The optimal anticoagulant for end-stage renal disease patients for stroke prophylaxis is unknown. The efficacy and safety of warfarin in this population are debatable. In addition, real-world ...evidence of direct oral anticoagulants in patients with end-stage renal disease is limited. The aim of this study was to evaluate the clinical outcomes of rivaroxaban compared with warfarin in Taiwanese patients with end-stage renal disease with nonvalvular atrial fibrillation in a real-world setting.
This was a retrospective population-based cohort study conducted using Taiwan's National Health Insurance Research Database. Patients with nonvalvular atrial fibrillation and end-stage renal disease who started on rivaroxaban or warfarin between February 2013 and September 2017 were eligible to participate in the study. The inverse probability of treatment weighting approach was used to balance baseline characteristics. Bleeding and thromboembolic outcomes were compared using competing risk analyses. The study population consisted of 3358 patients (173 and 3185 patients on rivaroxaban and warfarin, respectively). In the rivaroxaban group, 50.8%, 38.7%, and 10.4% of the patients received 10, 15, and 20 mg of the drug, respectively. The cumulative incidence of major bleeding was similar between the two groups; however, the gastrointestinal bleeding rate was lower in the rivaroxaban group (adjusted subdistribution hazard ratio SHR: 0.56, 95% confidence interval CI: 0.34-0.91) than in the warfarin group. Furthermore, the composite risk of ischemic stroke or systemic embolism was significantly lower in the rivaroxaban group (adjusted SHR: 0.36, 95% CI: 0.17-0.79). Similar findings were observed for patients who received 10 mg of rivaroxaban.
In Taiwanese patients with end-stage renal disease and nonvalvular atrial fibrillation, rivaroxaban may be associated with a similar risk of major bleeding but a lower risk of thromboembolism compared with warfarin. The potential benefit of 10 mg of rivaroxaban in this population requires further investigation.
Abstract Superparamagnetic iron oxide (SPIO) nanoparticles are very useful in cell imaging; meanwhile, however, biosafety concerns associated with their use, especially on therapeutic stem cells, ...have arisen. Most studies of biosafety issues focus on whether the nanoparticles have deleterious effects. Here, we report that Ferucarbotran, an ionic SPIO, is not toxic to human mesenchymal stem cells (hMSCs) under the conditions of these experiments but instead increases cell growth. Ferucarbotran-promoted cell growth is due to its ability to diminish intracellular H2 O2 through intrinsic peroxidase-like activity. Also, Ferucarbotran can accelerate cell cycle progression, which may be mediated by the free iron (Fe) released from lysosomal degradation and involves the alteration of Fe on the expression of the protein regulators of the cell cycle.
Abstract
Cellular retinoic acid binding protein 1 (CRABP1) participates in the regulation of retinoid signaling. Previous studies showed conflicting results regarding the role of CRABP1 in tumor ...biology, including protumorigenic and tumor‐suppressive effects in different types of cancer. Our bioinformatics analyses suggested that CRABP1 expression was downregulated in thyroid cancer. Ectopic expression of CRABP1 in thyroid cancer cells suppressed migratory and invasive activity without affecting cell growth or cell cycle distribution. In transformed normal thyroid follicular epithelial cells, silencing of CRABP1 expression increased invasiveness. Additionally, CRABP1 overexpression was associated with downregulation of the mesenchymal phenotype. Kinase phosphorylation profiling indicated that CRABP1 overexpression was accompanied by a decrease in phosphorylation of epidermal growth factor (EGF) receptor and downstream phosphorylation of Akt, STAT3, and FAK, which were reversed by exogenous EGF treatment. Immunohistochemical analysis of our tissue microarrays revealed an inverse association between CRABP1 expression and disease stage of differentiated thyroid cancer. Taken together, our results suggest that CRABP1 expression is aberrantly lost in thyroid cancer, and this downregulation promotes the epithelial–mesenchymal transition at least partly through modulating EGF receptor signaling.
We propose a model selection criterion for correlated survival data when the cluster size is informative to the outcome. This approach, called Resampling Cluster Survival Information Criterion ...(RCSIC), uses the Cox proportional hazards model that is weighted with the inverse of the cluster size. The RCSIC based on the within-cluster resampling idea takes into account the possible variability of the within-cluster subsampling and the possible informativeness of cluster sizes. The RCSIC allows for easy execution for the within-cluster resampling idea without a large number of resamples of the data. In contrast with the traditional model selection method in survival analysis, the RCSIC has an additional penalization for the within-cluster subsampling variability. Our simulations show the satisfactory results where the RCSIC provides a more robust power for variable selection in terms of clustered survival analysis, regardless of whether informative cluster size exists or not. Applying the RCSIC method to a periodontal disease studies, we identify the tooth loss in patients associated with the risk factors, Age, Filled Tooth, Molar, Crown, Decayed Tooth, and Smoking Status, respectively.
Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that ...regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation.
Cell migration requires the fine spatiotemporal integration of many proteins that regulate the fundamental processes that drive cell movement. Focal adhesion (FA) dynamics is a continuous process ...involving coordination between FA and actin cytoskeleton, which is essential for cell migration. We studied the spatiotemporal relationship between the dynamics of focal adhesion kinase (FAK) and paxillin at FAs in the protrusion of living endothelial cells. Concurrent dual-color imaging showed that FAK was assembled at FA first, which was followed by paxillin recruitment to the FA. By tracking and quantifying FAK and paxillin in migrating cells, the normalized FAK/Paxillin fluorescence intensity (FI) ratio is > 1 (≈ 4 fold) at cell front, ≈ 1 at cell center, and < 1 at cell rear. The significantly higher FAK FI than paxillin FI at cell front indicates that the assembly of FAK-FAs occurs ahead of paxillin at cell front. To determine the time difference between the assemblies of FAK and paxillin at nascent FAs, FAs containing both FAK and paxillin were quantified by image analysis and time correlation. The results show that FAK assembles at the nascent FAs earlier than paxillin in the protrusions at cell front.
The early diagnosis, prognostic prediction, and personalized therapy of lung adenocarcinoma (LUAD) remains a challenging issue.
(potassium voltage-gated channel subfamily Q Member 1) is implicated in ...long QT syndrome (LQTS) and cardiac arrhythmia, while its significance in LUAD remains unclear. In this study, we aimed to explore the significance of
in terms of clinical value, tumor immunity, underlying mechanisms, and a precision medicine approach by means of multi-omics analysis. The association of
with LUAD was first explored. Both altered variants and high expression of
in a TCGA-LUAD cohort indicated a favorable outcome.
levels had a negative correlation with tumor proliferation index
levels. siRNA-knockdown of
promoted the migration ability of lung cancer cells.
levels were decreased in LUAD tissue compared to normal tissue. A receiver operating characteristic (ROC) curve indicated good diagnostic efficiency of
. High
is associated with an immunoactive profile of immune infiltration and immunomodulators and is involved in the inhibition of the cell cycle and DNA replication. Lapatinib was identified as a potent drug for LUAD in the context of low
. This study unveiled the significance of
in diagnosis and prognosis and provided a corresponding precision medicine strategy for LUAD.
Ubiquitin chains are formed as structurally distinct polymers via different linkages, and several chain types including K33-linkage remain uncharacterized. Here, we describe a role for ...K33-polyubiquitination in protein trafficking. We show that the Cullin 3 (Cul3) substrate adaptor KLHL20 is localized to the trans-Golgi network (TGN) and is important for post-Golgi trafficking by promoting the biogenesis of TGN-derived transport carriers. The Cul3-KLHL20 ubiquitin E3 ligase catalyzes a nondegradable, K33-linked polyubiquitination on coronin 7 (Crn7), which facilitates Crn7 targeting to TGN through a ubiquitin-dependent interaction with Eps15. Blockage of K33-chain formation, Crn7 ubiquitination, or disruption of Crn7-Eps15 interaction impairs TGN-pool F-actin assembly, a process essential for generating transport carriers. Enforced targeting of Crn7 to TGN bypasses the requirement of K33-ubiquitination for TGN-pool F-actin assembly and post-Golgi trafficking. Our study reveals a role of KLHL20-mediated K33-ubiquitination of Crn7 in post-Golgi transport and identifies a cellular recognition mechanism for this ubiquitin chain type.
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•Cul3-KLHL20 E3 ligase promotes post-Golgi transport to plasma membrane and endosomes•The trafficking effects of KLHL20 are mediated by K33-polyubiquitination of Crn7•K33-polyubiquitination targets Crn7 to TGN by interacting with Eps15 UIMs•Crn7 TGN recruitment facilitates F-actin assembly and transport carrier biogenesis
Ubiquitin chains are formed as structurally distinct polymers via different linkages. Yuan et al. report that K33-linked ubiquitination connects an actin-regulatory protein coronin 7 to Golgi-localized ubiquitin-binding protein Eps15. This connection enables actin assembly at Golgi to promote protein trafficking, thus identifying a function of this atypical ubiquitin chain.
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