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 objectively evaluate the clinical efficacy and safety of acupuncture in regulating the mood of patients with post-stroke depression(PSD)and explore the possible target of acupuncture intervention.Methods 76 patients with PSD were randomly divided into treatment group and control group.The control group was treated with routine treatment measures for stroke,and the treatment group was treated with acupuncture on this basis.The main acupoints were Shangxing,Baihui,Shenting,Fengchi and Dugu,supplemented by acupuncture on Taichong,Hegu,Quchi,Neiguan,Yanglingquan,Zusanli and Taixi,5 times a week,continuously treated for 4 weeks,followed up on the 90th day after treatment.The levels of serum 5-hydroxytryptamine,norepinephrine and intestinal microflora before and after treatment were compared with the 17 Hamilton Depression Scale scores(HAMD),modified Barthel Index(MBI),and the levels of serum 5-hydroxytryptamine and norepinephrine before and after treatment.Results The HAMD score and MBI index of the two groups after treatment and follow-up were lower than those before treatment.The levels of 5-hydroxytryptamine and norepinephrine in the treatment group after treatment were higher than those before treatment(P<0.01),and significantly higher than those in the control group(P<0.01).After acupuncture,the dominant bacterial groups of Bacteroides,Thick-wall bacteria and Broughter bacteria in patients showed an upward trend(P>0.05).The difference of bacteria before and after treatment was mainly concentrated in signal pathways such as ECM-receptor interaction,and the difference was statistically significant(P<0.01).Conclusion Acupuncture can help patients improve their ability of daily living,and also improve the relative abundance of intestinal flora in PSD patients to a certain extent,so as to regulate the levels of 5-HT and NE to relieve the depression of patients,which is worthy of promotion in clinical practice.

Objective:To measure the morphological parameters of the fetal vertebral centrum ossification centers (COC) in the second-third trimester using MRI susceptibility weighted imaging (SWI), and to explore the growth and development trajectory of the vertebrae.Methods:Fetus in the second-third trimester with normal vertebrae development were prospectively and continuously included in Shandong Provincial Hospital Affiliated to Shandong First Medical University from December 2015 to December 2021, and the SWI scanning of fetal spine was performed. The following morphometric parameters of the C4, T6, L3, S1 vertebrae COC were measured, including sagittal diameter, transverse diameter, height, cross-sectional area and volume. The linear and nonlinear regression analysis was used to derive the best-fit curve for each parameters and gestational age.Results:A total of 112 fetuses were recruited with gestatonal age 21-39 (29.4±3.9) weeks, including 30 cases of C4, 58 cases of T6, 92 cases of L3, 62 cases of S1. Fetal spine in utero with global curvature was kyphosis, presenting two primary curves (thoracic and sacral kyphosis). The morphological parameters sagittal diameter, transverse diameter, height, cross-sectional area and volume of C4 followed the quadratic polynomial rule during 25 to 38 weeks (R 2=0.938, 0.943, 0.952, 0.957, 0.982). During 21 to 38 weeks, the sagittal diameter, transverse diameter and height of the T6 followed the exponential growth pattern (R 2=0.915, 0.923, 0.849) and the growth of the area and volume followed the quadratic polynomial growth pattern (R 2=0.943, 0.961). The L3 followed the quadratic polynomial rule during 21 to 39 weeks (R 2=0.910, 0.916, 0.914, 0.942, 0.948) The sagittal diameter, transverse diameter and height of the S1 followed the linear growth pattern (R 2=0.905, 0.911, 0.922) and the area and volume followed the quadratic polynomial growth pattern (R 2=0.930, 0.964) during 23 to 39 weeks. Conclusions:The growth and development of C4, T6, L3 and S1 COC of fetus in the second-third trimester has a good correlation with gestational age. The growth of fetal vertebral COC in the early stage is slow, but with the growth of gestational age, the growth rate of vertebral bodies accelerates.

Pregnancy ; Female ; Humans ; Pregnancy Outcome ; Cross-Sectional Studies ; Lupus Erythematosus, Systemic/epidemiology* ; Pregnancy Complications/epidemiology* ; Menstruation Disturbances