Background Methyltransferase SETDB1 is highly expressed in breast cancer (BC), however, the mechanisms by which SETDB1 promotes BC progression to endocrine therapy resistance remains elusive. In this study, we examined the mechanisms by which SETDB1 contribute to BC endocrine therapy resistance. Methods We utilized therapy sensitive (MCF7 and ZR75), therapy resistant (MCF7-TamR, MCF7-FR, MCF7-PELP1cyto, MCF7-SETDB1) estrogen receptor alpha positive (ER+)BC models and conducted in vitro cell viability, colony formation, 3-dimensional cell growth assays to investigate the role of SETDB1 in endocrine resistance. RNA-seq of parental and SETDB1 knock down ER+ BC cells was used to identify unique pathways. SETDB1 interaction with PELP1 was identified by yeast-two hybrid screen and confirmed by immunoprecipitation and GST-pull down assays. Mechanistic studies were conducted using Western blotting, reporter gene assays, RT-qPCR, and in vitro methylation assays. Xenograft assays were used to establish the role of PELP1 in SETDB1 mediated BC progression. Results RNA-seq analyses showed that SETDB1 regulates expression of a subset of estrogen receptor (ER) and Akt target genes that contribute to endocrine therapy resistance. Importantly, using yeast-two hybrid screen, we identified ER coregulator PELP1 as a novel interacting protein of SETDB1. Biochemical analyses confirmed SETDB1 and PELP1 interactions in multiple BC cells. Mechanistic studies confirmed that PELP1 is necessary for SETDB1 mediated Akt methylation and phosphorylation. Further, SETDB1 overexpression promotes tamoxifen resistance in BC cells, and PELP1 knockdown abolished these effects. Using xenograft model, we provided genetic evidence that PELP1 is essential for SETDB1 mediated BC progression in vivo. Analyses of TCGA datasets revealed SETDB1 expression is positively correlated with PELP1 expression in ER+ BC patients. Conclusions This study suggests that the PELP1/SETDB1 axis play an important role in aberrant Akt activation and serves as a novel target for treating endocrine therapy resistance in breast cancer.
Objective: We evaluated whether radiomic features extracted from planning computed tomography (CT) scans predict clinical end points in patients with locally advanced cervical cancer (LACC) undergoing intensity-modulated radiation therapy and brachytherapy.Design: A retrospective cohort study.
Introduction: The treatment strategy for low-grade gliomas (LGGs) is still controversial, and there are no standardized criteria to predict the prognosis of patients with LGGs. Magnetic resonance imaging (MRI) is a routine test for preoperative diagnosis for LGG and can reflect the destructive features for the tumor. In the present study, we aimed to explore the relationship between the MRI features and prognosis in patients with LGG. Methods: Clinical data of 80 patients with pathologically proved LGGs between January 2010 and December 2016 were analyzed retrospectively. MRI features were classified as contrast enhancement pattern (focal enhancement, diffuse enhancement and ring-like enhancement), necrosis and cysts based on the preoperative MR images. Kaplan–Meier method and multivariate analysis were performed on the data by SPSS software to explore the prognostic significance of MRI features. Results: Patients with cystic LGG had a significantly longer 5-year progression-free survival (PFS) than that with no cyst (90.9 ± 8.7 vs 65.7 ± 9.1%, P=0.045). Multivariate analysis further verified cyst as an independent prognosis factor for PFS (P=0.027, hazard ratio [HR] = 0.084). Additionally, patients with ring-like enhancement exhibited significantly longer 5-year PFS time in the Kaplan–Meier survival curves (100 vs 67.2 ± 7.7%, P=0.049). There was no significant difference in PFS and overall survival (OS) between patients with or without necrosis. Conclusion: Our study suggests that cyst formation and ring-like enhancement on preoperative MR images can be useful to predict a favorable prognosis in patients with LGGs.
Gut dysbiosis is observed in Alzheimer's disease (AD) and is frequently associated with AD-induced metabolic dysfunction. However, the extent and specific underlying molecular mechanisms triggered by alterations of gut microbiota composition and function mediating ADinduced metabolic dysfunction in AD remain incompletely uncovered. Here, we indicate that Helicobacter pylori (H. pylori) is abundant in AD patients with relative metabolic dysfunction. Fecal microbiota transplantation from the AD patients promoted metabolic dysfunction in mice and increased gut permeability. H. pylori increased gut permeability through activation of the TLR4/Myd88 inflammation pathway in a p53-dependent manner, leading to metabolic dysfunction. Moreover, p53 deficiency reduced bile acid concentration, leading to an increased abundance of H. pylori colonization. Overall, these data identify H. pylori as a key promoter of ADinduced metabolic dysfunction.
Glioma is a primary tumor derived from gliocyte, accounting for approximately 40% to 50% of intracranial brain tumors. Glioma is classified into I-IV grade based on different histopathological characteristics, among which grade IV glioma is the most malignant glioblastoma (GBM), representing the most common form of glioma in the adult population. 1 Because of the malignant proliferation, radiotherapy, and chemotherapy resistance and high recurrence rate of GBM, patients' median survival time is only 12-15 months. 2,3 Therefore, it is urgent to explore the molecular mechanism causing GBM to be more malignant than low-grade glioma (LGG).
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