Liver cancer stem cells (CSCs) play a pivotal role in the initiation, progression, and recurrence of hepatocellular carcinoma (HCC), but their molecular and metabolic heterogeneity remains largely undefined. Characterizing subpopulations with enriched stemness features is crucial for understanding liver cancer biology and developing targeted therapies. We integrated two single-cell RNA sequencing datasets (GSE149614 and GSE156625) of HCC to identify malignant cell subpopulations through clustering and annotation. Mitochondrial scoring, CytoTRACE, pseudotime, and pathway enrichment analyses were employed to systematically assess stemness-related features and metabolic features of each cluster. Survival analysis and prognostic modeling based on key cluster signature genes led to the development and validation of the Cluster 3 and Cluster 4 Stemness-based Prognostic Signature (C3C4-SPS). A total of 4,155 malignant cells were re-clustered into eight subpopulations, as revealed by tSNE visualization, highlighting pronounced intratumoral heterogeneity. Mitochondrial scoring demonstrated that Cluster 3 and Cluster 4 had significantly higher metabolic activity than other clusters. CytoTRACE analysis identified higher enrichment of stemness-associated features in these two clusters, and pseudotime trajectory analysis located them at the origins of distinct differentiation pathways, suggesting that they may represent stemness-enriched subpopulations, though this interpretation requires experimental confirmation. Functional enrichment revealed that Cluster 3 was predominantly involved in oxidative phosphorylation (respiratory electron transport chain and ATP synthesis), whereas Cluster 4 was more active in mitochondrial fatty acid β-oxidation and tRNA aminoacylation pathways. Both clusters showed high expression of core stem cell markers (POU5F1, SOX2, MYC, CD44). Multi-cohort survival analyses demonstrated that high expression of signature gene sets from Cluster 3 and Cluster 4 was closely associated with unfavorable prognosis in HCC patients. The C3C4-SPS model effectively stratified patients by risk, with high-risk groups exhibiting significantly worse outcomes, and performed robustly in ROC and PCA validation. This study systematically characterized the molecular and metabolic heterogeneity of liver cancer stem cell subpopulations and elucidated their decisive roles in tumor progression and patient prognosis. These findings are primarily based on computational analyses and warrant further experimental validation. The C3C4-SPS model provides a novel tool for prognostic assessment and potentially individualized therapy targeting stemness-associated features in hepatocellular carcinoma.

Background : Exogenous lipoid pneumonia is a condition that often manifests as recurrent consolidations, ground glass opacities, and interlobular septa. However, dendritic sputum morphology is rarely documented in exogenous lipoid pneumonia, which may lead to diagnostic confusion with fibrinous bronchitis. This case highlights underrecognized etiologies of persistent pulmonary inflammation and the unique diagnostic challenges associated with unusual bronchial cast pathology. Case presentation : A 60-year-old man presented with a one-week exacerbation of chronic respiratory symptoms, including cough, dendritic sputum production, and dyspnea, which had persisted for 27 years. His symptoms initially emerged after heavy physical exertion in 1997. He had a history of intermittently sucking gasoline through the mouth from 1990 to 2021. Imaging revealed multifocal patchy consolidations and linear opacities. Bronchoscopy showed a large amount of yellow sticky sputum in the right bronchi. Initially diagnosed and treated for fibrinous bronchitis, his condition worsened after corticosteroid discontinuation. Pathological examination of the sputum plug revealed macrophages with intracytoplasmic lipid vacuoles and abundant extracellular lipid droplets, confirming the diagnosis of exogenous lipoid pneumonia. Conclusions : Chronic respiratory symptoms accompanied by dendritic sputum should prompt a detailed exploration of hydrocarbon exposure history. When transbronchial biopsies lack classic lipid-laden macrophages, analyzing the mucous plug is paramount for confirming exogenous lipoid pneumonia.

Previous studies have shown that higher levels of physical activity (PA) are generally associated with a lower risk of developing gestational diabetes mellitus (GDM). however, evidence regarding the dose-response relationship remains limited. This study aims to investigate the dose-response relationship between PA and GDM during the second trimester of pregnancy. A hospital-based cross-sectional study was conducted at Beijing Changping Hospital of Integrated Chinese and Western Medicine from August 2018 to October 2019. A total of 476 pregnant women, between 14 and 22 weeks of gestation, were enrolled in the study. Participants were categorized into a GDM group (n = 84) and a non-GDM group (n = 392) based on the results of a 75-g oral glucose tolerance test (OGTT) performed at 24–28 weeks of pregnancy. General information, PA, and dietary data were collected through validated questionnaires. PA levels and daily dietary energy intake (DDEI) were calculated using standard methods. Statistical analyses were performed using SAS 9.4 and R 4.2.1 software. The dose-response analysis was conducted, and optimal cut-off values of PA for the prevention of GDM were determined using the restricted cubic spline (RCS) model. Additionally, univariate and multivariate logistic regression analyses were employed to validate the identified cut-off values. (1) Compared to the non-GDM group, levels of total PA, moderate-to-vigorous intensity physical activity (MVPA), and walking PA were significantly lower (p < 0.05). (2) Non-linear dose-response relationships were identified between total PA, MVPA, and walking PA and the risk of GDM (p < 0.001), with optimal cut-off values established at 1714 MET-min/w, 638 MET-min/w, and 1098 MET-min/w, respectively. (3) Logistic regression analysis indicated that the risk of GDM significantly decreased as PA levels surpassed the established cut-off values (p < 0.001). A non-linear dose-response relationship exists between PA and GDM during the second trimester of pregnancy. The risk of GDM diminishes as PA levels increase, suggesting that effective prevention of GDM may require achieving adequate levels of PA.

Background Super-enhancers (SEs) typically govern the expression of critical oncogenes and play a fundamental role in the initiation and progression of cancer. Focusing on genes that are abnormally regulated by SE in cancer may be a new strategy for understanding pathogenesis. In the context of this investigation, we have identified a previously unreported SE-driven gene IRF2BP2 in neuroblastoma (NB).Methods The expression and prognostic value of IRF2BP2 were detected in public databases and clinical samples. The effect of IRF2BP2 on NB cell growth and apoptosis was evaluated through in vivo and in vitro functional loss experiments. The molecular mechanism of IRF2BP2 was investigated by the study of chromatin regulatory regions and transcriptome sequencing.Results The sustained high expression of IRF2BP2 results from the activation of a novel SE established by NB master transcription factors MYCN, MEIS2, and HAND2, and they form a new complex that regulates the gene network associated with the proliferation of NB cell populations. We also observed a significant enrichment of the AP-1 family at the binding sites of IRF2BP2. Remarkably, within NB cells, AP-1 plays a pivotal role in shaping the chromatin accessibility landscape, thereby exposing the binding site for IRF2BP2. This orchestrated action enables AP-1 and IRF2BP2 to collaboratively stimulate the expression of the NB susceptibility gene ALK, thereby upholding the highly proliferative phenotype characteristic of NB.Conclusions Our findings indicate that SE-driven IRF2BP2 can bind to AP-1 to maintain the survival of tumor cells via regulating chromatin accessibility of the NB susceptibility gene ALK. Graphical Abstract Graphical representation of the regulatory mechanism of SE-driven-IRF2BP2 mediation in NB. The master TFs MYCN, HAND2, and MEIS2 bind to the IRF2BP2 SE region, thereby enhancing its transcriptional activation, and resulting in the upregulation of IRF2BP2 expression in NB. Meanwhile, IRF2BP2 recruits the chromatin pioneer factor AP-1 family, enhancing the transcriptional activation of ALK by regulating chromatin accessibility. Image created with Figdraw.com.

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism. METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL -6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha) in the rats. Histological analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in rats. The expression of vascular endothelial growth factor A (VEGF-A), phosphoinositide 3 -kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt), and phosphorylated Akt (p -Akt) in the small intestine was analyzed via Western blotting. RESULTS: XBJ improved intestinal microcirculation dysfunction in septic rats, alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa, and reduced the systemic inflammatory response. Moreover, XBJ upregulated the expression of VEGF-A, p-PI3K/total PI3K, and p-Akt/total Akt in the rat small intestine. CONCLUSION: XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway.

Emodin, derived from Rheum officinale and aloe, is known for its diverse benefits such as anti-inflammatory, antioxidant, and antibacterial properties. Currently, the impact of emodin on urosepsis is unclear. This study aims to investigate the mechanism of action of emodin in urosepsis. Peripheral blood mononuclear cells (PBMCs) were purchased from Cloud-Clone Animal Inc. and treated with emodin. Cell viability and the lactate dehydrogenase (LDH) level were then assessed. In a separate experiment, a urosepsis model was established in Sprague Dawley rats which were subsequently treated with emodin. The levels of oxidative stress-related factors, serum complements and inflammatory factors were measured using commercial kits. Blood urea nitrogen and serum creatinine levels were determined using a fully automatic biochemical analyzer. The levels of pro-inflammatory proteins and AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) pathway-related proteins were evaluated via Western blot. PBMCs were unaffected by emodin concentrations below 60 μg/mL, and minimal LDH levels were detected in the cells. Emodin attenuated the effects of Escherichia coli and diminished the production of serum complements, oxidative stress-related proteins, and inflammatory factors in PBMCs. Notably, the effects of emodin were lessened by an AMPK pathway inhibitor. Additionally, emodin alleviated oxidative stress, complement system activation, inflammation, and kidney injury in urosepsis rats through the AMPK/SIRT1 signaling pathway. Emodin improved kidney damage in urosepsis rats by activating the AMPK/SIRT1 signaling pathway, which reduced oxidative stress, inflammation, and complement system activation.

Objectives:To observe the mitochondrial morphology of normal and triple-negative breast cancer cells, extract mitochondria from normal cells, and investigate the effects of mitochondrial transplantation on proliferation, apoptosis, and stemness of triple-negative breast cancer cells.Methods:The morphology of mitochondria was observed by transmission electron microscope. Mitochondria were extracted by mitochondrial extraction kit, mitochondrial protein was identified by western blot, and mitochondrial activity was detected by mitochondrial membrane potential detection kit. MitoTracker Green or MitoTracker Deep Red fluorescent probes were used to label the mitochondria of living cells, and the degree of mitochondria entering LTT cells was observed by confocal laser microscopy at 12, 24, and 96 hours. The effects of mitochondrial transplantation on proliferation, apoptosis, and stemness of breast cancer cells were examined by CCK8, colony formation assay, flow cytometry, and sphere formation assay after 24 hours of mitochondrial transplantation.Results:The mitochondria of normal cells were rod-shaped or elongated, while the mitochondria of triple-negative breast cancer cells were swollen and vacuolated. Western blot results showed that cytochrome c oxidase subunit I (MT-CO1) protein encoded by mitochondria was present in the isolated mitochondria. The content of heat shock protein 60 (HSP60) was higher in mitochondria than that in cytoplasm. The result of the multi-mode microplate reader showed that the content of mitochondrial J-aggregates/monomer was 1.67±0.06, which was significantly higher than 0.35±0.04 of the control group ( P＜0.001). Exogenous mitochondria were observed in LTT cells at 12, 24, and 96 hours after mitochondrial transplantation. The results of the CCK8 experiment showed that OD450 of LTT cells was 0.27±0.13 after 48 hours transplantation, which was lower than 0.62±0.36 of the control group ( P=0.023). The OD450 of MDA-MB-468 cells was 0.30±0.03, which was lower than 0.65±0.10 of the control group ( P=0.004). After 120 hours of mitochondrial transplantation, OD450 in both groups was still significantly lower than that in the control group (P＜0.01). The number of clones formed by mitochondrial transplantation of LTT cells was 21.33±7.31, which was lower than 35.22±13.59 of the control group ( P=0.016). Flow cytometry showed that the early apoptosis rate of LTT cells was (30.07±2.15)% after 24 hours of mitochondrial transplantation, which was higher than 2.07±1.58 of the control group ( P＜0.001). The proportion of early apoptosis in MDA-MB-468 cells was 24.47%±5.22%, which was higher than (7.83±2.06)% in the control group ( P=0.007). In addition, the number of mitochondria transplanted LTT cells into the cell sphere was 46.25±5.40, which was significantly lower than 62.58±6.43 of the control group ( P＜0.001). Conclusion:Normal mitochondria can enter triple-negative breast cancer cells by co-culture, inhibit the proliferation and stemness of triple-negative breast cancer cells, and promote the apoptosis of triple-negative breast cancer cells.

Abstract Background Cancer stem cells (CSCs) are responsible for drug resistance, cancer relapse, and metastasis. Here, we report the first analysis of Palladin expression and its impacts on stem cell‐like properties in lung cancer. Methods Tissue microarrays were used to investigate Palladin expression and its association with prognosis. Immunofluorescence (IF), flow fluorescence assay, and Western blot were performed to detect Palladin expression in 6 NSCLC cell lines. Cell phenotypes and drug resistance were evaluated. Xenograft models were constructed to confirm the role of Palladin in vivo. Results By using the tissue microarrays, Palladin was identified to be highly expressed in the cytoplasm, specifically in the cytomembrane of NSCLC, and its high expression is associated with poor prognosis. Palladin is widely expressed and enriched in the sphere cells. The in vitro and in vivo studies showed that Palladin promoted stem cell‐like properties, including cell viability, invasion, migration, self‐renewal abilities, taxol resistance, and tumorigenicity. Western blot revealed that Palladin promoted the accumulation of β‐catenin and activated Wnt/β‐catenin signaling. Tissue microarrays analysis further confirmed the positive correlation between Palladin and β‐catenin. Wnt/β‐catenin pathway inhibitor blocked the Palladin‐induced enhancement of sphere‐forming. Conclusions Palladin might act as an oncogene by promoting CSCs‐like properties and tumorigenicity of NSCLC cells via the Wnt/β‐catenin signaling pathway. Besides, Palladin was identified to have the potential as a cell surface marker for LCSCs identification. These findings provide a possible target for developing putative agents targeted to LCSCs.

Objective:To investigate the mechanism of dexmetomidine (DEX) in improving lung injury in septic mice.Methods:Male C57BL/6 mice were randomly assigned to the blank group (NC), sham operation group (sham), cecal ligation and puncture group (CLP), and Dex treatment group (CLP+DEX), 36 mice per group. Mice in the CLP group were intraperitoneally injected with 1 mL sterile saline 15 min before CLP, and mice in the CLP + DEX group were intraperitoneally injected with 50 μg/kg DEX 15 min before CLP. The survival rate was recorded within 24 h after CLP. The mice were sacrificed at 0, 3, 6, 12, and 24 h after CLP, and lung tissues were collected. The expression levels of cytokines (IL-6, IL-1β, TNF-α) and lncRNA-HOTAIR in the lung of mice were detected by qPCR. RAW264.7 cell were cultured in vitro, LPS (100 ng/mL) and DEX (1 μ mol/L) were used to establish a cell model for studying the mechanism of Dex, and the expression of cytokines (IL-6, IL-1β, TNF-α) and lncRNA-HOTAIR in RAW264.7 cell model were detected by qPCR. In addition, the effect of lncRNA-HOTAIR on sepsis was explored in vivo and in vitro by knockdown or overexpression of HOTAIR.Results:The survival rate of the CLP+DEX group was higher than that of the CLP group within 24 h after surgery, and the levels of IL-6, IL-1β, and TNF-α in the lungs were significantly lower than those in the CLP group at 6, 12, and 24 h after surgery ( P<0.05). In addition, the level of lncRNA HOTAIR showed that the expression level of lncRNA HOTAIR in the lungs of mice were decreased after Dex treatment, and were decreased 1.1 times ( P<0.05), 4.0 times ( P<0.01) and 3.8 times ( P<0.01) at 6, 12, and 24 h, respectively. Compared with the NC group, knockdown of HOTAIR significantly decreased the levels of IL-1β, IL-6, and TNF-α in septic mice ( P<0.05), and overexpression of HOTAIR significantly increased the levels of IL-1β, IL-6, and TNF-α in septic mice ( P<0.01). Conclusions:DEX can reduce the production of inflammatory factors in the lungs of septic mice and improve the survival rate of septic mice. The mechanism may be related to the inhibition of HOTAIR expression.

目的 探讨高转移潜能肝癌细胞来源的外泌体对肝癌细胞的迁移侵袭能力、干性特征及上皮-间质转化等恶性表型的影响及其可能的作用机制.方法 差速离心法提取高转移潜能肝癌细胞HCCLM3的外泌体,采用透射电镜(TEM)、蛋白质印迹、纳米颗粒跟踪分析(NTA)实验对外泌体进行鉴定,免疫荧光实验检测高转移肝癌细胞外泌体可以被肝癌细胞内吞而发挥作用;分别采用无血清成球实验、Transwell实验、CCK-8实验、克隆形成实验检测高转移肝癌细胞外泌体对肝癌细胞的自我更新、迁移侵袭和增殖能力的影响;蛋白质印迹实验检测高转移肝癌细胞外泌体处理后肝癌细胞中干性相关标志物以及PI3K/AKT/mTOR信号通路蛋白表达量的变化.结果 高转移潜能细胞条件培养基(CM)促进肝癌细胞的迁移侵袭和自我更新能力.在MHCC97L细胞中,迁移结果显示,高转移条件培养基组迁移数(92.33±5.03)明显高于正常培养基组(57.66±4.04)和移除外泌体条件培养基组(32.33±3.05),F=160.10,P＜0.001;侵袭结果显示,高转移条件培养基组迁移数(105.33±12.58)高于正常培养基组(65.33±9.01)和移除外泌体条件培养基组(26.00±4.35),F=54.75,P＜0.001.在Bel-7402细胞中,迁移结果显示,高转移条件培养基组迁移数(143.66±23.00)明显高于正常培养基组(73.33±12.58)和移除外泌体条件培养基组(38.00±6.08),F=35.94,P＜0.001;侵袭结果显示,高转移条件培养基组迁移数(155.33±6.65)也显著高于正常培养基组(75.33±10.21)和移除外泌体培养基组(38.00±3.61),F=200.00,P＜0.001.无血清成球结果显示,在MHCC97L细胞中,高转移条件培养基组成球个数(165.66±19.21)高于正常培养基组(113.0±14.17)和移除外泌体条件培养基组(74.33±7.76),F=29.99,P＜0.001;在Bel-7402细胞中,高转移条件培养组(165.66±28.02)也显著高于正常培养基组(99.66±11.67)及移除外泌体条件培养基组(63.00±7.21),F=25.02,P＜0.01.成功提取高转移潜能肝癌细胞HCCLM3的外泌体,透射电镜下细胞的外泌体呈双层囊泡样结构并且表达外泌体的分子标志物CD63、CD81和TSG101.Nanogsight纳米粒径分析仪显示,外泌体颗粒呈现无规则的布朗运动,直径在40～150 nm HCCLM3细胞的外泌体直径最高峰为132 nm;经HCCLM3细胞外泌体处理48 h后,肝癌细胞MHCC97L、Bel-7402增殖能力显著增强,在MHCC97L中,对照组和外泌体组克隆形成数分别为278.80±33.47和354.00±47.18,t=3.183,P＜0.01;在Bel-7402细胞中,对照组和外泌体组克隆形成数分别为205.83±29.86和290.20±53.38,t=3.377,P＜0.01;迁移、侵袭能力也显著增强,在MHCC97L中,对照组和加入外泌体组迁移数分别为37.67±8.32和81.00±12.77,t=4.924,P＜0.01;侵袭数分别为24.67±5.85和63.00±9.00,t=6.182,P＜0.01.在Bel-7402中,对照组和加入外泌体组迁移数分别为62.00±8.54和113.33±11.50,t=6.205,P＜0.01;侵袭数分别为 47.00±9.16 和 175.00±20.66,t=9.808,P＜0.001.自我更新能力也显著增强,在MHCC97L中,对照组和外泌体组成球数分别为22.67±4.51和42.00±5.00,t=4.973,P＜0.01;在Bel-7402 中,对照组和外泌体组成球数分别16.66±4.04和31.33±4.04,t=4.445,P＜0.05.蛋白质印迹实验结果显示,MH-CC97L和Bel-7402外泌体组和对照组相比,干性相关标志物OCT4、SOX2表达含量升高,均P＜0.05;上皮-间质转化蛋白E-cadherin含量下降(P＜0.05),Vimentin、Snail蛋白含量增高(均P＜0.05);2组细胞加入外泌体处理后,PI3K、AKT、mTOR磷酸化水平升高,均P＜0.05.结论 高转移潜能肝癌细胞外泌体可以增强肝癌细胞的干性和上皮-间质转化能力来促进其转移,同时可以通过激活PI3K/AKT/mTOR信号通路来发挥其作用.

Liver cancer stem cells (LCSCs) are recognized as key contributors to hepatocarcinogenesis, progression, and recurrence. Consequently, eradicating LCSCs has a great chance of increasing long-term survival in patients with liver cancer. Parthenolide (PTL), a natural sesquiterpene lactone product, possesses robust antitumor activity. However, the effects of PTL on LCSCs and underlying mechanisms remain unknown. Here we show that administration of PTL stimulated cell cycle arrest at the G1 phase, induced apoptosis, and decreased the stemness of LCSCs. Further research indicates that PTL caused the production of ROS and the reduction of oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential (MMP) levels of LCSCs. RNA sequencing (RNA-Seq) further shows that PTL decreased SLC25A1 expression at the mRNA level and that inhibition of SLC25A1 synergistically decreased the expression of IDH2 and several pivotal genes involved in mitochondrial respiratory chain complex, resulting in the production of ROS and mitochondrial dysfunction. In addition, the inhibitory effect of PTL on mitochondrial function and self-renewal capacity of LCSCs was abolished by the knockdown of SLC25A1 or treatment with SLC25A1 inhibitor CTPI-2. Importantly, PTL prevented liver cancer growth in vivo without clearly causing toxicity. Our research shows that PTL inhibits the growth and stemness of LCSCs through SLC25A1-mediated mitochondrial function. PTL may be a potential candidate natural agent for liver cancer treatment.

Liver cancer is among the leading causes of cancer-related death worldwide and China accounts for nearly half of the global burden of liver cancer. Effective interventions such as hepatitis vaccinations, new blood tests and imaging tests significantly decreased the incidence worldwide, especially in China. Unraveling the systemic and molecular mechanisms of liver cancer would contribute to develop more effective therapies to prolong the 5 year survival of the patients. The Chinese funding agencies have been paying high attention to the basic and translational research of liver cancer. Over the last decade, the National Natural Science Foundation of China (NSFC) initiated a panel of research programs which supported liver cancer research in multiple directions. Besides, great progress has been made in basic and clinical research, platform construction and drug development in the field of liver cancer. In this article, we summarized the funding landscape, research progress, cooperation among countries and institutions, and drug discovery in China, with an attempt to compare the status and outcome with our peers globally.

CRISPR-Cas base editing (BE) system is a powerful tool to expand the scope and efficiency of genome editing with single-nucleotide resolution. The editing efficiency, product purity, and off-target effect differ among various BE systems. Herein, we developed CRISPRbase (http://crisprbase.maolab.org), by integrating 1 252 935 records of base editing outcomes in more than 50 cell types from 17 species. CRISPRbase helps to evaluate the putative editing precision of different BE systems by integrating multiple annotations, functional predictions and a blasting system for single-guide RNA sequences. We systematically assessed the editing window, editing efficiency and product purity of various BE systems. Intensive efforts were focused on increasing the editing efficiency and product purity of base editors since the byproduct could be detrimental in certain applications. Remarkably, more than half of cancer-related off-target mutations were non-synonymous and extremely damaging to protein functions in most common tumor types. Luckily, most of these cancer-related mutations were passenger mutations (4840/5703, 84.87%) rather than cancer driver mutations (863/5703, 15.13%), indicating a weak effect of off-target mutations on carcinogenesis. In summary, CRISPRbase is a powerful and convenient tool to study the outcomes of different base editors and help researchers choose appropriate BE designs for functional studies.

乳腺癌是全球女性发病率第一的癌症,也是导致女性癌症死亡的主要原因.线粒体异常广泛存在于多种肿瘤中,并且在细胞癌变和肿瘤进展中发挥重要作用.乳腺癌中线粒体的异常主要包括线粒体形态异常、氧化磷酸化异常、动力学异常和线粒体DNA突变.近年来,研究发现外源性线粒体移植可替代肿瘤细胞中受损的线粒体,缓解肿瘤细胞的线粒体功能障碍,帮助细胞进行自我修复.本文就乳腺癌线粒体异常和线粒体移植在乳腺癌中的治疗策略作一综述.

Supplementary Data from Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis

BACKGROUND:Sepsis-induced liver injury is a fatal complication of sepsis.Trichostatin A(TSA)regulates inflammation and autophagy in some human diseases,and forkhead box O3a(FoxO3a)has been shown to regulate autophagy.The present study aims to investigate whether TSA exerts its effects on septic liver injury through the FoxO3a/autophagy signaling pathway.METHODS:Asepsis mouse model was constructed by the cecal ligation and puncture(CLP)method,and AML12 cells were pretreated with lipopolysaccharide(LPS)(1 μg/mL)to establish a sepsis cell model.Forty mice were divided into four groups,namely control group,TSA group,CLP group,and CLP+TSA group,with 10 mice in each group.Cells were divided into control group,TSA group,LPS group,and LPS+TSA group.Hematoxylin-eosin(H&E)staining and biochemical methods were used to evaluate liver tissue injury.Enzyme-linked immunosorbent assay(ELISA)was applied to detect the expression of proinflammatory cytokines,and Western blotting and immunofluorescence were used to measure autophagy-related protein expression.RESULTS:Compared with the CLP group(mice),the proinflammatory cytokines(interleukin-β[IL-β]2,665.27±324.90 pg/mL to 2,080.26±373.66 pg/mL;interleukin-6[IL-6]399.01±60.98 pg/mL to 221.90±46.89 pg/mL)and the hepatocyte injury markers(aspartate transaminase[AST]from 198.18±27.07 U/L to 128.42±20.55 U/L;alanine aminotransferase[ALT]from 634.98±74.10 U/L to 478.60±32.56 U/L)were notably decreased after TSA intervention.Moreover,LC3 II and FoxO3a showed an obvious increase and P62 showed an obvious decrease in the CLP+TSA group.Cell experiment results showed the similar trend.After FoxO3a gene was knocked down in AML12 cells,the promotion of autophagy and the improvement of liver enzyme index and inflammation by TSA were weakened.CONCLUSION:TSA may improve the inflammatory response and liver injury in septic mice through FoxO3a/autophagy.

目的 本文研究羟基红花黄色素A(Hydroxysaffior yellow A,HSYA)对重症急性胰腺炎(severe acute pancreatitis,SAP)相关肺损伤的保护作用及其机制.方法 50只小鼠随机数字法分成5组(每组10只):假手术组,SAP组和不同剂量(20,40和80 mg/kg)HSYA预处理组.在SAP诱导前24 h,采用HSYA预处理小鼠,并在造模72 h后分离胰腺和肺组织用于组织病理学检查,并收集支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)用于生化分析.结果 与对照组相比,SAP组血清淀粉酶活性、肺损伤病理评分和BALF蛋白浓度均显著增高[(2120.44±354.5)U/L vs.(226.72±20.84)U/L;(6.91±0.28)vs.(0.53±0.18);(2563.25±348.22)μ g/mL vs.(345.62±56.35)μ g/mL,均P＜0.05];炎性因子 tumor necrosis factor(TNF)-α 和 interleukin(IL)-6 水平和髓过氧化物酶(myeloperoxidase,MPO)活性升高[(120.5±14.25)pg/mL vs.(31.5±4.82)pg/mL;(214.72±10.62)pg/mL vs.(39.26±5.66)pg/mL;(4.52±0.34)Units/mg vs.(1.03±0.17)Units/mg].与SAP组相比,HSYA预处理显著减轻SAP相关胰腺和肺组织损伤以及BALF中炎性因子TNF-α、IL-6和MPO活性.此外,HSYA促进抗氧化蛋白血红素氧合酶l(heme oxygenase-1,HO-1)表达,并阻断NF-κB信号通路激活.结论 HSYA可以发挥抗炎和抗氧化活性从而抑制SAP相关肺损伤,表明HSYA可能是SAP诱导肺损伤的潜在治疗药物.

Background: mRNA-based cancer vaccines have been considered a promising anticancer therapeutic approach against various cancers, yet their efficacy for malignant mesothelioma (MESO) is still not clear. The present study is designed to identify MESO antigens that have the potential for mRNA vaccine development, and to determine the immune subtypes for the selection of suitable patients. Methods: A total of 87 MESO datasets were used for the retrieval of RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA) databases. The possible antigens were identified by a survival and a genome analysis. The samples were divided into two immune subtypes by the application of a consensus clustering algorithm. The functional annotation was also carried out by using the DAVID program. Furthermore, the characterization of each immune subtype related to the immune microenvironment was integrated by an immunogenomic analysis. A protein–protein interaction network was established to categorize the hub genes. Results: The five tumor antigens were identified in MESO. FAM134B, ALDH3A2, SAV1, and RORC were correlated with superior prognoses and the infiltration of antigen-presenting cells (APCs), while FN1 was associated with poor survival and the infiltration of APCs. Two immune subtypes were identified; TM2 exhibited significantly improved survival and was more likely to benefit from vaccination compared with TM1. TM1 was associated with a relatively quiet microenvironment, high tumor mutation burden, and enriched DNA damage repair pathways. The immune checkpoints and immunogenic cell death modulators were also differentially expressed between two subtypes. Finally, FN1 was identified to be the hub gene. Conclusions: FAM134B, ALDH3A2, SAV1, RORC, and FN1 are considered as possible and effective mRNA anti-MESO antigens for the development of an mRNA vaccine, and TM2 patients are the most suitable for vaccination.

目的 阐述结直肠癌脑转移患者的临床病理特征,综述其诊断和治疗进展,为我国结直肠癌脑转移患者的全程管理提供参考.方法 对结直肠癌脑转移的最新研究结果和既往文献进行综述.结果 结直肠癌脑转移患者预后较差,其分子病理机制复杂多样,已发现一些与结直肠癌脑转移发生相关的危险因素.结直肠癌脑转移的典型影像学特征有助于对其诊断.目前,放射治疗仍然是结直肠癌脑转移患者的主要治疗手段,贝伐珠单抗治疗、免疫治疗联合放射治疗有望提高结直肠癌脑转移患者的生存率及延长生存期.结论 科学规范的预防和诊治有利于降低结直肠癌脑转移发病率和提高患者生存率.