Backgrounds and aims: As a central event during liver fibrosis, hepatic stellate cells (HSC) have been thought to be a potential therapeutic target for liver fibrosis. Previous studies have shown that runt‐related transcription factor 2 (Runx2) is associated with the development of non‐alcoholic fatty liver disease, while its specific role in HSC activation and hepatic fibrosis remains elusive.Approach and results: In this study, we found that Runx2 expression was significantly upregulated in human liver fibrosis with different aetiologies. Runx2 expression was also gradually elevated in mouse liver during fibrosis, and Runx2 was mainly expressed in the activated HSC. Knockdown of Runx2 in HSC markedly alleviated CCl₄‐induced, 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine‐induced or methionine‐choline deficient (MCD)‐induced liver fibrosis, while hepatic overexpression of Runx2 via HBAAV‐Runx2 or VA‐Lip‐Runx2 injection exacerbated CCl₄‐induced liver fibrosis. In vitro analysis demonstrated that Runx2 promoted HSC activation and proliferation, whereas Runx2 knockdown in HSC suppressed these effects. RNA‐seq and Runx2 ChIP‐seq analysis demonstrated that Runx2 could promote integrin alpha‐V (Itgav) expression by binding to its promoter. Blockade of Itgav attenuated Runx2‐induced HSC activation and liver fibrosis. Additionally, we found that cytokines (TGF‐β1, PDGF, EGF) promote the expression and nuclear translocation of Runx2 through protein kinase A (PKA) in HSC.Conclusions: Runx2 is critical for HSC activation via transcriptionally regulating Itgav expression during liver fibrosis, and may be a promising therapeutic target for liver fibrosis.

Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

Background. Receptor activator of nuclear factor‐κB (NF‐κB) ligand (RANKL) is significant in the activation of inflammation. Runt‐related transcription factor 2 (Runx2) promotes the hepatic infiltration of macrophages in nonalcoholic fatty liver disease (NAFLD). We studied how RANKL affects Runx2‐triggered macrophage infiltration in NAFLD. Method. 30 male C57BL/6J mice at 4 weeks of age were utilized in this study, 20 mice received a high‐fat diet (HFD), and 10 mice received standard rodent chow over 8 months. The histopathologic features of the liver were identified by H&E, Oil red O, and Masson staining. Runx2, RANKL, and F4/80 were analyzed by western blot, real‐time PCR, and immunohistochemistry in vivo, respectively. Lentivirus or siRNA was utilized for transwell assay to investigate the role of RANKL in Runx2‐induced macrophage migration in vitro. Results. Compared to controls, during NAFLD development, HFD increased Runx2 and RANKL in vivo in NASH (P < 0.01). Meanwhile, a correlation between the expression of Runx2 and RANKL (P < 0.05) was evident. In addition, the hepatic infiltration of macrophages was increased upon HFD feeding, and analysis showed that the macrophage infiltration was correlated with the expression of Runx2 or RANKL (P < 0.05). In vitro, we found that overexpression or deficiency of Runx2 increased or decreased the production of RANKL in mHSCs. Then, transwell assay revealed that RANKL was involved in Runx2‐induced macrophage migration. Conclusions. Overall, RANKL is involved in Runx2‐triggered macrophage migration during NAFLD pathogenesis, which may provide an underlying therapeutic target for NAFLD.

Background: BRCA2 mutation has a more substantial impact on the homologous recombination and superior therapeutic response to platinum-based chemotherapy than BRCA1 mutation. Whether BRCA2-mutated patients could benefit more from PARPi than BRCA1-mutated patients remains unclear. We performed a meta-analysis to assess the efficacy difference of PARPi between BRCA1 mutation carriers and BRCA2 mutation carriers.Methods: Pubmed, Embase, and Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) of PARPi that had available hazard ratios (HRs) of progression-free survival (PFS) in both BRCA1-mutated population and BRCA2-mutated population. We calculated the pooled PFS HRs and 95%CI using randomized-effect models, and the difference between the two estimates was compared by interaction test.Results: A total of 11 eligible RCTs of high quality were identified through search. Overall, 1544 BRCA1 mutation carriers and 1191 BRCA2 mutation carriers were included in the final analysis. The pooled PFS HR was 0.42 (95% CI: 0.35-0.50) in BRCA1-mutated patients who were treated with PARPi compared with patients in the control group. In BRCA2-mutated patients treated with PARPi, the pooled PFS HR compared with the control groups was 0.35 (95% CI: 0.24-0.51). The difference in efficacy of PARPi was not significant between the two subgroups (P_{heterogeneity} = 0.40, for interaction).Conclusion: BRCA1-mutated patients and BRCA2-mutated patients could benefit from PARPi, and the efficacy is comparable. Currently, there is no evidence that BRCA2-mutated patients would benefit more from PARPi than BRCA1-mutated patients.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020214582.

Observational studies report some association between circulating bilirubin levels and osteoporosis, but it is unknown if this association is causal or confounded. In this two-sample Mendelian randomization (MR) study, we included a large genome-wide association study (GWAS) associated with total bilirubin levels among 317,639 people, a large meta-analysis to identify genetic variants associated with bone mineral density (BMD) estimated by heel quantitative ultrasound (eBMD) among 426,824 individuals and fracture among 1.2 million individuals. The results revealed that circulating bilirubin levels had no causal influence on eBMD (beta-estimate: 0.004, 95% confidence interval [CI]: -0.019 to 0.028, SE:0.012, P-value=0.705) or the risk of fracture (beta-estimate: -0.009, 95% CI: -0.035 to 0.017, SE:0.013, P-value=0.488), which were both confirmed by multiple sensitivity analyses. Our results confirm that circulating bilirubin levels have no causal role in eBMD or the incidence of fracture, indicating that circulating bilirubin levels is unlikely to be a causal risk factor for osteoporosis or fracture.