Comprehensive characterization of ferroptosis in hepatocellular carcinoma revealing the association with prognosis and tumor immune microenvironment

BackgroundFerroptosis is a type of regulatory cell death (RCD) mode that depends on iron-mediated oxidative damage. It has the potential to improve the efficacy of tumor immunotherapy by modulating the tumor microenvironment (TME). Currently, immunotherapy has significantly improved the overall treatment strategy for advanced hepatocellular carcinoma (HCC), but the distinct immune microenvironment and high tolerance to the immune make massive differences in the immunotherapy effect of HCC patients. As a result, it is imperative to classify HCC patients who may benefit from immune checkpoint therapy. Simultaneously, the predictive value of ferroptosis in HCC and its potential role in TME immune cell infiltration also need to be further clarified.MethodsThree ferroptosis molecular models were built on the basis of mRNA expression profiles of ferroptosis-related genes (FRGs), with notable variations in immunocyte infiltration, biological function, and survival prediction. In order to further investigate the predictive impact of immunotherapy response in HCC patients, the ferroptosis score was constructed using the principal component analysis (PCA) algorithm to quantify the ferroptosis molecular models of individual tumors.ResultsIn HCC, there were three totally different ferroptosis molecular models. The ferroptosis score can be used to assess genetic variation, immunotherapy response, TME characteristics, and prognosis. Notably, tumors with low ferroptosis scores have extensive tumor mutations and immune exhaustion, which are associated with a poor prognosis and enhanced immunotherapy response.ConclusionsOur study indicates that ferroptosis plays an indispensable role in the regulation of the tumor immune microenvironment. For HCC, the ferroptosis score is an independent prognostic indicator. Assessing the molecular model of ferroptosis in individual tumors will assist us in better understanding the characteristics of TME, predicting the effect of immunotherapy in HCC patients, and thus guiding a more reasonable immunotherapy program

Transcriptomic study for identification of major nitrogen stress responsive genes in Australian bread wheat cultivars

High nitrogen use efficiency (NUE) in bread wheat is pivotal to sustain high productivity. Knowledge about the physiological and transcriptomic changes that regulate NUE, in particular how plants cope with nitrogen (N) stress during flowering and the grain filling period, is crucial in achieving high NUE. Nitrogen response is differentially manifested in different tissues and shows significant genetic variability. A comparative transcriptome study was carried out using RNA-seq analysis to investigate the effect of nitrogen levels on gene expression at 0 days post anthesis (0 DPA) and 10 DPA in second leaf and grain tissues of three Australian wheat (Triticum aestivum) varieties that were known to have varying NUEs. A total of 12,344 differentially expressed genes (DEGs) were identified under nitrogen stress where down-regulated DEGs were predominantly associated with carbohydrate metabolic process, photosynthesis, light-harvesting, and defense response, whereas the up-regulated DEGs were associated with nucleotide metabolism, proteolysis, and transmembrane transport under nitrogen stress. Protein–protein interaction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis further revealed that highly interacted down-regulated DEGs were involved in light-harvesting and photosynthesis, and up-regulated DEGs were mostly involved in steroid biosynthesis under N stress. The common down-regulated genes across the cultivars included photosystem II 10 kDa polypeptide family proteins, plant protein 1589 of uncharacterized protein function, etc., whereas common up-regulated genes included glutamate carboxypeptidase 2, placenta-specific8 (PLAC8) family protein, and a sulfate transporter. On the other hand, high NUE cultivar Mace responded to nitrogen stress by down-regulation of a stress-related gene annotated as beta-1,3-endoglucanase and pathogenesis-related protein (PR-4, PR-1) and up-regulation of MYB/SANT domain-containing RADIALIS (RAD)-like transcription factors. The medium NUE cultivar Spitfire and low NUE cultivar Volcani demonstrated strong down-regulation of Photosystem II 10 kDa polypeptide family protein and predominant up-regulation of 11S globulin seed storage protein 2 and protein transport protein Sec61 subunit gamma. In grain tissue, most of the DEGs were related to nitrogen metabolism and proteolysis. The DEGs with high abundance in high NUE cultivar can be good candidates to develop nitrogen stress-tolerant variety with improved NUE

HER2 Targeted Molecular MR Imaging Using a De Novo Designed Protein Contrast Agent

The application of magnetic resonance imaging (MRI) to non-invasively assess disease biomarkers has been hampered by the lack of desired contrast agents with high relaxivity, targeting capability, and optimized pharmacokinetics. We have developed a novel MR imaging probe targeting to HER2, a biomarker for various cancer types and a drug target for anti-cancer therapies. This multimodal HER20targeted MR imaging probe integrates a de novo designed protein contrast agent with a high affinity HER2 affibody and a near IR fluorescent dye. Our probe can differentially monitor tumors with different expression levels of HER2 in both human cell lines and xenograft mice models. In addition to its 100-fold higher dose efficiency compared to clinically approved non-targeting contrast agent DTPA, our developed agent also exhibits advantages in crossing the endothelial boundary, tissue distribution, and tumor tissue retention over reported contrast agents as demonstrated by even distribution of the imaging probe across the entire tumor mass. This contrast agent will provide a powerful tool for quantitative assessment of molecular markers, and improved resolution for diagnosis, prognosis and drug discovery

Simultaneous Determination of 8 Compounds in Gancao-Ganjiang-Tang by HPLC-DAD and Analysis of the Relations between Compatibility, Dosage, and Contents of Medicines

Gancao-Ganjiang-Tang (GGT) is a traditional Chinese medicine (TCM) prescription and is a representative prescription for recuperating depleted Yang in Treatise on Febrile Diseases. The TCM theory believes that the efficacy of medicinal herbs is decided by the multicompounds which consist of different kinds of chemical constituents with bioactivities, but not by a monomeric constituent. From ancient times until today, GGT have 5 different kinds of compatibilities that can be verified. In this study, a HPLC-DAD method was established for the simultaneous determination of 8 compounds including 6-gingerol, 8-gingerol, 6-shogaol, liquiritin, liquiritigenin, isoliquiritin, isoliquiritigenin, and glycyrrhizic acid in the five GGT. The total contents of the 8 compounds in GGT varied from 555.56 to 956.33 μg/mL. The effects showed that the dosage and compatibility of medicinal herbs have influenced the content of chemical compounds of TCM prescription while the content of chemical compounds has acted on clinical efficacy. Quality evaluation and active essence screening of TCM (including single herb and prescription) should be based on the TCM theory and clinical effectiveness. The method was proven to be suitable for quality control of GGT

Mesoscopic-Functionalization of Silk Fibroin with Gold Nanoclusters Mediated by Keratin and Bioinspired Silk Synapse

2017年9月，厦门大学物理科学与技术学院刘向阳教授团队与河北大学闫小兵副教授团队合作, 在Small上发表此论文，第一次将功能化蚕丝用于制造阻变存储/神经元突触电子元件。这种蚕丝基生物仿生元器件, 可制成生物相容/可植入/可降解生物电子芯片, 在人工智领域以及生物医药方面，具有重要的应用前景。【Abstract】Silk fibroin (SF) offers great opportunities in manufacturing biocompatible/partially biodegradable devices with environmental benignity and biomedical applications. To obtain active SF devices of next generation, this work is to demonstrate a new functionalization strategy of the mesoscopic functionalization for soft materials. Unlike the atomic functionalization of solid materials, the meso-functionalization is to incorporate meso-dopants, i.e., functional molecules or nanomaterials, quantum dots, into the mesoscopic networks of soft materials. In this work, wool keratin (WK) molecules were adopted as mediating molecules to incorporate gold nanoclusters (AuNCs), into the mesoscopic networks of SF. It follows from our analyses that the β-crystallites between WK and SF molecules establish the binding between WK@AuNCs and the SF networks. The incorporated WK@AuNCs are electron rich and serve as electronically charged nano particles to bridge the growth of Ag filaments in bio-degradable WK@AuNCs–SF memristors. The meso-functionalization can greatly enhance the performance of SF materials and endows them with new functionalities. This can be highlighted by biocompatible/partly degradable WK@AuNCs functionalized SF resistive random-access memories, having the enhanced resistive switching memory performance, and the unique synapse characteristics and the capability of synapse learning compared with neat SF devices, and of great importance in nonvolatile memory, analog circuits, and neuromorphic applications.The work was supported by NUS tear 1 funding (WBS: R-144-000-367-112), the 111 Project (Grant No. B16029), National Natural Science Foundation of China (Grant Nos. 21404087 and 61674050, U1405226), Fujian Provincial Department of Science & Technology (Grant Nos. 2014H6022, 2015J05109), Natural Science Foundation of Guangdong Province (Grant No. 2015A030310007), 1000 Talents Program, and President Foundation from Xiamen University (Grant No. 20720160088), Ph. D. Programs Foundation of Ministry of Education of China (Grant No. 20130121110018). One of the authors, the primary affiliation of X.Y.L. is the Department of Physics, National University of Singapore. The authors are grateful to the China Scholarship Council (CSC) for the scholarship (Grant No. 201506630067) provided to one of the authors (Xing)

Effects of ACEIs and ARBs on the Residual Renal Function in Peritoneal Dialysis Patients: A Meta-Analysis of Randomized Controlled Trials

Background. In peritoneal dialysis (PD) patients, whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could protect residual renal function is still controversial. To assess the effects of ACEIs and ARBs on the residual renal function and cardiovascular (CV) events in peritoneal dialysis patients, we performed a meta-analysis of randomized controlled trials. Materials and Methods. We searched PubMed, EMBASE, the Cochrane Library, the CNKI database, and the Wanfang database for relevant articles from database inception to November 30, 2019. Randomized controlled trials were included. The primary outcome was the decline in the residual renal function (RRF). Results. Thirteen trials with 625 participants were included in the meta-analysis. The average residual GFR declined by 1.79 ml/min per 1.73 m2 in the ACEI/ARB group versus 1.44 ml/min per 1.73 m2 in the placebo or active control group at 3 mo. The average residual GFR declined by 2.02 versus 2.06, 2.16 versus 2.72, and -0.04 versus 2.74 ml/min per 1.73 m2 in the placebo or active control group at 6 months (mo), 12 mo, and 24 mo, respectively. The decline in residual GFR showed a significant difference between the ACEI/ARB group and the placebo or active control group at 12 mo (MD=−0.64 ml/min per 1.73 m2; 95% CI: -0.97~-0.32; I2=44%; P<0.0001). No significant difference was observed in Kt/V, urinary protein excretion, weekly creatinine clearance, CV events, or serum potassium levels. Conclusions. In the present study, we found that the use of ACEIs and ARBs, especially long-term treatment, decreased the decline of RRF in patients on PD. ACEIs and ARBs do not cause an additional risk of side effects

Numerical Simulation Algorithm Study on Dynamic Programming of Training Airspace

The dynamic planning of the training airspace is of great significance for improving the utilization rate of the airspace, improving the efficiency of military training, and alleviating the contradiction between military and civilian air. The spatial dynamic programming problem is processed in stages, and the total occupation time is minimized by the optimal scheme of each stage. Aiming at the dynamic programming problem in each stage, on the basis of analyzing the complexity of the problem, the spatial planning model is constructed, and the genetic-discrete particle swarm optimization(DPSO) algorithm is proposed. By integrating the crossover and mutation ideas in the genetic algorithm, the DPSO algorithm’s ability to get rid of the local optimal solution is improved, and the convergence speed and accuracy of the algorithm are improved. At the same time, in order to ensure the diversity of population, the adaptive crossover operator and mutation operator are designed to ensure the individual feasibility, and the Gantt chart is used to represent the whole spatial planning process. Finally, the improved genetic-particle swarm optimization algorithm is used as an example. Compared with the traditional particle swarm optimization, the results show that the algorithm is of better results and faster convergence speed