Background and Purpose: CX-5461 is a novel selective RNA polymerase I (Pol I) inhibitor. Previously, we found that CX-5461 could inhibit pathological arterial remodelling caused by angioplasty and transplantation. In the present study, we explored the pharmacological effects of CX-5461 on experimental pulmonary arterial hypertension (PAH) and PAH-associated vascular remodelling.
Background: Low-grade endometrial stromal sarcoma (LGESS) is the second most common malignant mesenchymal tumor of the uterus which usually affects young women. However, the researches on the safety and feasibility of the fertility-sparing management of it are limited.Methods: A retrospective analysis was performed including 5 women diagnosed with LGESS treated with fertility-sparing management at Qilu Hospital of Shandong University from 2010 to 2019. Besides that, 1,070 patients diagnosed with LGESS in SEER database from 1973 to 2016 were examined. By using the Kaplan-Meier method, survival curves were estimated, and comparisons of statistical significance were performed with the stratified log-rank test within each group.Results: Five patients with LGESS were enrolled in this study. All patients were submitted to fertilitysparing surgeries, after surgery, they all continued hormonal therapy for one year. Four out of the 5 patients recurred, to be more exact, 3 of them recurred in uterus and the other one in the uterus and iliac vascular region. They all suffered further surgery and all 5 patients were alive at the time of last contact. Besides, among these patients, two conceived naturally and delivered a healthy baby by cesarean section. Among 1,070 patients in SEER database, only 28 (2.6%) patients underwent local tumor excision, including excisional biopsy (39%), myomectomy (25%), laser ablation or excision (4%) and polypectomy (4%). There was no statistical significance was observed among TH±BSO, radical hysterectomy, subtotal hysterectomy and local tumor excision (P=0.29).Conclusions: Our analysis indicated that for those young LGESS patients who wish to preserve their fertility, the feasibility and safety of fertility-sparing management should be considered after gynecological oncologist and gynecological pathologist making professional decisions.
In this study, we tested the possibility that macrophages might contribute to neointima formation by stimulating microRNA expressions in mural cells. Thoracic aortas from F344 rats were transplanted into recipient Lewis rats. Clodronate liposome was used for in vivo macrophage depletion. Using miR-21 as a prototypic example of vascular enriched microRNA, we showed that macrophage depletion reduced the expression level of miR-21, which was upregulated in the allograft. This effect of macrophage depletion was accompanied by attenuations in neointimal hyperplasia and transplantation-induced vascular inflammation. Using in vitro assays, we identified that macrophages might stimulate miR-21 expression in smooth muscle cells and adventitial fibroblasts via the release of tumor necrosis factor-α. We also showed that silencing of miR-21 suppressed tumor necrosis factor-induced proliferation, migration, and inflammatory responses in mural cells. Our results suggest that macrophage may promote transplantation-induced neointima formation by stimulating miR-21 expression in vascular mural cells, which promotes mural cell proliferation, migration and/or inflammation. Moreover, we have established that tumor necrosis factor-α has a major role in mediating this paracrine process.
Background Missed abortion is a nonviable pregnancy before the 20th week of gestation with retained products of conception. The de nite etiology and pathogenesis are not fully understood. β-arrestin1, the important dynamic multitask scaffold protein, it play an important regulatory role in interacting with G proteincoupled receptor (GPCR) to mediate its homologous desensitization and internalization. Recent studies have demonstrated that p53/Mdm2-mediated ubiquitination of the IGF-1R maybe closely related to G protein-coupled receptor kinases (GRK)/β-arrestin1 system. Our previous studies have con rmed that the elevated expression of p53 and Mdm2 may be responsible for apoptosis during missed abortion. However, there was no information surrounding β-arrestin1 in missed abortion. Methods The mRNA levels of β-arrestin1 in villous samples of 31 missed abortion patients and 31 healthy controls were determined by real-time quantitative PCR. Immunohistochemistry was used to explore the expression and location of β-arrestin1, p53, Mdm2, VEGF, HIF-lα in trophoblasts. We up-regulated and silenced the expression of β-arrestin1 by lentiviral transfection, transwell assays were performed to examine the in uences of β-arrestin1 expression on cell invasion. Furthermore, we explored the expression of several important proteins which may be related to β-arrestin1. Results β-arrestin1 mRNA levels in the villous samples from women with missed abortion were found to be dramatically lower than in women who had normal pregnancies. The immunohistochemistry results showed that β-arrestin1 positive staining was signi cantly lower in missed abortion group than that in normal pregnancies group. Furthermore, the patients with missed abortion showed signi cantly higher levels of p53, Mdm2 and HIF-lα, lower level of VEGF than healthy controls by immunohistochemistry. The protein expressions of pERK p-AKT p-p53 in HRT-8 cells were signi cantly downregulated by reducing β-arrestin1 expression, while the expression of p-NF-ΚB p-Mdm2 were enhanced. Overexpression of β-arrestin1 exhibited the adverse effect. The loss expression of β-arrestin1 expression was signi cantly related with decreased cell invasion ability. Conclusion Our data indicated that β-arrestin1 could play an important role in maintaining the maternal-fetal tolerance, the decreased β-arrestin1 expression in the villous samples may be related to the development of missed abortion.
Clinical treatment of psoriasis remains challenging because of possible long-term drug toxicities and loss of therapeutic effects over time. CX-5461 is a novel selective inhibitor of RNA polymerase I. Our previous studies have shown that CX-5461 has potent anti-inflammatory effects. Here we investigated whether CX-5461 could inhibit the development of imiquimod-induced experimental psoriasis in mice. Adult male C57BL/6 mice were used, and psoriasis-like lesions were induced by topical imiquimod treatment. In vivo, we demonstrated that topical application of CX-5461 prevented the development of imiquimod-induced psoriasis, with decreases in keratinocyte proliferation, T-cell infiltration and pathological angiogenesis. CX-5461 also reversed existing skin inflammation induced imiquimod and retarded the development of 12 -O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and inflamma-
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