Background/Aims: Biliary tract cancer (BTC) frequently harbors KRAS mutations, which are associated with resistance to traditional treatment and a poor prognosis. Synthetic lethality (SL) strategy may provide other targets of KRAS. Therefore, we aim to identify and validate potential therapeutic targets of KRAS for the treatment of BTC via SL. Methods: The dependency (DepMap) projects were used to predict the synthetic lethal gene of KRAS. FDA-approved anticancer drug library was applied to screen potential drugs effective against KRAS-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using KRAS-mutant and KRAS-wild type BTC cell lines, patient-derived xenografts (PDX), and KRAS oncogene-driven tumor models, as well as other KRAS-mutant cancer cell lines. Results: Initially, we discovered that the loss of GATA2 reduced the viability of KRAS-mutant but not KRAS-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1β (IL-1β) in KRAS-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1β to promote NF-κB signaling in KRAS-mutant BTC. IL-1β inhibition phenocopied GATA2 deficiency, leading to reduced KRAS-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a KRAS oncogene-driven tumor model, as well as in other KRAS-mutant cancer cell lines. Conclusions In summary, these results indicate that inhibiting GATA2/IL1β could be a therapeutic strategy in KRAS-mutant BTC and potentially other cancers.

Objective:To evaluate the reliability and validity of the Chinese version of the Edinburgh visual gait score (EVGS-CN) for children with cerebral palsy.Methods:The EVGS-CN was established following international guidelines for translation and cross-cultural validation of health status questionnaires. Videos of 30 children with cerebral palsy were assessed independently by six raters (with different levels of experience in gait analysis) using the EVGS-CN. Inter- and intra- observer reliability were evaluated using intraclass correlation coefficients (ICCs). The correlation analysis and group comparison were used to test the technique′s criteria-related validity, convergent validity, and discriminant validity.Results:The ICC values of the 17 items in the EVGS-CN ranged from 0.20 to 0.87 for inter-observer reliability, and from 0.41 to 0.90 for intra-observer reliability. Most items showed good inter- and intra-observer reliability among experienced raters, but only a moderate level when used by inexperienced raters. The EVGS-CN results were strongly correlated with those of physician rating scale (PRS) ( r=0.77, P≤0.001) and observational gait scale (OGS) ( r=-0.85, P≤0.001), moderately correlated with the total gross motor function measure-D/E (GMFM-D/E) score ( r=-0.55, P≤0.01), and strongly correlated with 10MWT times ( r=-0.69, P≤0.001) and timed up and go (TUG) times ( r=0.60, P≤0.001). Moreover, significant differences in average EVGS score were found between different gross motor function classification system (GMFCS) levels and between affected limbs on different sides. Conclusion:The EVGS-CN demonstrates satisfactory reliability and validity in evaluating children with cerebral palsy when it is used by an experienced or inexperienced rater.

OBJECTIVETo study major human UGT isoforms involved in trans-resveratrol (TR) phase II metabolism.

METHODtrans-resveratrol and 12 major human UGT isoforms were incubated in vitro and then glucuronic acid metabolites were determined by HPLC-MS, in order to preliminarily analyze the structure and observe the effect of different UGT isoforms on the generation rate of glucuronic acid metabolites.

RESULTIn in vitro metabolic system, two metabolites-4'-O-monoglucuronide resveratrol (M-1) and 3-0-monoglucuronide resveratrol (M-2)-were generated from trans-resveratrol after being catalyzed by UGT. During the cause, generation of M-1 and M-2 were catalyzed by UGT1A1, UGT1A3, 1A8, 1A9 andlA10, whereas only UGT1A6 and 1A7 contributed to the forma-tion of M-2. Both the formation rate of M-1 and M-2 catalyzed by UGT1A1, 1A10 and the formation of M-2 catalyzed by UGT1A8 slowed down with the increasing concentration of substrates, causing the phenomenon of "substrate inhibition".

CONCLUSIONUGT1A1, 1A8, 1A9, 1A10 get involved in the formation of M-1, and of them UGTIA9 is the most important contributor. UGT1A3 also makes small contribution to the formation of M-1 and M-2, while other UGT isoforms show hardly any reaction with the trans-resveratrol phase II metabolites.

Glucuronic Acid ; metabolism ; Glucuronosyltransferase ; metabolism ; Humans ; Isoenzymes ; metabolism ; Kinetics ; Stilbenes ; chemistry ; metabolism

OBJECTIVEStudy the effect of self-microemulsifying drug delivery system(SMEDDS) on the solubility and absorption of tanshinones to guide the selection of composition of tanshinone SMEDDS.

METHODThe solubility of tanshinones in the solution of SMEDDS was determined by UV-spectrometer and the absorption of tanshinone SMEDDS was determined by HPLC as the detection method.

RESULTThe solubility of tanshinones in solution of SMEDDS was 10 times in water and 2.5 times in micelle solution. The solubility of tanshinones in solution of SMEDDS was increased with the increasing of oil (MCT) in composition of tanshinone SMEDDS. The absorption constants (Ka) in SMEDDS and micelle solution was 0.479 h(-1) and 0.326 h(-1) respectively, and the absorption half life (t1/2) was 1.44 h and 2.12 h respectively. The absorption was increased with the oil increasing in composition of tanshinone SMEDDS.

CONCLUSIONSMEDDS can increase the solubility and absorption of tanshinones significantly and the increasing of oil content (MCT) in SMEDDS composition promote the dissolution and absorption of tanshinones.

Animals ; Diterpenes, Abietane ; Drug Delivery Systems ; methods ; Emulsions ; Intestinal Absorption ; drug effects ; Male ; Phenanthrenes ; chemistry ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Solubility