As the most malignant subtype of breast cancers, triple-negative breast cancer (TNBC) lacks effective targeted therapeutics clinically to date.In this study, one lead compound FZU-0025-065 with isochromanoindolenine scaffold was identified by a cell-based screening.Among nine breast cancer cell lines tested, TNBC are the most sensitive cell lines to FZU-0025-065.FZU-0025-065 inhibits TNBC cell growth in a time-and dosage-dependent manner.FZU-0025-065 suppresses the expression of cell cycle dependent kinase 4 (CDK4), Cyclin D1 and Cyclin B1; meanwhile, elevates the expression of cell cycle dependent kinase inhibitor p21 and p27.Importantly, we found that FZU-0025-065 suppresses AKT activation in a time-and dosage-dependent manner.Over-expression of constitutive active AKT partially rescues FZU-0025-065 induced cell growth inhibition in MDA-MB-468 cells, indicating FZU-0025-065 suppresses TNBC cell growth partially via inhibiting AKT activation.Finally, FZU-0025-065 suppresses TNBC cell growth in a xenograft mouse model.Taken together, our findings suggested that isochromanoindolenine derivative FZU-0025-065 inhibits TNBC via suppressing the AKT signaling and that FZU-0025-065 may be useful for TNBC treatment.
ABSTRACT In children, hyper‐IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. The antibody diversity is partially determined by the alternative splicing (AS) in the germline, which is mainly regulated by RNA‐binding proteins, including Breast cancer amplified sequence 2 (Bcas2). However, the effect of Bcas2 on AS and antibody production in activated B cells, the main immune cell type in the germline, remains unknown. To fill this gap, we created a conditional knockout (cKO, B cell‐specific AID‐Cre Bcas2 fl/fl ) mouse model and performed integrated mechanistic analysis on alternative splicing (AS) and CSR in B cells through the RNA‐sequencing approach, cross‐linking immunoprecipitation and sequencing (CLIP‐seq) analysis, and interactome proteomics. The results demonstrate that Bcas2‐ cKO significantly decreased CSR in activated B cells without inhibiting the B cell development. Mechanistically, Bcas2 interacts with SRSF7 at a conservative circular domain, forming a complex to regulate the AS of genes involved in the post‐switch transcription, thereby causing broad‐spectrum changes in antibody production. Importantly, we identified GAAGAA as the binding motif of Bcas2 to RNAs and revealed its essential role in the regulation of Bcas2‐dependent AS and CSR. In addition, we detected a mutation of at the 3’UTR of Bcas2 gene in children with HIGM1 and observed similar patterns of AS events and CSR in the patient that were discovered in the Bcas2‐ cKO B cells. Combined, our study elucidates the mechanism by which Bcas2‐mediated AS affects CSR, offering potential insights into the clinical implications of Bcas2 in HIGM1.
Here, we firstly report a wireless magnetoelastic (ME) nanobiosensor, based on ME materials and gold nanoparticles (AuNPs), for highly sensitive detection of atrazine employing the competitive immunoassay. In response to a time-varying magnetic field, the ME material longitudinally vibrates at its resonance frequency which can be affected by its mass loading. The layer of AuNPs coating on the ME material contributes to its biocompatibility, stability, and sensitivity. The atrazine antibody was oriented immobilized on the AuNPs-coated ME material surface through protein A, improving the nanobiosensor's performance. Atomic force microscope (AFM) analysis proved that the immobilization of atrazine antibody was successful. Furthermore, to enhance the sensitivity, atrazine–albumin conjugate (Atr–BSA) was induced to compete with atrazine for binding with atrazine antibody, amplifying the signal response. The resonance frequency shift is inversely and linearly proportional to the logarithm of atrazine concentrations ranging from 1 ng/mL to 100 μg/mL, with the sensitivity of 3.43 Hz/μg mL−1 and the detection limit of 1 ng/mL, which is significantly lower than the standard established by US Environmental Protection Agency (EPA). The experimental results indicated that the ME nanobiosensor displayed strong specificity and stability toward atrazine. This study provides a new convenient method for rapid, selective, and highly sensitive detection of atrazine, which has implications for its applications in water quality monitoring and other environmental detection fields.
Abstract Background : During the early stages after diagnosis, the time impact of radiotherapy and chemotherapy on the occurrence of fatal cardiac disease in lung cancer patients has received limited research attention. Patients and methods : Lung cancer patient data was obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Propensity-score matching methods were employed to equalize baseline confounding. The training set was utilized to construct a time-dependent (time cut = 6 months) Cox regression model and a Random survival forest model, whereas the test set was employed for model validation. The discrimination and accuracy of the model were assessed using the Concordance Index and the Integrated Brier score. Results : A total of 49,294 patients diagnosed with lung cancer between 2018 and 2019 were included in the analysis. Propensity score-matched analyses, accounting for important confounding covariates, demonstrated that patients who received CT only, RT only, or CT plus RT had significantly improved CHH-specific survival compared to those who did not receive CT and RT (P <0.001). Cox regression analysis indicated that within the first 6 months, RT and CT (P <0.001) independently acted as protective factors against CHH-specific mortality, while RT plus CT (P <0.001) was identified as an independent risk factor. At 6 months or later, RT (P <0.05) emerged as an independent risk factor, while the impact of CT on CHH-specific mortality became statistically insignificant compared to the initial six months. The results of the Rsf analysis indicated that the variables in descending order of importance were CT, RT, and CT plus RT. Additionally, independent risk factors included the year of diagnosis, T4, Stage Group, and Msite brain (P <0.05). Conclusions : These findings establish a critical time frame to raise awareness regarding the risk of CHH-specific death in lung cancer during the early post-diagnostic period.
As one of the most ominous malignancies, hepatocellular carcinoma (HCC) is frequently diagnosed at an advanced stage, owing to its aggressive invasion and metastatic spread.Emerging evidence has demonstrated that Rictor, as a unique component of the mTORC2, plays a role in cell migration, as it is dysregulated in various cancers, including HCC.However, the underlying molecular mechanism has not been well-characterized.Here, evaluation on a tissue-array panel and bioinformatics analysis revealed that Rictor is highly expressed in HCC tissues.Moreover, increased Rictor expression predicts poor survival of HCC patients.Rictor knockdown significantly suppressed cell migration and actin polymerization, thereby leading to decreased nuclear accumulation of MKL1 and subsequent inactivation of SRF/MKL1-dependent gene transcription, i.e.Arp3 and c-Fos.Mechanistically, we identified ABLIM1 as a previously unknown phosphorylation target of Rictor.Rictor interacts with ABLIM1 and regulates its serine phosphorylation in HCC cells.We generated ABLIM1 knockout cell lines of HCC, in which dominant negative mutations of Ser 214 and Ser 431 residues inhibited the ABLIM1-mediated actin polymerization and the MKL1 signaling pathway.Overall, ABLIM1 phosphorylation induced by Rictor plays an important role in controlling actin polymerization in HCC cells.
The experiments were conducted in the induction and differentiation of anther callus and rhizogenesis of adventitious bud with ornamental eggplant (Solanum melongena L.).And then a few haploid plantlets were obtained.The results showed that the addition of 2,4-D to MS medium was essential for anther callus induction and KT also promoted callus induction.The optimal medium for anther callus induction was MS+2,4-D 0.5 mg/ L + KT 0.25 mg/ L + LH 1 000 mg/ L + Gln 500 mg/ L. The optimum medium of differentiation was MS + ZT 1.0 mg/ L +NAA 0.005 mg/ L+ GA_3 0.5 mg/ L+ LH 1 000 mg/ L. Then the adventitious buds were transferred into the rhizogenesis medium of 1/ 2MS supplemented with 0-0.005 mg/ L NAA and 20 g/ L sucrose,and rooted well. The livability was more than 90 % when aftergrowthes were transplanted.
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