Search

RING finger 187 (RNF187), a ubiquitin-ligating (E3) enzyme, plays a crucial role in the proliferation of cancer cells. However, it remains unclear whether RNF187 exhibits comparable functionality in the development of germline cells. To investigate the potential involvement of RNF187 in germ cell development, we conducted interference and overexpression assays using GC-2 cells, a mouse spermatocyte-derived cell line. Our findings reveal that the interaction between RNF187 and histone H3 increases the viability, proliferation, and migratory capacity of GC-2 cells. Moreover, we provide evidence demonstrating that RNF187 interacts with H3 and mediates the ubiquitination of H3 at lysine 57 (K57) or lysine 80 (K80), directly or indirectly resulting in increased cellular transcription. This is a study to report the role of RNF187 in maintaining the development of GC-2 cells by mediating histone H3 ubiquitination, thus highlighting the involvement of the K57 and K80 residues of H3 in the epistatic regulation of gene transcription. These discoveries provide a new theoretical foundation for further comprehensive investigations into the function of RNF187 in the reproductive system.

Abstract Background Disease situations are more aggressive in patients with childhood-onset systemic lupus erythematosus (cSLE) than in those with adult-onset SLE (aSLE). However, information on pregnant women with cSLE and its association with pregnancy outcomes is limited. This study aimed to compare pregnancies in patients with cSLE vs. aSLE, and further analyse the characteristics of cSLE in pregnant women and explore its association with adverse pregnancy outcomes. Methods Altogether, data of 167 pregnancies from 150 women, including 22 pregnancies with cSLE and 145 pregnancies with aSLE, were retrospectively analysed. Characteristics and disease activity were compared between the cSLE and aSLE groups during pregnancy. Associations between cSLE and the risk of active SLE (SLEPDAI > 4), active lupus nephritis (LN), and adverse pregnancy outcomes were analysed using logistic regression. Results The cSLE group had a higher incidence of active SLE (12/22 vs. 30/145, P = 0.001) and active LN (11/22 vs. 26/145, P = 0.001) than the aSLE group. In the multivariable analysis, cSLE was a risk factor for active SLE and active LN during pregnancy, with ORs of 4.742 (95%CI 1.678–13.405, P = 0.003) and 4.652 (95%CI 1.630–13.279, P = 0.004), respectively. No significant association between cSLE and the risk of composite adverse gestational outcomes was identified after sequentially adjusting pre-pregnancy characteristics and pregnancy factors (P > 0.05). Conclusion Disease activity of women with cSLE in pregnancy was more aggressive than that of women with aSLE, which was similar to the characteristics of non-pregnant women with SLE. cSLE might have indirect effects on the risk of adverse pregnancy outcomes through LN and active disease. Therefore, closely monitoring patients with cSLE during pregnancy is crucial.

ObjectivesTo develop and validate predictive nomograms of cancer specific survival (CSS) and overall survival (OS) for synchronous colon cancer with liver metastasis (SCLM) patients.MethodsPatients with pathologically diagnosed colon cancer with liver metastasis were retrieved from the SEER database between 2010 and 2015. Only SCLM patients were included. Univariate and multivariate cox regression analyses were conducted to identify the potential predictors of patients’ survival outcomes. The selected variables were integrated to create predictive nomograms via R tools. Furthermore, the concordance index Harrell’s C statistic (C-index) was calculated to describe the discrimination of nomograms. Calibration (1000 bootstrap resamples) curves were plotted to compare the predictions of nomograms with the observed outcomes. Decision curve analysis (DCA) and clinical impact curves were performed to evaluate the clinical effects of nomograms.ResultsA total of 22,378 SCLM patients were included. The median time of OS and CSS was 13 and 17 months, respectively. The 1-, 2-, and 3-year rate of OS was 50.6, 28.1, and 14.8%, respectively. While the 1-, 2-, and 3-year rate of CSS was 58.7, 36.8, and 22.5%, respectively. SCLM patients with increased age, left primary tumor location, AJCC IVb stage, and no chemotherapy were associated with an obviously reduced OS and CSS. Variables including age, histological grade, T/N/M stage, tumor size, bone/lung metastasis, CEA, surgery of primary site, and chemotherapy were closely related to the prognoses of SCLM patients. Nomograms of OS and CSS were built and displayed online for convenient utilization. The C-index of OS and CSS monograms were 0.74 and 0.73, respectively, indicating relatively good discrimination of the nomograms. The calibration curves suggested a good agreement between the actual observation and the nomogram prediction. DCAs and clinical impact curves reflected favorable potential clinical effects of predictive nomograms.ConclusionChemotherapy, surgery of primary site, and age were important independent risk factors for the CSS and OS of SCLM patients. We built and validated two reliable nomograms of OS and CSS to predict the prognoses of SCLM patients, which can be accessed online at (https://predictive-tool.shinyapps.io/CSS-DynNomapp/; https://predictive-tool.shinyapps.io/OS-DynNomapp/).

Abnormal phenotypic switch, migration, and proliferation of vascular smooth muscle cells (VSMCs) are hallmarks for pathogenesis of thoracic aortic dissection (TAD). In the current study, we identified miR-134-5p as a critical regulator controlling human VSMC phenotypic switch and migration to investigate whether miR-134-5p affects human VSMC functions and development of TAD. Using miRNA microarray of aorta specimens from 12 TAD and 12 controls, we identified miR-134-5p, which was significantly downregulated in TAD tissues. With qPCR detection, we found that miR-134-5p was also evidently decreased in human AoSMCs. Ectopic expression of miR-134-5p obviously promoted VSMC differentiation and expression of contractile markers, such as α-SMA, SM22α, and MYH11. miR-134-5p potently inhibited PDGF-BB-induced VSMC phenotypic switch and migration. We further identified STAT5B and ITGB1 as downstream targets of miR-134-5p in human VSMCs and proved them to be mediators in VSMC phenotypic switch and progression of TAD. Finally, Ad-miR-134-5p obviously suppressed the aorta dilatation and vascular media degeneration by 39% in TAD mice after vascular injury induced by Ang II. Our findings revealed that miR-134-5p was a novel regulator in vascular remodeling and pathological progress of TAD via targeting STAT5B/ITGB1 expression. Targeting miR-134-5p or its downstream molecules in VSMCs might develop new avenues in clinical treatment of TAD. Keywords: miR-134-5p, media degeneration, VSMC, phenotypic switch, thoracic aortic dissection

Abstract Over the past years, vascular diseases have continued to threaten human health and increase financial burdens worldwide. Transplantation of allogeneic and autologous blood vessels is the most convenient treatment. However, it could not be applied generally due to the scarcity of donors and the patient’s condition. Developments in tissue engineering are contributing greatly with regard to this urgent need for blood vessels. Tissue engineering-derived blood vessels are promising alternatives for patients with aortic dissection/aneurysm. The aim of this review is to show the importance of advances in biomaterials development for the treatment of vascular disease. We also provide a comprehensive overview of the current status of tissue reconstruction from stem cells and transplantable cellular scaffold constructs, focusing on the combination of stem cells and tissue engineering for blood vessel regeneration and vascular disease treatment.

Recent studies indicate important roles for SMAD4 in SMCs proliferation, extracellular matrix maintenance, and blood vessel remodeling. However, the genetic effects of SMAD4 in the pathogenesis of thoracic aortic aneurysm and dissection (TAAD) are still largely unknown. Here we identified a functional variant of SMAD4 which might be involved in the pathological progression of TAAD. Five tagging SNPs of SMAD4 were genotyped in 202 TAAD cases and 400 controls using MALDI-TOF. rs12455792 CT or TT variant genotypes was associated with an significantly elevated TAAD risk (adjusted OR = 1.58, 95%CI = 1.09–2.30) under a dominant genetic model. It was located in the 5’UTR and predicted to influence transcription activity and RNA folding of SMAD4. In luciferase reporter assay, rs12455792 T allele markedly decreased luciferase activities. Accordingly, SMAD4 expression in tissues was lower in patients with CT or TT genotypes, compared with CC. Movat's pentachrome showed that rs12455792 T allele enhanced SMCs loss and fibers accumulation. With angiotensin II induction, rate of Apoptotic SMCs was significantly higher while SMAD4 silenced. Moreover, rs12455792 T allele also increased Versican degradation via ADAMTS-4. In conclusion, this variant might promote SMCs apoptosis and proteoglycans degradation, and further facilitate the progress of TAAD. Our findings identified rs12455792 as a predictor for progression of vascular media pathological changes related thoracic aortic disorders.

Vascular disorders are complex diseases with high morbidity and mortality. Among them, the dilated macrovascular diseases (MVD), such as aortic aneurysm and aortic dissection, have presented a huge threat to human health. The pathogenesis of vascular diseases is mostly associated with property alteration of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). Studies have confirmed that induced pluripotent stem cells (iPSCs) can be proliferated and differentiated into other somatic cells, such as VECs and VSMCs. And patient-specific cells could provide detailed human-associated information in regard to pathogenesis or drug responses. In addition, differentiated ECs from iPSC have been widely used in disease modeling as a cell therapy. In this review, we mainly discussed the application of hiPSCs in investigating the pathological mechanism of different inherited vascular diseases and provide a comprehensive understanding of hiPSCs in the field of clinical diagnosis and gene therapy.