在人工气道纤维支气管镜检查中使用不同氧疗模式的对比研究

目的探讨带有人工气道的患者在行纤维支气管镜检查治疗中使用不同氧疗模式的效果。方法采用便利抽样法,选择联勤保障部队第九八三医院重症医学科2018年3月—2019年3月收治的带有人工气道并需进行支气管镜检查的104例重症肺炎的患者为研究对象,随机分为对照组(52例)和试验组(52例)。比较两组患者干预前后生命体征变化。结果干预前,两组患者血压、心率比较,差异无统计学意义(P>0.05);干预中、干预后,对照组血压﹑心率均高于试验组,两组比较差异有统计学意义(P<0.05)。干预后,试验组患者低氧血症、心律失常发生例数均低于对照组,但两组比较差异无统计学意义(P>0.05)。结论高流量湿化氧疗仪在人工气道患者纤维支气管镜检查治疗中可降低患者术中的缺氧量,提高患者的舒适度,稳定生命体征,降低不良反应。     

多发性骨髓瘤患者行自体造血干细胞移植效果的相关因素研究

〔目的〕探究多发性骨髓瘤患者行自体造血干细胞移植效果的相关因素.〔方法〕回顾性分析2019年2月至2020年2月在某医院进行多发性骨髓瘤治疗的63例患者的临床资料.根据国际骨髓瘤工作组疗效标准,用总生存时间和无进展生存时间评价多发性骨髓瘤患者的治疗效果,采用Kaplan-Meier单因素分析法及Cox多因素回归模型分析...     

Reassembling of albumin-bound paclitaxel mitigates myelosuppression and improves its antitumoral efficacy via neutrophil-mediated targeting drug delivery

Albumin-bound paclitaxel (abPTX) has been widely used in cancer treatment. However, dose-related side effects, such as myelosuppression, restrict its clinical application. Cell-based targeting drug delivery is a promising way to mitigate systematic side-effects and improve antitumoral efficacy. In this study, we demonstrated that reassembled abPTX could be engulfed by neutrophils in vivo and delivered to tumor site, thus improving therapeutic efficacy and mitigating myelosuppression. First, in vitro analysis confirmed that reassembling of abPTX formed uniform and stable serum albumin nanoparticles (NP-abPTX) with size of 107.5 ± 2.29 nm and reserved the ability to kill tumor cells. Second, we found that NP-abPTX could be engulfed by activated neutrophil in vitro and in vivo but do not affect neutrophils’ function, such as chemotaxis and activation. In a murine tumor model, we further proved that local radiotherapy (RT) induced inflammation activated peripheral neutrophils to capture venous infused NP-abPTX and carry them into tumor tissue. As compared to abPTX, infusion of NP-abPTX dramatically enhanced inhibition of tumor growth treated by local RT and mitigated hematotoxicity. Therefore, our study demonstrated a novel strategy to mitigate side-effects and to improve tumor killing efficacy of abPTX through neutrophil-mediated targeting drug delivery.     

USP35 mitigates endoplasmic reticulum stress‐induced apoptosis by stabilizing RRBP1 in non‐small cell lung cancer

Deubiquitinating enzymes (DUBs) serve to maintain cellular homeostasis via protein ubiquitination and exert diverse regulatory functions in cancers and other diseases. Much progress has been made in characterizing biological roles of DUBs over the decades, yet the specific functions of many subclass members remain largely unexplored. It was not until recent years that the role of ubiquitin‐specific‐processing protease 35 (USP35) in cancers began to be understood. Here, we focus on delineating the roles and underlying mechanisms of USP35 in non‐small cell lung cancer (NSCLC). The isobaric tags for relative and absolute quantitation (iTRAQ) comparative proteomic approach were employed to identify differentially expressed proteins (DEPs) in H1299 cells induced by USP35 overexpression or silencing. Among the potential interactome of USP35, ribosome‐binding protein 1 (RRBP1), a membrane‐bound protein in endoplasmic reticulum (ER), captured our attentions. RRBP1 expression was found to positively correlate with USP35 levels in both genetically modified cells and human NSCLC tissues. Concordantly, both RRBP1 expression and USP35 expression were found to positively correlate with poor prognoses in lung adenocarcinoma patients. At the molecular level, USP35 was verified to directly interact with RRBP1 to prevent it from proteasomal‐dependent degradation. Functionally, USP35 alleviated ER stress‐induced cell apoptosis by stabilizing RRBP1 in NSCLC cells. Collectively, these findings indicate that USP35 plays a critical role in resisting ER stress‐induced cell death through deubiquitinating RRBP1, hence providing a rationale to target the USP35‐RRBP1 axis as an alternative therapeutic option for NSCLC.     

藤黄酸抗肿瘤作用机制及联合用药研究进展

恶性肿瘤是全球面临的共同难题,同时也给世界各国带来了超负荷的经济负担。藤黄酸是藤黄Garcinia hanburyi中一种笼状呫吨酮类活性成分,具有抗炎、改善视网膜病变、脏器保护等多种药理活性。近年来,大量研究证实藤黄酸可作为一种潜力巨大的抗肿瘤化合物用于肝癌、肺癌、乳腺癌、结直肠癌等多种癌症的治疗,其机制涉及抑制细胞增殖、阻碍迁移和侵袭、诱导凋亡和自噬、抑制血管生成、诱导铁死亡和焦亡、靶向肿瘤炎症微环境和免疫调控等。此外,大量研究发现藤黄酸可与多种化疗药物或天然产物联合用于癌症的协同治疗。因此,重点总结了藤黄酸的抗肿瘤作用机制及其协同其他药物抗肿瘤的研究进展,为藤黄酸抗肿瘤研究提供参考依据。     

Antioxidant and Anti-Inflammatory Properties of Rubber Seed Oil in Lipopolysaccharide-Induced RAW 267.4 Macrophages

Rubber seed oil (RSO) is a typical PUFA-enriched plant oil, but it has not been widely used as a healthy edible oil resource due to the lack of understanding of its nutritional values, health biological effects, and action mechanisms. This work was conducted to characterize the basic physicochemical properties, evaluate the antioxidant and anti-inflammatory properties, and explore the involved mechanisms of RSO in LPS-induced RAW 264.7 cells. In the present study, the basic physicochemical parameters of RSO indicated that RSO has good qualities as a potential edible plant oil resource. In LPS-induced macrophages, RSO supplementation displayed a significant antioxidant effect by decreasing ROS and MDA levels as well as elevating T-AOC. In addition, RSO supplementation showed an anti-inflammatory effect by reducing the production of NO, IL-1β, IL-6, and TNF-α while promoting the production of IL-10. Moreover, RSO supplementation decreased the mRNA expression of IL-6, IL-1β, TNF-α, iNOS, and MCP-1 genes while increasing the mRNA expression of the IL-10 gene. Furthermore, RSO supplementation increased Nrf2 protein expression and up-regulated antioxidant genes (HO-1 and NQO-1), which was accompanied by the decrease in TLR4 protein expression and NF-κB p65 phosphorylation as well as IκBα phosphorylation. This study provided some insight into the applications of RSO as a healthy edible oil resource.     

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3′-to-5′ exoribonuclease (ExoN) in nonstructural protein 14 (nsp14), which excises nucleotides including antiviral drugs misincorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here, we determined a 1.6-Å resolution crystal structure of severe acute respiratory syndrome CoV 2 (SARS-CoV-2) ExoN in complex with its essential cofactor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3′ end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. We also show that the ExoN activity can rescue a stalled RNA primer poisoned with sofosbuvir and allow RdRp to continue its extension in the presence of the chain-terminating drug, biochemically recapitulating proofreading in SARS-CoV-2 replication. Molecular dynamics simulations further show remarkable flexibility of multidomain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA binding to support its exonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN–nsp10 complex serves as a platform for future development of anticoronaviral drugs or strategies to attenuate the viral virulence.

The 29.9-kb single-stranded RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global COVID-19 pandemic, is replicated and transcribed by the viral RNA-dependent RNA polymerase (RdRp, nsp12) (1–3). Unlike the high-fidelity cellular replicative DNA polymerases, viral RdRp enzymes, including the CoV RdRp, do not contain a proofreading exonuclease domain to ensure high fidelity. The resulting higher mutation rate (10⁻⁴ to 10⁻⁶ substitutions per nucleotide per round of replication) is generally thought to promote rapid viral adaptation in response to selective pressure (4–6). However, the lack of proofreading activity in RdRp poses a particular challenge for the replication of CoVs, which feature the largest known RNA virus genomes (27 to 32 kb, up to twice the length as the next-largest nonsegmented RNA viral genomes) (7, 8). It has been reported that SARS-CoV nsp12 is the fastest viral RdRp known but with an error rate more than one order of magnitude higher than the generally admitted error rate of viral RdRps (9), clearly necessitating a unique proofreading mechanism.To mitigate the low fidelity of RdRp, all coronaviruses encode a 3′-to-5′ exoribonuclease (ExoN) in multifunctional nsp14 (10–12), which forms a complex with nsp10 critical for the ExoN activity, and additionally contains a C-terminal guanine N7 methyl transferase (N7-MTase) domain. Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load (13, 14), and genetic inactivation of ExoN in engineered SARS-CoV and murine hepatitis virus (MHV) leads to 15- to 20-fold increases in mutation rates (7, 15, 16). Furthermore, in a mouse model, SARS-CoV with inactivated ExoN shows a mutator phenotype with decreased fitness and lower virulence over serial passage, suggesting a potential strategy for generating a live, impaired-fidelity coronavirus vaccine (17). Alternatively, recent studies show that ExoN inactivation abrogates replication of SARS-CoV-2 and Middle East Respiratory Syndrome CoV (18), hinting at additional functions for ExoN in viral replication. Indeed, ExoN activity has been reported to mediate the extensive viral RNA recombination required for subgenomic messenger RNA (mRNA) synthesis during normal replication of CoVs, including SARS-CoV-2 (19), and it was shown to be required for resistance to the antiviral innate immune response for MHV (20). ExoN inactivation also significantly increases the sensitivity of CoVs to nucleoside analogs that target RdRp, which is consistent with the biochemical activity of ExoN to excise mutagenic or chain-terminating nucleotides misincorporated by RdRp (21–23). These observations combine to suggest that chemical inhibition of ExoN could be an effective antiviral strategy against CoVs. In this study, we determined high-resolution crystal structures of the SARS-CoV-2 ExoN–nsp10 complex and studied its biochemical activities. Furthermore, we used molecular dynamics (MD) simulations to better understand the dynamics of nsp14, nsp10, and their interaction with RNA.     

表面肌电生物反馈疗法结合吞咽训练治疗脑卒中患者吞咽障碍的疗效

目的:观察表面肌电生物反馈治疗结合吞咽训练治疗脑卒中患者吞咽障碍的效果.方法:选择2018年2月至2019年12月在广州市第一人民医院康复医学科和神经科接受治疗的65例脑卒中后吞咽障碍患者,根据患者意愿分为吞咽训练组33例和肌电生物反馈组32例.吞咽训练组采用吞咽训练,肌电生物反馈组在吞咽训练的基础上采用表面肌电生物反...     

Data-independent acquisition-based proteomics analysis correlating type 2 diabetes mellitus with osteoarthritis in total knee arthroplasty patients

Background:To explore the effects of type 2 diabetes mellitus (T2DM) on osteoarthritis (OA), 12 bone tissue samples were obtained surgically from the human total knee arthroplasty patients and analyzed by quantitative proteomics.Methods:Based on patient clinical histories, patient samples were assigned to diabetes mellitus osteoarthritis (DMOA) and OA groups. A data-independent acquisition method for data collection was used with proteomic data analysis to assess intergroup proteomic differences. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis were used to further find the correlation between T2DM and OA.Results:GO functional analysis found 153 differentially expressed proteins between DMOA and OA groups, of which 92 differentially expressed proteins were significantly up-regulated and 61 were significantly down-regulated. Kyoto Encyclopedia of Genes and Genome pathway analysis found 180 pathways, including 9 pathways significantly enriched. Further data analysis revealed that 6 signaling pathways were closely associated with T2DM and OA.Conclusion:OA and DMOA onset and progression were closely related to synthesis and metabolism of extracellular matrix components (e.g., fibronectin, decorin, etc.). The effects of T2DM on OA occur though 2 major ways of oxidative stress and low-grade chronic inflammation, involving in 2 inhibited signaling pathways and 4 activated signaling pathways.     

重症高血压脑出血患者临床特征与预后相关性研究

目的 探讨急诊重症监护病房(EICU)重症高血压脑出血(HICH)患者临床特征与预后的相关性.方法 收集EICU行手术治疗的154例重症HICH患者的临床资料,根据出院后3个月格拉斯哥预后评分(GOS)分级将患者分为预后不良组(GOS Ⅰ、Ⅱ、Ⅲ级)74例和预后良好组(GOS Ⅳ、Ⅴ级)80例.应用脑室改良Graeb量...