The present study investigated the role of long non-coding RNA (lncRNA) GABPB1-IT1 in ischemia-induced acute kidney injury (AKI).
The expression of GABPB1-IT1 in plasma of patients with ...ischemia-induced AKI and healthy controls was detected by RT-qPCR. GABPB1-IT1 and miR-204-5p were overexpressed in human renal proximal tubular epithelial cells (HRPTEpCs), followed by RT-qPCR to assess the overexpression effect and the regulatory relationship between GABPB1-IT1 and miR-204-5p. Methylation-specific PCR (MSP) was performed to assess the promoter methylation status of miR-204-5p. Additionally, cell apoptosis assay was carried out to evaluate the correlation between miR-204-5p and GABPB1-IT1 in the context of hypoxia-induced apoptosis of HRPTEpCs.
GABPB1-IT1 was upregulated in plasma of patients with ischemia-induced AKI. In HRPTEpCs, hypoxia upregulated the expression of GABPB1-IT1. MiR-204-5p was downregulated in ischemia-induced AKI, and the expression of miR-204-5p was inversely correlated with GABPB1-IT1. In HRPTEpCs, overexpression of GABPB1-IT1 decreased the expression levels of miR-204-5p and increased miR-204-5p gene methylation. In addition, overexpression of GABPB1-IT1 reduced the inhibitory effects of miR-204-5p on the apoptosis of HRPTEpC induced by hypoxia. Furthermore, overexpression of GABPB1-IT1 promoted kidney injury, renal tissue injury scores, and the level of serum creatinine. However, miR-204-5p had the opposite effect.
GABPB1-IT1 was upregulated in ischemia-induced AKI and may induce hypoxia-induced apoptosis of HRPTEpC by methylation of miR-204-5p.
Abstract
Molecular classification has improved diagnosis and treatment for patients with malignant gliomas. However, classification has relied on individual assays that are both costly and slow, ...leading to frequent delays in treatment. Here, we propose the use of DNA methylation, as an emerging clinical diagnostic platform, to classify gliomas based on major genomic alterations and provide insight into subtype characteristics. We show that using machine learning models, DNA methylation signatures can accurately predict somatic alterations and show improvement over existing classifiers. The established Unified Diagnostic Pipeline (UniD) we develop is rapid and cost-effective for genomic alterations and gene expression subtypes diagnostic at early clinical phase and improves over individual assays currently in clinical use. The significant relationship between genetic alteration and epigenetic signature indicates broad applicability of our approach to other malignancies.
Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We ...demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs
in vivo
is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.
Treatment effectiveness and overall prognosis for glioma patients depend heavily on the genetic and epigenetic factors in each individual tumor. However, intra-tumoral genetic heterogeneity is known ...to exist and needs to be managed. Currently, evidence for genetic changes varying spatially within the tumor is qualitative, and quantitative data is lacking. We hypothesized that a greater genetic diversity or "genetic distance" would be observed for distinct tumor samples taken with larger physical distances between them.
Stereotactic biopsies were obtained from untreated primary glioma patients as part of a clinical trial between 2011 and 2016, with at least one biopsy pair collected in each case. The physical (Euclidean) distance between biopsy sites was determined using coordinates from imaging studies. The tissue samples underwent whole exome DNA sequencing and epigenetic methylation profiling and genomic distances were defined in three separate ways derived from differences in number of genes, copy number variations (CNV), and methylation profiles.
Of the 31 patients recruited to the trial, 23 were included in DNA methylation analysis, for a total of 71 tissue samples (14 female, 9 male patients, age range 21-80). Samples from an 8 patient subset of the 23 evaluated patients were further included in whole exome and copy number variation analysis. Physical and genomic distances were found to be independently and positively correlated for each of the three genomic distance measures. The correlation coefficients were 0.63, 0.65, and 0.35, respectively for (a) gene level mutations, (b) copy number variation, and (c) methylation status. We also derived quantitative linear relationships between physical and genomic distances.
Primary brain tumors are genetically heterogeneous, and the physical distance within a given glioma correlates to genomic distance using multiple orthogonal genomic assessments. These data should be helpful in the clinical diagnostic and therapeutic management of glioma, for example by: managing sampling error, and estimating genetic heterogeneity using simple imaging inputs.
Recent evidence indicates the existence of a putative novel phosphatidylinositol‐linked D1 dopamine receptor in brain that mediates phosphatidylinositol hydrolysis via activation of phospholipase Cβ. ...The present work was designed to characterize the Ca2+ signals regulated by this phosphatidylinositol‐linked D1 dopamine receptor in primary cultures of hippocampal neurons. The results indicated that stimulation of phosphatidylinositol‐linked D1 dopamine receptor by its newly identified selective agonist SKF83959 induced a long‐lasting increase in basal Ca2+i in a time‐ and dose‐dependent manner. Stimulation was observable at 0.1 μm and reached the maximal effect at 30 μm. The Ca2+i increase induced by 1 μm SKF83959 reached a plateau in 5 ± 2.13 min, an average 96 ± 5.6% increase over control. The sustained elevation of Ca2+i was due to both intracellular calcium release and calcium influx. The initial component of Ca2+ increase through release from intracellular stores was necessary for triggering the late component of Ca2+ rise through influx. We further demonstrated that activation of phospholipase Cβ/inositol triphosphate was responsible for SKF83959‐induced Ca2+ release from intracellular stores. Moreover, inhibition of voltage‐operated calcium channel or NMDA receptor‐gated calcium channel strongly attenuated SKF83959‐induced Ca2+ influx, indicating that both voltage‐operated calcium channel and NMDA receptor contribute to phosphatidylinositol‐linked D1 receptor regulation of Ca2+i.
A novel protection for powerformers in NIEPS Wang, Yuanyuan; Jian, Jinbao; Zeng, Xiangjun ...
International journal of electrical power & energy systems,
2012, 2012-1-00, 20120101, Letnik:
34, Številka:
1
Journal Article
Recenzirano
► The stator single phase-to-ground fault protection for powerformers. ► Comparing the direction of zero-sequence current of each powerformer. ► Comparing the magnitude of zero-sequence current of ...each powerformer. ► Powerformers can be detected in 100% of the winding with resistance 1
kΩ.
A new type of high-voltage generator which offers a direct connection to the power network without the need for a step-up transformer is called powerformer. The neutral of the most powerformers is unearthed which belongs to NIEPS. When a stator single phase-to-ground fault occurs in a powerformer, every generator that is connected in parallel with the faulty powerformer has the same voltage. Traditional protection schemes using zero sequence voltage and third-harmonic voltage signals cannot detect which powerformer is faulted. In order to solve this problem for powerformer protection, a novel stator single phase-to-ground fault protection based on the direction and magnitude of zero-sequence currents is proposed in this paper. Simulation results have shown that, under different fault conditions, the new scheme can distinguish reliably internal faults from external faults, and can detect stator single phase-to-ground fault occurred in which powerformer with resistance 1
kΩ. A 100% of the winding can be fully protected.
Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether ...addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m
/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.
Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is ...unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.
Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) ...or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-κB activation correlate with poor radiation response and shorter survival in patients with GBM.
Display omitted
•Patient-derived GSCs differ in their molecular features compared to the parental GBM•PN GSCs undergo differentiation to a MES state in a TNF-α/NF-κB-dependent manner•Macrophages/microglia infiltration correlates with the MES signature in human GBM•NFκB activation, MES state, and CD44 levels associate with radio resistance in GBM
The automatic extraction of roads or buildings from remote sensing imagery plays a significant role in many urban applications. Recently, due to the impressive performance of deep learning, various ...road segmentation methods based on the fully convolutional network (FCN) have been proposed for optical remote sensing images. However, the existing FCN-based high-fidelity remote sensing image segmentation methods still have some limitations. As the repeated convolution and pooling operations employed in an FCN reduce the feature resolution and lose some detailed information, FCNs have a limited capacity to mine long-range dependencies among features. To address this issue, a context information capture network (CM-FCN) for road segmentation is proposed. To capture and aggregate multiscale contextual information, a dilated convolution module is designed. Furthermore, to boost the long-range dependencies of features for road detection, two attention modules employing the attention mechanism to adaptively combine local features with their global dependencies are designed. The context features extracted from the dilated convolution module are then fused into the attention modules to further improve the segmentation performance. The proposed model is evaluated on three challenging remote sensing image road segmentation datasets and one building segmentation dataset, including a dataset with our own manual labels. Comparisons demonstrate the effectiveness of our proposed method. We conclude that our proposed CM-FCN has the potential to automatically segment roads and buildings from high-resolution remote sensing images with an accuracy that renders it a useful tool for practical application scenarios.
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