STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression

Background: Deregulation of either RNA polymerase I (Pol I)-directed transcription or expression of signal transducer and activator of transcription 3 (STAT3) correlates closely with tumorigenesis. However, the connection between STAT3 and Pol I-directed transcription hasn’t been investigated. Methods: The role of STAT3 in Pol I-directed transcription was determined using combined techniques. The regulation of tumor cell growth mediated by STAT3 and Pol I products was analyzed in vitro and in vivo. RNAseq, ChIP assays and rescue assays were used to uncover the mechanism of Pol I transcription mediated by STAT3. Results: STAT3 expression positively correlates with Pol I product levels and cancer cell growth. The inhibition of STAT3 or Pol I products suppresses cell growth. Mechanistically, STAT3 activates Pol I-directed transcription by enhancing the recruitment of the Pol I transcription machinery to the rDNA promoter. STAT3 directly activates Rpa34 gene transcription by binding to the RPA34 promoter, which enhances the occupancies of the Pol II transcription machinery factors at this promoter. Cancer patients with RPA34 high expression lead to poor survival probability and short survival time. Conclusion: STAT3 potentiates Pol I-dependent transcription and tumor cell growth by activating RPA34 in vitro and in vivo

Multiparametric Cardiovascular Magnetic Resonance in Acute Myocarditis: Comparison of 2009 and 2018 Lake Louise Criteria With Endomyocardial Biopsy Confirmation.

Background: Cardiac magnetic resonance (CMR) has been shown to improve the diagnosis of myocarditis, but no systematic comparison of this technique is currently available. The purpose of this study was to compare the 2009 and 2018 Lake Louise Criteria (LLC) for the diagnosis of acute myocarditis using 3.0 T MRI with endomyocardial biopsy (EMB) as a reference and to provide the cutoff values for multiparametric CMR techniques. Methods: A total of 73 patients (32 ± 14 years, 71.2% men) with clinically suspected myocarditis undergoing EMB and CMR with 3.0 T were enrolled in the study. Patients were divided into two groups according to EMB results (EMB-positive and -negative groups). The CMR protocol consisted of cine-SSFP, T2 STIR, T2 mapping, early and late gadolinium enhancement (EGE, LGE), and pre- and post-contrast T1 mapping. Their potential diagnostic ability was assessed with receiver operating characteristic curves. Results: The myocardial T1 and T2 relaxation times were significantly higher in the EMB-positive group than in the EMB-negative group. Optimal cutoff values were 1,228 ms for T1 relaxation times and 58.5 ms for T2 relaxation times with sensitivities of 86.0 and 83.7% and specificities of 93.3 and 93.3%, respectively. The 2018 LLC had a better diagnostic performance than the 2009 LLC in terms of sensitivity, specificity, positive predictive value, and negative predictive value. T1 mapping + T2 mapping had the largest area under the curve (0.95) compared to other single or combined parameters (2018 LLC: 0.91; 2009 LLC: 0.76; T2 ratio: 0.71; EGEr: 0.67; LGE: 0.73; ). The diagnostic accuracy for the 2018 LLC was the highest (91.8%), followed by T1 mapping (89.0%) and T2 mapping (87.7%). Conclusion: Emerging technologies such as T1/ T2 mapping have significantly improved the diagnostic performance of CMR for the diagnosis of acute myocarditis. The 2018 LLC provided the overall best diagnostic performance in acute myocarditis compared to other single standard CMR parameters or combined parameters. There was no significant gain when 2018LLC is combined with the EGE sequence

Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm

Abstract Mesenchymal stem/stromal cells (MSCs) have been demonstrated to hold great potential for the treatment of several diseases. Their therapeutic effects are largely mediated by paracrine factors including exosomes, which are nanometer-sized membrane-bound vesicles with functions as mediators of cell-cell communication. MSC-derived exosomes contain cytokines and growth factors, signaling lipids, mRNAs, and regulatory miRNAs. Increasing evidence suggests that MSC-derived exosomes might represent a novel cell-free therapy with compelling advantages over parent MSCs such as no risk of tumor formation and lower immunogenicity. This paper reviews the characteristics of MSC exosomes and their fate after in vivo administration, and highlights the therapeutic potential of MSC-derived exosomes in liver, kidney, cardiovascular and neurological disease. Particularly, we summarize the recent clinical trials performed to evaluate the safety and efficacy of MSC exosomes. Overall, this paper provides a general overview of MSC-exosomes as a new cell-free therapeutic paradigm

Study on the Drug Targets and Molecular Mechanisms of Rhizoma Curcumae in the Treatment of Nasopharyngeal Carcinoma Based on Network Pharmacology

Aim. To analyse the target of Rhizoma Curcumae in nasopharyngeal carcinoma by using network pharmacological techniques and to explore the associated molecular mechanism. Methods. The targets of nasopharyngeal carcinoma were retrieved from the GeneCards database. At the same time, the drug therapeutic targets of Rhizoma Curcumae were obtained from the TCMSP and SymMap databases. The data were imported into the STRING database and Cytoscape 3.7.1 to construct a network of “Chinese medicine component-target-disease” interactions; then, the intersection was screened as the core Rhizoma Curcumae antinasopharyngeal cancer targets. Through GO target function and KEGG pathway enrichment analyses of the core targets, we predicted the biological processes and key signalling pathways involved in the Rhizoma Curcumae treatment of nasopharyngeal carcinoma. Results. Twenty-five core targets of Rhizoma Curcumae in nasopharyngeal carcinoma were mined: TP53, BCL2 ICAM1 RXRA, TLR3 and TLR9, TNF, PTGS2, IL-6, CTSD, MMP2, MMP9, MMP14, TIMP2, ABCC1, ABCB1, ABCG2, and so on. The results of visual analysis showed that the Rhizoma Curcumae treatment of nasopharyngeal carcinoma mainly involves leukocyte adhesion to vascular endothelial cells, positive regulation of NF-κB import into the nucleus, regulation of the reactive oxygen species biosynthetic and metabolic process, regulation of the chemokine biosynthetic and metabolic process, various cancer-related signalling pathways, and a variety of cytokine signal transduction pathways, such as the NF-κB, TLR, IL-17, and TNF signalling pathways. Conclusion. The core targets predicted by our research can be used as molecular markers for the treatment and prediction of nasopharyngeal carcinoma. The mechanism of Rhizoma Curcumae treatment in NPC may be related to immune regulatory pathways, the inhibition of cancer cell proliferation, metastasis, and angiogenesis, as well as the regulation of tumour microenvironment. Combined with the prediction of its associated mechanism of action, the core targets can provide targeted reference value for subsequent drug development related to Curcuma

Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges

Abstract In order to dissect amyotrophic lateral sclerosis (ALS), a multigenic, multifactorial, and progressive neurodegenerative disease with heterogeneous clinical presentations, researchers have generated numerous animal models to mimic the genetic defects. Concurrent and comparative analysis of these various models allows identification of the causes and mechanisms of ALS in order to finally obtain effective therapeutics. However, most genetically modified rodent models lack overt pathological features, imposing challenges and limitations in utilizing them to rigorously test the potential mechanisms. Recent studies using large animals, including pigs and non-human primates, have uncovered important events that resemble neurodegeneration in patients’ brains but could not be produced in small animals. Here we describe common features as well as discrepancies among these models, highlighting new insights from these models. Furthermore, we will discuss how to make rodent models more capable of recapitulating important pathological features based on the important pathogenic insights from large animal models

Prescription Function Prediction Using Topic Model and Multilabel Classifiers

Determining a prescription’s function is one of the challenging problems in Traditional Chinese Medicine (TCM). In past decades, TCM has been widely researched through various methods in computer science, but none concentrates on the prediction method for a new prescription’s function. In this study, two methods are presented concerning this issue. The first method is based on a novel supervised topic model named Label-Prescription-Herb (LPH), which incorporates herb-herb compatibility rules into learning process. The second method is based on multilabel classifiers built by TFIDF features and herbal attribute features. Experiments undertaken reveal that both methods perform well, but the multilabel classifiers slightly outperform LPH-based method. The prediction results can provide valuable information for new prescription discovery before clinical test

Research into Autonomous Vehicles Following and Obstacle Avoidance Based on Deep Reinforcement Learning Method under Map Constraints

Compared with traditional rule-based algorithms, deep reinforcement learning methods in autonomous driving are able to reduce the response time of vehicles to the driving environment and fully exploit the advantages of autopilot. Nowadays, autonomous vehicles mainly drive on urban roads and are constrained by some map elements such as lane boundaries, lane driving rules, and lane center lines. In this paper, a deep reinforcement learning approach seriously considering map elements is proposed to deal with the autonomous driving issues of vehicles following and obstacle avoidance. When the deep reinforcement learning method is modeled, an obstacle representation method is proposed to represent the external obstacle information required by the ego vehicle input, aiming to address the problem that the number and state of external obstacles are not fixed