Genetic interactions reveal distinct biological and therapeutic implications in breast cancer.

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations.

[Effects of cordyceps acid and cordycepin on the inflammatory and fibrogenic response of hepatic stellate cells].

OBJECTIVE: To investigate the effects of cordyceps acid and cordycepin on the inflammatory phenotype and fibrogenic property of hepatic stellate cells (HSCs). METHODS: An immortalized mouse HSC line (JS1) was stimulated with lippolysaccharide (LPS; 100 ng/ml) to induce an inflammatory response with or without co-administration of cordyceps acid or cordycepin in various concentrations (10, 50, or 200 mumol/L). Effects of the treatments on the chemokine monocyte chemotactic protein-1 (MCP-1) mRNA expression in the cells and the protein secretion in the cell culture supernatants were determined by reverse transcription and real-time quantitative PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. In addition, JS1 cells were treated with transforming growth factor-b1 (TGFb1; 10 ng/ml) to induce a fibrogenic response with or without co-administration of cordyceps acid or cordycepin in various concentrations (10, 50, or 200 mumol/L). Effects on the expression of fibrogenic proteins including collagen type I and a-smooth muscle actin (a-SMA), were investigated by Western blot. RESULTS: High-concentration (200 mumol/L) treatments of both cordyceps acid and cordycepin significantly inhibited the LPS-induced up-regulation of MCP-1 transcription and secretion (mRNA: 2.07 +/- 0.29 vs. 3.35 +/- 0.26, t = 15.90 and 1.15 +/- 0.23 vs. 4.17 +/- 0.61, t = 8.93; protein: 1.88 +/- 0.06 vs. 2.33 +/- 0.06, t = 10.39 and 1.47 +/- 0.25 vs. 1.97 +/- 0.04, t = 4.60; all P less than 0.05). All concentrations of cordyceps acid and cordycepin inhibited the TGFb1-induced up-regulation of collagen type I and a-SMA protein expression. However, the effects were more robust with the 200 mumol/L concentrations (P less than 0.05). CONCLUSION: Cordyceps acid and cordycepin ameliorate the LPS-induced inflammatory phenotype and TGFb1-induced fibrogenic response of cultured HSCs. These effects may contribute significantly to the drugs' therapeutic mechanisms to inhibit and resolve liver fibrosis.

[HMGB1-mediated activation of TLR4 signaling in hepatic stellate cells].

To determine the potential of the high mobility group box-1 protein 1 (HMGB1) to activate Toll-like receptor 4 (TLR4) signaling in hepatic stellate cells (HSCs) and investigate the subsequent transition of HSC towards the inflammatory phenotype. Three immortalized mouse HSC cell lines, wild-type (JS1), TLR4-/- (JS2) and MyD88-/- (JS3), were subcultured in plates and divided into groups of normal control (untreated), postive control (lipopolysaccaride, LPS treatment), and experimental (HMGB1 treatment). All groups were transfected with luciferase reporter plasmids carrying responsive elements for either the nuclear factor-kappa B (NF-kB) or activator protein-1 AP-1 transcription factors. Following stimulation with normal saline, LPS (100 ng/mL) or HMGB1 (100 ng/mL), the activation of NF-kB or AP-1 was detected by a dual-luciferase reporter assay system. The induction of monocyte chemotactic protein-1 (MCP-1) transcription was determined by measuring the mRNA levels using real time quantitative reverse transcription PCR (qRT-PCR). The secreted protein levels of MCP-1 were determined by enzyme-linked immunosorbent assay (ELISA) of the culture supernatants. Activation of NF-kB- and AP-1-responsive reporters was significantly up-regulated in JS1 cells treated with HMGB1 or LPS, and the activation was coincident with markedly up-regulated transcription and secretion of MCP-1. However, HMGB1 and LPS treatment produced no responsive of the NF-kB and AP-1 reporters, and no increase in expression or secretion of MCP-1, in JS2 or JS3 cells. As an endogeous ligand of TLR4, HMGB1 may activate TLR4 signaling and the TLR4-mediated inflammatory response of HSC.

The study of anti-metabolic syndrome effect of puerarin in vitro.

Puerarin is an isoflavone extracted from Chinese plant, Pueraria lobata (Wild.) Ohwi. It has been reported to have comprehensive pharmacological action in treatment of diabetes and cardiovascular diseases. The purpose of this study was to link the scattered effects of puerarin and to find the common mechanisms underlying. We investigated the effect of puerarin on the pivotal common pathogenic factors of metabolic syndrome, which includes obesity, Type II diabetes and cardiovascular diseases. Recently, a large body of evidence indicates that there is a complicated interplay among insulin resistance, adipocytes and endothelial dysfunction that links the abnormalities of metabolic syndrome. Results of present study showed that puerarin could potentiate insulin-induced preadipocyte differentiation, promote glucose-uptake of adipocytes that have been induced insulin resistance by high glucose, and prevent TNF-a-induced apoptosis and viability loss of endothelial cells. Furthermore, we found that these effects are probably due to promote PPARgamma expression and partly through inhibiting abnormal TNF-a-induced intracellular-free Ca(2+) accumulation of endothelial cells. Overall, our synthetical study links the comprehensive pharmacological actions of puerarin to the recognized common pathogenesis of metabolic syndrome, and provides a new insight into the mechanism of puerarin effect.

Outcome of endoscopic submucosal dissection for early gastric cancer of conventional and expanded indications: systematic review and meta-analysis.

OBJECTIVE: Current guidelines for treating early gastric cancer (EGC) with endoscopic submucosal dissection (ESD) are being developed with broader criteria. This systematic review and meta-analysis aimed to assess the application of expanded indications (EIN) by comparing outcomes between conventional indication (CIN) and EIN groups. METHODS: Literature databases were searched. Short-term outcomes, including endoscopic resection rates, complications and local recurrence, and long-term outcomes including gastric cancer-specific mortality and overall mortality were compared in the two groups. RESULTS: In all, 13 studies were identified and evaluated. The EIN group had lower rates of en bloc (93.6% vs 97.0%, P < 0.0001), complete (87.8% vs 95.8%, P < 0.00001) and curative resection (82.4% vs 94.0%, P < 0.00001) than the CIN group. The rates of delayed bleeding and perforation were both significantly higher in the EIN group (3.9% vs 2.8%, P = 0.04 and 3.9% vs 1.8%, P < 0.0001). Local recurrence rates were 0.6% in the CIN group and 1.5% in the EIN group (P = 0.03). There were no significant differences between the two groups in the gastric-cancer specific mortality (P = 0.22) and the overall mortality (P = 0.37). CONCLUSIONS: Long-term mortality in the EIN group did not significantly differ from those in the CIN group, although the EIN group was associated with more unfavorable short-term outcomes. Thus, ESD could be recommended as an effective therapy for EGC of EIN.

Effects of astragaloside IV on pathogenesis of metabolic syndrome in vitro.

AIM: To investigate the diverse pharmacological actions of astragaloside IV from the perspective of metabolic syndrome, and to investigate the effect of the drug on the pathogenesis of metabolic syndrome. METHODS: Adipogenesis was used as an indicator of the effect of astragaloside IV on preadipocyte differentiation, and was measured by using an oil red O assay. Glucose uptake was determined by measuring the transport of [2-(3)H]-deoxyglucose into the cells. The concentrations of peroxisome proliferator-activated receptor-gamma (PPARgamma) and aP2 mRNA were determined by using reverse transcription-polymerase chain reaction. Apoptosis and viability loss of endothelial cells were detected by using flow cytometry and the WST-1 assay, respectively. Intracellular free Ca2+ was labeled with Fluo-3 AM and measured by using a laser scanning confocal microscope. RESULTS: Astragaloside IV can significantly potentiate insulin-induced preadipocyte differentiation at concentrations of 3, 10, and 30 microg/mL, improve high glucose-induced insulin resistance in adipocytes at a concentration of 30 microg/mL, and prevent tumor necrosis factor (TNF)-alpha-induced apoptosis and viability loss at concentrations of 10 and 30 microg/mL, and 30 microg/mL, respectively, in endothelial cells. Furthermore, we found that these effects were partly due to the promotion of PPARgamma expression and to the inhibition of abnormal TNF-alpha-induced intracellular free Ca(2+) accumulation in endothelial cells. CONCLUSION: The diverse pharmacological actions of astragaloside IV can all be linked to metabolic syndrome pathogenesis. Our study provides a new insight into the mechanism by which astragaloside IV exerts its effect.

A preadipocyte differentiation assay as a method for screening potential anti-type II diabetes drugs from herbal extracts.

A cell-based method for screening drug candidates from herbal extracts that have possible anti-type II diabetic effects was established. The differentiation of preadipocytes into adipocytes was used as a sensitive primary indicator of a drug's potential effect on type II diabetes. We established a quantitative method by using a computer image analysis system for assessing the morphological alterations. The assay was validated by screening compounds extracted from Chinese herbs and the known drug rosiglitazone for their capability of modulating PPARgamma gene expression and glucose uptake by adipocytes. Two drug candidates having possible anti-type II diabetic effects were identified.