Genomic analysis quantifies pyroptosis in the immune microenvironment of HBV-related hepatocellular carcinoma

Pyroptosis, a way of pro-inflammatory death, plays a significant part in the tumor microenvironment (TME). A recent study has shown that the hepatitis C virus changes the TME by inducing pyroptosis against hepatocellular carcinoma (HCC). However, compared to TME in hepatitis C virus-infected HCC, the exploration of immune characteristics and response to immunotherapy associated with the pyroptosis phenotype is still insufficient in hepatitis B virus-related HCC (HBV-HCC). Our study constructed pyroptosis-score (PYS) via principal-component analysis (PCA) to unveil the link between pyroptosis and tumor immunity in 369 HBV-HCC patients. Compared with the low-PYS group, subjects with higher PYS were associated with poor prognosis but were more susceptible to anti-PD-L1 treatment. In addition, we found that PYS can serve independently as a prognostic factor for HBV-HCC, making it possible for us to identify specific small molecule drugs with a potential value in inhibiting tumors via targeting pyroptosis. Also, the target genes predicted by the Weighted gene co-expression network analysis (WGCNA) and pharmacophore model were enriched in the HIF-1 signaling pathway and NF-kB transcription factor activity, which were related to the mechanism of inflammation-driven cancer. The PYS is extremely important in predicting prognosis and responses to immunotherapy. New treatment strategies for inflammation-driven cancers may be found by targeting pyroptosis

miRNA-558 promotes tumorigenesis and aggressiveness of neuroblastoma cells through activating the transcription of heparanase

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Small RNA interference-mediated gene silencing of heparanase abolishes the invasion, metastasis and angiogenesis of gastric cancer cells

<p>Abstract</p> <p>Background</p> <p>Heparanase facilitates the invasion and metastasis of cancer cells, and is over-expressed in many kinds of malignancies. Our studies indicated that heparanase was frequently expressed in advanced gastric cancers. The aim of this study is to determine whether silencing of heparanase expression can abolish the malignant characteristics of gastric cancer cells.</p> <p>Methods</p> <p>Three heparanase-specific small interfering RNA (siRNAs) were designed, synthesized, and transfected into cultured gastric cancer cell line SGC-7901. Heparanase expression was measured by RT-PCR, real-time quantitative PCR and Western blot. Cell proliferation was detected by MTT colorimetry and colony formation assay. The <it>in vitro </it>invasion and metastasis of cancer cells were measured by cell adhesion assay, scratch assay and matrigel invasion assay. The angiogenesis capabilities of cancer cells were measured by tube formation of endothelial cells.</p> <p>Results</p> <p>Transfection of siRNA against 1496-1514 bp of encoding regions resulted in reduced expression of heparanase, which started at 24 hrs and lasted for 120 hrs post-transfection. The siRNA-mediated silencing of heparanase suppressed the cellular proliferation of SGC-7901 cells. In addition, the <it>in vitro </it>invasion and metastasis of cancer cells were attenuated after knock-down of heparanase. Moreover, transfection of heparanase-specific siRNA attenuated the <it>in vitro </it>angiogenesis of cancer cells in a dose-dependent manner.</p> <p>Conclusions</p> <p>These results demonstrated that gene silencing of heparanase can efficiently abolish the proliferation, invasion, metastasis and angiogenesis of human gastric cancer cells <it>in vitro</it>, suggesting that heparanase-specific siRNA is of potential values as a novel therapeutic agent for human gastric cancer.</p

Small RNAs Targeting Transcription Start Site Induce Heparanase Silencing through Interference with Transcription Initiation in Human Cancer Cells

Heparanase (HPA), an endo-h-D-glucuronidase that cleaves the heparan sulfate chain of heparan sulfate proteoglycans, is overexpressed in majority of human cancers. Recent evidence suggests that small interfering RNA (siRNA) induces transcriptional gene silencing (TGS) in human cells. In this study, transfection of siRNA against −9/+10 bp (siH3), but not −174/−155 bp (siH1) or −134/−115 bp (siH2) region relative to transcription start site (TSS) locating at 101 bp upstream of the translation start site, resulted in TGS of heparanase in human prostate cancer, bladder cancer, and gastric cancer cells in a sequence-specific manner. Methylation-specific PCR and bisulfite sequencing revealed no DNA methylation of CpG islands within heparanase promoter in siH3-transfected cells. The TGS of heparanase did not involve changes of epigenetic markers histone H3 lysine 9 dimethylation (H3K9me2), histone H3 lysine 27 trimethylation (H3K27me3) or active chromatin marker acetylated histone H3 (AcH3). The regulation of alternative splicing was not involved in siH3-mediated TGS. Instead, siH3 interfered with transcription initiation via decreasing the binding of both RNA polymerase II and transcription factor II B (TFIIB), but not the binding of transcription factors Sp1 or early growth response 1, on the heparanase promoter. Moreover, Argonaute 1 and Argonaute 2 facilitated the decreased binding of RNA polymerase II and TFIIB on heparanase promoter, and were necessary in siH3-induced TGS of heparanase. Stable transfection of the short hairpin RNA construct targeting heparanase TSS (−9/+10 bp) into cancer cells, resulted in decreased proliferation, invasion, metastasis and angiogenesis of cancer cells in vitro and in athymic mice models. These results suggest that small RNAs targeting TSS can induce TGS of heparanase via interference with transcription initiation, and significantly suppress the tumor growth, invasion, metastasis and angiogenesis of cancer cells

Experimental Study on Sand Inrush Hazard of Water-Sand Two-Phase Flow in Broken Rock Mass

In the western region of China, coal mining activities are prone to induce water and sand inrush disasters, which seriously threaten the safe production of the coal resources. In this paper, an experimental device was designed to simulate the process of water and sand inrush, and then, the control factors of the disasters in the broken rock mass in the goaf were investigated. Also, the seepage fracture channels in the broken rock mass were simplified by using the 3D printing technology, and the effects of fracture aperture and angle on the seepage characteristics of water-sand mixtures were analyzed. The experimental results showed that the porosity and skeleton structure of the broken rock mass were the key factors to control the water and sand inrush disasters. The smaller the initial porosity of the broken rock mass, the weaker its permeability, and the less probable to form a dominant channel for the water and sand inrush disasters. Conversely, the broken rock mass structure with larger size gradation was more likely to form the permeable channels, and the quality of the sand inrush was greater. In addition, it was also found that the angle of the fractures within the broken rock mass affected the seepage characteristics of water-sand mixture, and the permeability showed an exponential relationship with the fracture angle. Meanwhile, as the fracture aperture increased, the fracture angle generated greater influence on the permeability. Finally, we proposed the water and sand inrush prevention and control technology based on the experiment results. The results of this study can provide a reference for the control of water and sand inrush disasters in western China

Mirna-337-3P Suppresses Neuroblastoma Progression By Repressing The Transcription Of Matrix Metalloproteinase 14

Recent evidence shows the emerging roles of endogenous microRNAs (miRNAs) in repressing gene transcription. However, the miRNAs inhibiting the transcription of matrix metalloproteinase 14 (MMP-14), a membrane-anchored MMP crucial for the tumorigenesis and aggressiveness, still remain largely unknown. In this study, through mining computational algorithm program and genome-wide Argonaute profiling dataset, we identified one binding site of miRNA-337-3p (miR-337-3p) within the MMP-14 promoter. We demonstrated that miR-337-3p was under-expressed and inversely correlated with MMP-14 expression in clinical specimens and cell lines of neuroblastoma (NB), the most common extracranial solid tumor in childhood. Patients with high miR-337-3p expression had greater survival probability. miR-337-3p suppressed the promoter activity, nascent transcription, and expression of MMP-14, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines. Mechanistically, miR-337-3p recognized its binding site and recruited Argonaute 2 to facilitate the enrichment of repressive epigenetic markers and decrease the binding of RNA polymerase II and specificity protein 1 on the MMP-14 promoter. Gain- and loss-of-function studies demonstrated that miR-337-3p suppressed the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. In addition, restoration of MMP-14 expression rescued the NB cells from changes in these biological features. Taken together, these data indicate that miR-337-3p directly binds the MMP-14 promoter to repress its transcription, thus suppressing the progression of NB

A novel GRU-TCN network based Interactive Behavior Learning of multi-energy Microgrid under incomplete information

The interactive operation of multi-energy Microgrid (MEMG) in energy market is facing more and more incomplete information decision-making requirements due to the enhanced privacy of users, which brings great challenges to the participation flexibility of MEMG in demand response programs. Meanwhile, considering the uncertainty of the external MEMG unit combination, the randomness of the environmental meteorology, the interactive characteristics of the external MEMGs are complex and time-varying. To solve these problems, a novel GRU-TCN network based Interactive Behavior Learning method for MEMG interactive operation is proposed. The proposed Interactive Behavior Learning framework needs merely externally available input information and historical interaction power data to efficiently predict the interaction power, which protects the data privacy of users. Besides, the GRU-TCN network also leverages the strengths of Recurrent Neural Network and Convolutional Neural Networks while incorporating the self-attention mechanism. This combination enables the GRU-TCN network to effectively capture the relationship between interactive power and the available resources data beyond the MEMG. The example analysis and test are carried out on a typical MEMG system, and the case study turns out that the proposed GRU-TCN network has the capability to capture coupling mechanisms even in the presence of incomplete information and present more accurate prediction of multi-energy interactive data

Necessary conditions for sustainable water and sanitation service delivery in schools: A systematic review.

Access to water, sanitation, and hygiene (WASH) services confers significant health and economic benefits, especially for children, but only if those services can be delivered on a consistent basis. The challenge of sustainable, school-based WASH service delivery has been widely documented, particularly in resource-constrained contexts. We conducted a systematic review of published research that identifies drivers of, or tests solutions to, this challenge within low- and middle-income countries (PROSPERO 2020 CRD42020199163). Authors in the first group employ cross-sectional research designs and interrogate previously implemented school WASH interventions. Most conclude that dysfunctional accountability and information sharing mechanisms drive school WASH service delivery failures. By contrast, most of the interventions developed and tested experimentally by authors in the second group focus on increasing the financial and material resources available to schools for WASH service delivery. Overall, these authors find negligible impact of such infusions of cash, infrastructure, and supplies across a variety of sustainability outcome metrics. Taken together, the evidence suggests that sustainable service delivery depends on three simultaneously necessary components: resources, information, and accountability. Drawing upon theory and evidence from social psychology, public management, and political science, we identify priority knowledge gaps that can meaningfully improve the design of effective interventions. We also highlight the importance of both interdisciplinary collaboration and local expertise in designing WASH programming that aligns with sociocultural and institutional norms, and is thus more likely to generate sustainable impact