, a transmembrane α-helices 11 (TM11)-TM17 axis, and anticancer drugs. This structure is crucial in MRP1 transportation. It triggers the motion of TM11 and TM17, followed by the movement of nucleotide-binding domains 1 (NBD1) and 2 (NBD2), and finally an occluded structure is formed. Trp1246, Lys332, and Phe594 were identified as the main contributors in the formation of the sandwich-like structure. Our findings clearly explain the synergy of GSH with an anticancer drug in MRP1 transportation and have significant meanings for the rational design of novel inhibitors against MRP1.

Metabolic detoxification of bakuchiol is mediated by oxidation of CYP 450s in liver microsomes.

Bakuchiol, one of bioactive compounds isolated from the dried ripe fruits of Psoralea corylifolia L., possesses a variety of pharmacological activities. In this study, the metabolites of bakuchiol in rat liver microsomes as well as their cytotoxicities were studied. A total of eight metabolites were isolated and identified as 14-carboxylbakuchiol (M1), 14,15-dihydroxybakuchiol (M2), 12,13-dihydroxybakuchiol (M3), 15-hydroxybakuchiol (M4), 14-hydroxybakuchiol (M5), bakuchiol hydrate (M6), 15-hydroxybakuchiol acetate (M7), and 14-hydroxybakuchiol acetate (M8). All the metabolites are new compounds except for M3. The main type of biotransformation is oxidation reaction, including hydroxylation, epoxidation and carboxylation. Cytotoxicities of bakuchiol and its metabolites against human kidney-2 (HK-2) cell line were evaluated. The median inhibition concentration (IC50) values of bakuchiol, M4, M6 and M8 were (29.48 ± 0.22) µM, (67.51 ± 6.80) µM, (90.23 ± 3.89) µM, and (86.62 ± 6.08) µM, respectively, and the IC50 values of M1, M2, M3, M5, and M7 were all in excess of 100 µM. To further verify the metabolic reliability, the metabolits of bakuchiol in vivo and the metabolic species variations in human and rat liver microsomes were studied using UPLC-MS/MS method. This study provides valuable information for further investigation of metabolism and toxicity of bakuchiol in vivo.

[Toxicokinetics of bakuchiol, hepatic and renal toxicity in rats after single oral administration of Psoraleae Fructus and combination with Glycyrrhizae Radix et Rhizoma].

To study the toxicokinetics of bakuchiol, hepatic and renal toxicity in rats after single oral administration of Psoraleae Fructus and combined with Glycyrrhizae Radix et Rhizoma, in order to provide scientific evidences for clinical safe medication use. A total of 35 SD rats were randomly divided into seven groups: vehicle (distilled water) control group, Glycyrrhizae Radix et Rhizoma group, positive control (aristolochic acid A) group, Psoraleae Fructus (40 g x kg(-1)) group( both male and female rats), Psoraleae Fructus and Glycyrrhizae Radix et Rhizoma (40 +20) g x kg(-1) group (both male and female rats). HPLC-UV method was used to determine the concentration of bakuchiol in rat plasma at different time points after single oral administration. Plasma alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), plasma creatinine (Cr), N-acetyl-ß-D-glucosaminidase (NAG) and kidney injury molecule 1 (Kim-1) were measured after administration for 24 h. The main toxicokinetics parameters of bakuchiol in rats exert significantly gender difference. When Psoraleae Fructus combination with Glycyrrhizae Radix et Rhizoma, the total area under the plasma concentration-time curve( AUC), C(max), and plasma clearance (CL) of bakuchiol were increased, respectively; CL, half-life (t½) were decreased, and T(max) were prolonged. The biochemical indicators (including ALT, AST, BUN, Cr and KIM-1 level) in different dose of Psoraleae Fructus groups, were found no statistically significant difference when compared with vehicle control group. The level of NAG in both Psoraleae Fructus and compatibility with Glycyrrhizae Radix et Rhizoma groups were significant increased (P < 0.05). There are obvious effects on toxicokinetics of bakuchiol in rats when Psoraleae Fructus combined with Glycyrrhizae Radix et Rhizoma. Renal toxicity induced by Psoraleae Fructus at high dose was observed after single oral administration and no liver damage in rats was found.