Prognostic values of blood urea nitrogen/creatinine and cystatin C in patients with radical nephrectomy for renal cell carcinoma.

Background: To evaluate the prognostic value of blood urea nitrogen/creatinine ratio (BUN/SCr) and cystatin C (Cys C) in patients with renal cell carcinoma (RCC) after radical nephrectomy. Methods: The study analysed 348 patients with RCC who underwent radical nephrectomy. The optimal cut-off was obtained based on the ROC of specific survival outcomes and the maximum Youden index. The patients were divided into four groups: Group 1 (low BUN/SCr-low Cys C), Group 2 (low BUN/SCr-high Cys C), Group 3 (high BUN/SCr-low Cys C), and Group 4 (high BUN/SCr-high Cys C). The primary endpoint was cancer-specific survival (CSS), and the secondary endpoint was disease-free survival (DFS).

Hsa-miR-134-5p predicts cardiovascular risk in circulating mononuclear cells and improves angiogenic action of senescent endothelial progenitor cells.

This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa-miR-134-5p, which targeted transforming growth factor ß-activated kinase 1-binding protein 1 (TAB1) gene, down-regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen-activated protein kinase (p38) in hsa-miR-134-5p-overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down-regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF-ß1) was down-regulated in hsa-miR-134-5p-overexpressed senescent EPCs and addition of TGF-ß1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa-miR-134-5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa-miR-134-5p expression level. In summary, hsa-miR-134-5p is involved in the regulation of senescence-related change of angiogenic activity via TAB1-p38 signalling and via TGF-ß1 reduction. Hsa-miR-134-5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC-derived hsa-miR-134-5p predicts cardiovascular risk.

Heterogenous liver parenchymal enhancement in CT is a favorable prognosis of HCC after hepatic resection.

This study aimed to define the role of heterogeneity of liver parenchymal enhancement on computed tomography (CT) in the survival of patients with hepatocellular carcinoma (HCC) after hepatic resection. The medical records of patients with HCCs and who had undergone hepatic resection were retrospectively reviewed. The standard deviation (SD) of three different enhanced CT scan images was used to estimate the heterogeneity of liver parenchymal enhancement: SD of > 5.6, heterogenous enhancement, and SD of ≤ 5.6, homogeneous enhancement. A total of 57 patients had heterogenous enhancement, and 143 patients had homogeneous enhancement. The patients with heterogenous enhancement had longer disease-free and overall survivals than those with other enhancements (log-rank test, P < 0.001 and P = 0.036). The pathologic exam showed that heterogenous enhancement tended to develop septa in the peritumoral liver tissues. The prevalence of CD8+ cells was significantly higher in the peritumor liver tissues with septa than in those without (0.83% vs. 0.26%, P < 0.001). The peritumoral CD8/Foxp3 ratio was higher in the liver tissues with septa than in those without (1.22 vs. 0.47, P = 0.001), and patients with CD8/Foxp3 of > 0.8 had better overall survival than those with CD8/Foxp3 of ≤ 0.8 (log-rank test, P = 0.028). In conclusion, patients who had undergone hepatic resection with a heterogenous liver parenchymal enhancement tended to develop hepatic septa, which was associated with a higher CD8/Foxp3 ratio and longer survival. Therefore, contrast-enhanced CT scans might be a useful tool to predict the outcome of HCC.

The RAE1-STOP1-GL2-RHD6 module regulates the ALMT1-dependent aluminum resistance in Arabidopsis.

Aluminum (Al) toxicity is one of the major constraints for crop production in acid soils, Al-ACTIVATED MALATE TRANSPORTER1 (ALMT1)-dependent malate exudation from roots is essential for Al resistance in Arabidopsis, in which the C2H2-type transcription factor SENSITIVE TO PROTONRHIZOTOXICITY1 (STOP1) play a critical role. In this study, we reveal that the RAE1-GL2-STOP1-RHD6 protein module regulated the ALMT1-mediated Al resistance. GL2, STOP1 and RHD6 directly target the promoter of ALMT1 to suppress or activate its transcriptional expression, respectively, and mutually influence their action on the promoter of ALMT1 by forming a protein complex. STOP1 mediates the expression of RHD6 and RHD6-regulated root growth inhibition, while GL2 and STOP1 suppress each other's expression at the transcriptional and translational level and regulate Al-inhibited root growth. F-box protein RAE1 degrades RHD6 via the 26S proteasome, leading to suppressed activity of the ALMT1 promoter. RHD6 inhibits the transcriptional expression of RAE1 by directly targeting its promoter. Unlike RHD6, RAE1 promotes the GL2 expression at the protein level and GL2 activates the expression of RAE1 at the transcriptional level by directly targeting its promoter. The study provides insights into the transcriptional regulation of ALMT1, revealing its significance in Al resistance and highlighting the crucial role of the STOP1-associated regulatory networks.

Modulation of external and internal aluminum resistance by ALS3-dependent STAR1-mediated promotion of STOP1 degradation.

The ALMT1 transporter aids malate secretion, chelating Al3+ ions to form nontoxic Al-malate complexes, believed to exclude Al from the roots. However, the extent to which malate secreted by ALMT1 is solely used for the exclusion of Al3+ or can be reutilized by plant roots for internal Al tolerance remains uncertain. In our investigation, we explored the impact of malate secretion on both external and internal Al resistance in Arabidopsis thaliana. Additionally, we delved into the mechanism by which the tonoplast-localized bacterial-type ATP-binding cassette (ABC) transporter complex STAR1/ALS3 promotes the degradation of the Al resistance transcription factor STOP1 to regulate ALMT1 expression. Our study demonstrates that the level of secreted malate influences whether the Al-malate complex is excluded from the roots or transported into root cells. The nodulin 26-like intrinsic protein (NIP) subfamily members NIP1;1 and NIP1;2, located in the plasma membrane, coordinate with STAR1/ALS3 to facilitate Al-malate transport from root apoplasm to the symplasm and eventually to the vacuoles for the internal Al detoxification. ALS3-dependent STAR1 interacts with and promotes the degradation of STOP1, regulating malate exudation. Our findings demonstrate the dual roles of malate exudation in external Al exclusion and Al absorption for internal Al detoxification.

Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells.

This study explores the impact of senescence on autocrine C-C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication-induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs in vitro and in vivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up-regulation of miR-409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age-related cardiovascular disorders.

Visualization of therapeutic intervention for acute liver injury using low-intensity pulsed ultrasound-responsive phase variant nanoparticles.

Acute liver injury (ALI) is a highly fatal condition characterized by sudden massive necrosis of liver cells, inflammation, and impaired coagulation function. Currently, the primary clinical approach for managing ALI involves symptom management based on the underlying causes. The association between excessive reactive oxygen species originating from macrophages and acute liver injury is noteworthy. Therefore, we designed a novel nanoscale phase variant contrast agent, denoted as PFP@CeO2@Lips, which effectively scavenges reactive oxygen species, and enables visualization through low intensity pulsed ultrasound activation. The efficacy of the nanoparticles in scavenging excess reactive oxygen species from RAW264.7 and protective AML12 cells has been demonstrated through in vitro and in vivo experiments. Additionally, these nanoparticles have shown a protective effect against LPS/D-GalN attack in C57BL/6J mice. Furthermore, when exposed to LIPUS irritation, the nanoparticles undergo liquid-gas phase transition and enable ultrasound imaging.

Aortic Characteristic Impedance and Suspected Mild Cognitive Impairment in a Community-Based Healthy Population.

BACKGROUND: Aging of the proximal aorta can lead to increased pressure and flow pulsatility in the cerebral microcirculation, which may cause cognitive impairment. This study investigated the association between aortic characteristic impedance (Zc), an indicator of regional stiffness of the proximal aorta, and suspected mild cognitive impairment (MCI), compared with carotid-femoral pulse wave velocity (CFPWV). METHODS AND RESULTS: A total of 1461 healthy community residents (46.4% men; age range, 35-96 years [mean±SD, 59.9±11.8 years]) without a history of cardiovascular events or stroke were included in the study. Zc was estimated using applanation tonometry and echocardiography. Cognitive function was assessed using the Mini-Mental State Examination. Education-adjusted cut points were used to define suspected MCI. Subjects with suspected MCI (n=493 [33.7%]) had significantly higher Zc and CFPWV than those without. In multivariable analysis, both Zc and CFPWV were inversely associated with Mini-Mental State Examination score. Zc (odds ratio per 1 SD, 1.22 [95% CI, 1.09-1.37] and CFPWV (odds ratio per 1 SD, 1.18 [95% CI, 1.01-1.38]) was also significantly associated with suspected MCI, after adjusting for age, sex, education level, mean arterial pressure, hypertension, diabetes, low-density lipoprotein cholesterol, and smoking status. In joint analysis, Zc was significantly associated with suspected MCI, but CFPWV was not. In the age subgroups of <50 years and 50 to 70 years, only Zc was significantly associated with suspected MCI. CONCLUSIONS: This study found that Zc was significantly associated with Mini-Mental State Examination score and suspected MCI, especially in younger and middle-aged adults. These findings suggest that Zc may be a useful biomarker for identifying individuals at risk for MCI.

A deep learning-based semiautomated workflow for triaging follow-up MR scans in treated nasopharyngeal carcinoma.

It is imperative to optimally utilize virtues and obviate defects of fully automated analysis and expert knowledge in new paradigms of healthcare. We present a deep learning-based semiautomated workflow (RAINMAN) with 12,809 follow-up scans among 2,172 patients with treated nasopharyngeal carcinoma from three centers (ChiCTR.org.cn, Chi-CTR2200056595). A boost of diagnostic performance and reduced workload was observed in RAINMAN compared with the original manual interpretations (internal vs. external: sensitivity, 2.5% [p = 0.500] vs. 3.2% [p = 0.031]; specificity, 2.9% [p < 0.001] vs. 0.3% [p = 0.302]; workload reduction, 79.3% vs. 76.2%). The workflow also yielded a triaging performance of 83.6%, with increases of 1.5% in sensitivity (p = 1.000) and 0.6%-1.3% (all p < 0.05) in specificity compared to three radiologists in the reader study. The semiautomated workflow shows its unique superiority in reducing radiologist's workload by eliminating negative scans while retaining the diagnostic performance of radiologists.