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.

The adsorption of methylene blue (MB) in plasma on cross-linked agarose beads entrapped activated charcoal (CAAC-I), cross-linked agarose coated activated charcoal (CAAC-II) and cross-linked agar beads entrapped attapulgite (CAA) was tested in this study. These adsorbents are intended to be applied to blood purification for eliminating MB from virucidal MB-phototrated plasma units. The experimental results indicated that the adsorption of MB in plasma on CAAC-I and CAA was quick and efficacious, but it was slower on CAAC-II. The relationship between the adsorption time and the adsorption rate was examined with reference to the plasma with a specific concentration of MB flowing over a certain volume of CAA. A flow rate of about 1 ml.min-1 through 10 ml CAA at 25 degrees C could eliminate more than 95% of the MB in 200 ml human plasma (1 mumol.L-1).
Adsorption ; Agar ; chemistry ; Animals ; Charcoal ; chemistry ; Hemofiltration ; instrumentation ; Humans ; In Vitro Techniques ; Methylene Blue ; isolation & purification ; Rabbits

The leukocytic phagocytosis rate and the index of phagocytosis of rats on cross-linked agar beads entrapped attapulgite clay (CAA) hemoperfusion were studied. The results revealed that the leukocytic phagocytosis rate and the index of phagocytosis descended significantly after 1 hour and rose gradually after 6 hours. Finally it reached the normal level after 48 hours. Hemoperfusion repeated two times gave similar results. In conclusion, the function of leukocytic phagocytosis declined temporarily during CAA hemoperfusion. Many times hemoperfusion will not notably affect the body's defense system of rats.
Agar ; Animals ; Biocompatible Materials ; Hemoperfusion ; methods ; Leukocytes ; drug effects ; physiology ; Magnesium Compounds ; Male ; Materials Testing ; Microspheres ; Phagocytosis ; drug effects ; Rats ; Rats, Wistar ; Silicon Compounds

The preparation and properties of a new adsorbent cross-linked agar beads entrapped attapulgite clay (CAA) are reported in detail. Medicinal attapulgite clay made in China was encapsulated with agar, shaped in organic solvent, and cross-linked by epichlorohydrin . The products withstood autoclaving at 121 ℃ for half an hour with no breakage, and had a good selective adsorption ability for some model compounds and medicaments such as methylene blue and phenothiazine drugs. Preliminary investigations and SEM photographs indicate that the CAA as an adsorbent is relatively hemocompatible for hemoperfusion.