OBJECTIVE:To explore the potential molecular targets and mechanisms of sodium butyrate (NaB) in the treatment of Hirschsprung disease (HSCR), with a focus on analyzing its regulatory effects on enteric glial cell function and neurogenesis. METHODS:A HSCR rat model was established, and targeted metabolomics was used to detect differences in short-chain fatty acids (SCFAs) between sham and model groups. Rats were treated with a mixture of SCFAs and immunofluorescence was used to assess the expression of neurogenesis markers in colon tissues. Network pharmacology identified potential targets of NaB, a major SCFA component. Molecular docking was performed to evaluate the binding affinity between NaB and selected target proteins. Sodium butyrate was applied to the enteric glial cell line in vitro. The expression levels of glial cell and neural stem cell markers were measured using qRT-PCR, Western blot, and immunofluorescence assays. Cell migration was assessed by Transwell assays, apoptosis and proliferation were analyzed by flow cytometry. siRNA transfection was conducted to knock down candidate genes in vitro. RESULTS:Targeted metabolomics showed significantly reduced SCFAs in HSCR rats; exogenous SCFAs treatment increased Nestin and p75NTR in colon tissue. Network pharmacology showed significant overlap between NaB and HSCR targets, with Klf4 as a core node. After NaB treatment, the expression of the glial cell marker Gfap decreased, while the expression levels of stem cell markers Nes and p75NTR were upregulated. Correspondingly, low concentrations of NaB significantly enhanced the migratory ability of EGCs, with no obvious effect on proliferation and apoptosis. Mechanistically, NaB inhibits demethylase Kdm2a, increases H3K36me2 levels, and activates Klf4 expression. CONCLUSION:This study reveals that NaB promotes the transformation of enteric glial cells into an undifferentiated stem cell-like state and reshapes the neurogenic microenvironment through epigenetic reprogramming (Kdm2a/H3K36me2/Klf4 axis), providing new potential targets and therapeutic strategies for the treatment of HSCR.

Bile reflux, resulting from pancreaticobiliary reflux (PBR), not only alters the chemical of bile but also constitutes a significant risk factor for the occurrence and development of gallbladder cancer. In previous studies, the authors identified a marked elevation of palmitic acid (PA) levels in the bile of patients with PBR. This study seeks to elucidate the mechanisms of promoting the migration of gallbladder cancer cells, with the objective of contributing novel strategies and theoretical foundations for the treatment of gallbladder cancer. We performed a cytotoxicity screening on the NOZ and GBC-SD human gallbladder cancer cell line using varying concentrations of palmitic acid. These following methodologies were employed to investigate the mechanism of PA in NOZ and GBC-SD cells. Intracellular lipid droplet accumulation was assessed using Oil red O staining, while cell migration capability was evaluated through the Transwell migration assay. Reactive oxygen species (ROS) levels were quantified using the superoxide anion fluorescent probe, Dihydroethidium (DHE), in conjunction with a ROS detection kit. The expression levels of relevant genes and proteins were analyzed using Western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence (IF) techniques. In NOZ and GBC-SD cells, it was observed that palmitic acid facilitates the accumulation of intracellular lipid droplets and diminishes cellular activity while augmenting the cells’ migratory capacity. Furthermore, elevated concentrations of PA have been shown to increase ROS levels in NOZ and GBC-SD cells. This elevation also activates the Nuclear factor-kappa B (NF-κB) and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Antioxidant Response Element (ARE) signaling pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) to NOZ and GBC-SD cells treated with high concentrations of PA effectively inhibits the enhancement of cell migration and epithelial-mesenchymal transition (EMT) induced by PA. PA promotes EMT in human gallbladder cancer cells by overproducing ROS and activating the NF-κB and NRF2/ARE signaling pathways, thereby facilitating increased migration.

Objective:To explore the neuro-genesis/-protection of short-chain fatty acids (SCFAs) in model mice of Hirschsprung disease (HSCR).Methods:Eighteen Ednrb -/- HSCR model mice were randomized into three groups of blank, normal control and treatment of short chain fatty acids (SCFAs) (n=6 each). The treatment group received a daily rectal dose of 0.1 ml of SCFAs starting from Day 5 after birth for 1 week.Routine primary culture of enteric neural crest precursor cells, after the intervention of SCFAs, cell migration was detected by cell scratch healing assay.The oxidative stress model of enteric neural crest precursor cells was established and cell proliferation/viability detected by combining CCK-8 method.Ednrb -/- immunohistochemical assessment of ganglion cell distribution was conducted in distal colon.Statistical analysis was performed with Graphpad Prism 8.0. Results:After 48-hour treatment, the diameter of enteric neurospheres derived from enteric neural crest cells was (85.7±22.0) μm in SCFAs group and (61.4±18.6) μm in normal control group.The proportion of neurospheres with a diameter in the range of 100-150 μm was 28.3% in SCFAs group while no neurospheres with a diameter in that range was present in normal control group.In cell scratch assay, healing rate was significantly higher in SCFAs group than that in normal control group [(35.4±4.5)% vs (20.2±1.7)%] with a statistical significance ( P<0.05). In cell oxidative stress model, CCK-8 OD values in normal control, oxidative stress and oxidative stress plus SCFAs groups were (0.55±0.02), (0.44±0.01) and (0.61±0.03) and the differences among three groups were statistically significant ( P<0.01). After SCFAs intervention, the median survival time was 21 days in SCFAs group and 10.5 days in control group with a statistical significance ( P<0.01). The densities of Hu c/d-positive cells in normal control and Ednrb -/-+ SCFAs groups were (950.3±72.1) and (205.7±11.0) cells/mm 2 and no positive cells was present in blank group with a statistical significance ( P<0.01). The densities of Tuj1-positive nerve fibers were (32.9±1.4)%, (1.7±0.3)% and (8.4±0.4)% in normal control, Ednrb -/- and Ednrb -/-+ SCFAs groups and the differences were statistically significant ( P<0.01). Conclusions:ENCCs in SCFAs group have statistical advantages in terms of proliferation, migration and oxidative stress.The Ednrb -/-+ SCFAs group of mice had statistically significant differences in terms of survival time, number of Hu c/d-positive cells and nerve fiber density, indicating that SCFAs have neuro-genesis/-protection on the nerves of mice with HSCR model.

PURPOSES:To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT).METHODS:The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration.RESULTS:By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression.CONCLUSIONS:The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.

Background: Circulating tumor cells (CTCs) can adsorb and activate platelets to form a microthrombus protective barrier around them, so that therapeutic drugs and immune cells cannot effectively kill CTCs. The platelet membrane (PM) bionic carrying drug system has the powerful ability of immune escape, and can circulate in the blood for a long time.Materials and methods: we developed platelet membrane coated nanoparticles (PM HMSNs) to improve the precise delivery of drugs to tumor sites and to achieve more effective immunotherapy combined with chemotherapy strategy.Results: Successfully prepared aPD-L1-PM-SO@HMSNs particles, whose diameter is 95-130 nm and presenting the same surface protein as PM. Laser confocal microscopy and flow cytometry experimental results showed that the fluorescence intensity of aPD-L1-PM-SO@HMSNs was greater than SO@HMSNs that are not coated by PM. Biodistribution studies in H22 tumor-bearing mice showed that due to the combined action of the active targeting effect and the EPR effect, the high accumulation of aPD-L1-PMSO@HMSNs in the local tumor was more effective in inhibiting tumor growth than other groups of therapeutic agents.Conclusion: Platelet membrane biomimetic nanoparticles have a good targeted therapeutic effect, which can effectively avoid immune clearance and have little side effects. It provides a new direction and theoretical basis for further research on targeted therapy of CTCs in liver cancer.& COPY; 2023 Elsevier Inc. All rights reserved.

The emergence of targeted drugs brings hope to patients with advanced liver cancer. However, due to the complex and diverse environment in the human body, the overall response rate of targeted drugs is not high. Therefore, how to efficiently deliver targeted drugs to tumor sites is a major challenge for current research. The project intends to construct mPEG-PLGA nanoparticles loaded with Sora and encapsulate them with exosomes for targeted therapy of hepatocellular carcinoma. mPEG-PLGA drug-loaded nanoparticles were prepared by the dialysis method and characterized by TEM and DLS. The obtained nanoparticles were incubated with the exosomes of liver cancer cells, and the exosomes-encapsulated drug-loaded nanoparticles (Exo-Sora-NPs) were obtained under pulsed ultrasound conditions, and they were characterized by Western blot, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The toxic effect of Exo-Sora-NPs on liver cancer cells was detected by the CCK-8 experiment. The uptake efficiency of nanoparticles by liver cancer cells was detected by a confocal microscope. The accumulation and infiltration depth of nanomedicine in liver cancer tissues were observed by confocal microscope on frozen sections of liver cancer tissue after the H22 liver cancer subcutaneous tumor transplantation model was constructed. The tumor size, body weight, pathology, and serology analysis of mice were measured after administration. The mPEG-PLGA polymer drug-loaded particles encapsulated by exosomes have high targeting ability and biosafety. To a certain extent, they can target the drug to the tumor site with a smaller systemic response and have a highly effective killing effect on the tumor. Nanodrug-loaded particles encapsulated by exosomes have great potential as drug carriers.

有限集模型预测控制(finite control set model predictive control,FCS-MPC)由于便于植入、可实现多目标跟踪等优点,在并网变换器控制系统中获得了广泛关注.然而,电感参数失配将直接影响FCS-MPC的预测精度.此外,传统FCS-MPC开关频率不固定导致并网电流纹波大、权重因子取值困难、迭代寻优过程繁琐.基于此,该文针对Vienna整流器预测控制存在的控制误差大、权重系数整定难、运算量大的问题,在建立滤波电感对并网性能的解析基础上,提出一种引入电感参数在线辨识的直接功率快速模型预测恒频控制策略(fast model predictive with constant frequency based on parameters online identification,F-MPCCF).通过优选对中点电位平衡有利的冗余矢量,构建了基于直接功率的单目标代价函数,有效避免了权重因子选取问题,结合零矢量调节的方式进而实现类SVPWM调制,实现了开关状态的平滑切换.最后,从静态、暂态、中点电位平衡控制等多个维度进行了仿真与测试分析验证,结果表明所提出的F-MPCCF具有良好的稳态和动态性能.

Background Increasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; however, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized. Methods The expression levels of TUG1, miR-524-5p, and sine oculis homeobox homolog 1 (SIX1) were determined using quantitative real-time PCR. The regulatory relationships were confirmed by dual-luciferase reporter assay. Cell proliferation and invasion were assessed using Cell Counting Kit 8 and transwell assays. Glucose uptake, cellular levels of lactate, lactate dehydrogenase (LDH), and adenosine triphosphate (ATP) were detected using commercially available kits. Silencing of TUG1 or SIX1 was performed by lentivirus transduction. Protein levels were measured by immunoblotting. Results Cancer-associated fibroblasts (CAFs)-secreted exosomes promoted migration, invasion, and glycolysis in HepG2 cells by releasing TUG1. The promotive effects of CAFs-secreted exosomes were attenuated by silencing of TUG1. TUG1 and SIX1 are targets of miR-524-5p. SIX1 knockdown inhibited the promotive effects of miR-524-5p inhibitor. Silencing of TUG1 suppressed tumor growth and lung metastasis and therefore increased survival of xenograft model mice. We also found that TUG1 and SIX1 were increased in HCC patients with metastasis while miR-524-5p was decreased in HCC patients with metastasis. Conclusions CAFs-derived exosomal TUG1 promoted migration, invasion, and glycolysis in HCC cells via the miR-524-5p/SIX1 axis. These findings may help establish the foundation for the development of therapeutics strategies and clinical management for HCC in future.

An eco-friendly biosynthesized Ag NPs immobilized Hibiscus rosa-sinensis extract has been introduced. The as-prepared nanoparticles were characterized using UV–Vis, SEM, and FT-IR analysis. In the FT-IR test, the presence of many antioxidant compounds with related bonds caused the excellent condition for reducing of silver in the silver nanoparticles. In UV–Vis, the clear peak in the wavelength of 428 nm indicated the formation of silver nanoparticles. The synthesized nanoparticles had very low cell viability and high anti-liver cancer activities dose-dependently against pleomorphic hepatocellular carcinoma (SNU-387), hepatic ductal carcinoma (LMH/2A), morris hepatoma (McA-RH7777), and novikoff hepatoma (N1-S1 Fudr) cell lines without any cytotoxicity on the normal cell line (HUVEC). The synthesized nanoparticles inhibited half of the DPPH molecules in the concentration of 78 µg/mL. Perhaps notable anti-liver cancer activities of the synthesized nanoparticles against common liver cancer cell lines are linked to their antioxidant activities.

目的 分析不同人种乳腺癌的差异表达基因及关键蛋白调控基因与预后的关系.方法 基于TC-GA数据库中不同人种乳腺癌转录组表达谱来筛选差异表达基因,并进行基因本体论注释和京都基因与基因组百科全书(KEGG)富集分析.应用STRING数据库构建蛋白质互相作用网络,并在Cytoscape软件中进行可视化和模块挖掘,获取关键蛋白调控基因.结合对应的临床信息使用R软件对这些关键蛋白调控基因绘制生存曲线进行验证.结果 共筛选出差异表达基因894个,其中上调基因875个,下调基因19个.差异表达基因主要与角化作用、表皮细胞分化等生物学过程有关,与角质化包膜、中间丝细胞骨架、角蛋白丝等细胞组分有关,与皮肤表皮的结构成分、葡萄糖醛酸转移酶活性等分子功能有关.KEGG通路主要与细胞色素P450代谢异种生物、戊糖和葡萄糖醛酸转换、化学致癌作用等有关.结论 关键蛋白调控基因CASP14、MYF6、ALB与不同人种乳腺癌的发生和预后有紧密的关系,为精准治疗提供了新思路.

目的:探索三维数字成像手术计划系统在肝切除术中的应用.方法:采用三维手术计划系统(Myrian)用于临床精准肝切除.2015年1月至2018年1月,95例肝癌患者,其中传统手术组67例采用传统肝切除,手术的设计、规划和实施都是基于传统的二维图像.3D组28例均采用三维数字成像手术计划系统指导下的精准肝切除.比较两组手术时间、出血量、住院时间和并发症.结果:(1)术前三维手术系统预估的病灶切除体积与术后肝脏实际切除体积差异无统计学意义(P>0.05);(2)3D组患者术后胸腔积液、胆漏、肺部感染、切口感染、肝衰竭的发生率以及1年生存率分别为5.26％、0、1.75％、2.6％、0、92.31％,传统手术组分别为8.9％、1.49％、4.47％、2.98％、1.49％、78.85％,两组差异无统计学意义(P>0.05).3D组肿瘤复发率(7.69％)低于传统手术组(15.38％)(P<0.05);(3)传统手术组患者术中出血量、术后住院时间、手术时间、肝血管阻断时间、围手术期死亡病例数为(628.5±124.4)mL、(11.4±4.3)d、(117.1±32.4)min、(38.4±10.2)min、1例,3D组分别为(416.7±83.8)mL、(7.6±2.4)d、(178.5±40.9)min、(48.3±12.7)min、0例,两组差异有统计学意义(P<0.05).结论:三维重建技术对肝癌患者术前评估有利于术者优化、选择精准肝切除手术方案.

交流微电网和直流微电网之间多通过电力电子变压器(PET)构成交直流混合微电网以减少额外的电能转换环节.但是PET中高频变压器的谐振参数常常限值了效率的提升,且谐振拓扑的细微变化也会进一步加剧参数设计的难度.针对该问题,提出一种面向交直流混合微电网(HADM)的双向谐振型高频直流变压器(HFT)通用型参数设计方法,明确只有在谐振电流与输入方波电压基频部分同频同相时传输的平均功率最高.并指出当变压器励磁电感与漏感之比大于一定值时,CLLC、LLC和CLL谐振型高频变压器均可工作在双向功率传输状态,且获得的标幺化增益和效率均满足HADM系统要求,CLLC更有利于功率的有效传输.最后,搭建了一台采用SiC器件的6 kW实验样机,实验结果进一步验证了所提设计方法的可行性和有效性.该样机在双向工作模式下的最高效率大于97％.

目的 探讨体外乏氧环境下低氧诱导因子-1α (hypoxia inducible factor-1α,HIF-1α)对诱导肝癌细胞逆向分化为肝癌干细胞并维持恶性生物学行为的影响.方法 采用免疫磁珠分选出HepG2细胞中的CD133阴性细胞,分为2个大组:转染组转染siRNA-HIF-1α以沉默HIF-1α基因的表达,空白对照组不转染任何siRNA片段.2类细胞分别进行常氧及乏氧条件培养,本实验共分4组.采用MTT、克隆形成实验及Transwell小室实验检测细胞的增殖和侵袭能力,采用Western blot法及RT-PCR法检测细胞中HIF-1α、CD133、CD90及CD44的mRNA及其蛋白的表达.结果 MTT实验结果显示:4组细胞的增殖率随乏氧培养时间延长而增高;24 h及以后,与空白对照组相比,经siRNA-HIF-1α转染后,转染常氧组和乏氧组的细胞增殖率降低(P＜0.05).平板克隆实验结果显示:转染常氧组与转染乏氧组、空白对照常氧组与空白对照乏氧组比较其细胞形成克隆数的差异均有统计学意义(P＜0.05).Transwell小室实验结果显示:乏氧培养后,转染组与空白对照组相比,迁移至下室的细胞数目减少(P＜0.05).Western blot及RT-PCR结果显示:空白对照乏氧组中HIF-1α及肿瘤干细胞标志物(CD133、CD90、CD44)蛋白及其mRNA的表达水平均高于其余3组(P＜0.05);经siRNA-HIF-1α转染后,转染乏氧组中HIF-1α及肿瘤干细胞标志物(CD133、CD90、CD44)蛋白及mRNA的表达水平均较转染常氧组和空白对照常氧组降低(P＜0.05).结论 在乏氧环境下,低氧诱导因子HIF-1α可促进肝癌细胞逆向分化为肝癌干细胞并增强其恶性生物学行为.

目的 探索导师制结合PBL教学模式在普通外科临床教学中的作用.方法 选择西安交通大学第二附属医院五年制见习学生,抽取2个班分为对照组与实验组,每组20人.对照组采用传统的教学方法,实验组采用导师制结合PBL教学模式,学习结束后对两组的教学效果 进行评估.结果 实验组教师教学效果评估及学生成绩评估均优于对照组(P＜0.05).结论 导师责任制结合PBL教学模式可以弥补单独使用PBL 教学模式的不足,有助于培养全面发展的适应新时代社会发展需要的高素质医学人才.

目的 探讨体素内不相干运动成像(IVIM)定量参数与直肠癌分期及分化程度的关系.方法 选取2015年3月至2019年2月西安交通大学第二附属医院收治的95例直肠癌患者,所有患者均行MRI检查,测定IVIM纯扩散系数(D)、灌注相关假扩散系数(D*)、灌注分数(f).MRI检查后2周内予以根治性手术.根据术中探查结果与术后病理报告确定患者TNM分期、分化程度、脉管神经侵犯情况.比较不同TNM分期、分化程度、脉管神经侵犯情况患者的D、D*、f值.结果 Ⅰ、Ⅱ期患者与Ⅲ、Ⅳ期患者的D、D*、f值的差异无统计学意义(P＞0.05).不同分化程度患者D *、f的差异无统计学意义(P＞0.05).高分化患者的D值显著高于中分化与低分化患者,中分化患者显著高于低分化患者(P＜0.05).脉管神经侵犯患者与未侵犯患者的D*、f的差异无统计学意义(P＞0.05).脉管神经侵犯患者的D显著低于未侵犯患者(P＜0.05).结论 IVIM-DWI参数可无创评估直肠癌恶性程度,分化程度低、发生脉管神经侵犯的D值相对更低,对直肠癌恶性程度的评估价值较高.

Colorectal cancer (CRC) is one of the most common cancers worldwide, and genetic variations exert distinct roles in its pathogenesis. Single nucleotide polymorphisms (SNPs) in interleukin 1 alpha (IL1A) were reported to be correlated to the susceptibility of diverse cancers. The aim of this study was to assess the association of IL1A SNPs with the risk of colorectal cancer in a Chinese Han population. To evaluate the correlation between IL1A polymorphisms and CRC risk, Agena MassARRAY platform was used for genotype determination among 248 CRC patients and 463 controls. The relationships between IL1A variants and CRC susceptibility were examined by logistic regression analysis. Stratified analysis was conducted for the association detection in males and females. Haplotype construction and analysis were applied to evaluate the potential relationship between the genetic block and the risk of CRC. SNP functional exploration was performed with available bioinformatics datasets. After adjusting for age and gender, the “AA” genotype of rs2856838 exhibited a risk association with colorectal cancer in the recessive model (adjusted OR = 1.98, 95% CI: 1.05–3.72, p = 0.036). With stratified analysis, the recessive models of rs3783550 (OR = 2.17, 95% CI: 1.03–4.60, p = 0.043), rs2856838 (OR = 2.58, 95% CI: 1.13–5.87, p = 0.024), rs1609682 (OR = 2.20, 95% CI: 1.04–4.65, p = 0.040), and rs3783521 (OR = 2.13, 95% CI: 1.01–4.49, p = 0.048) revealed significant relationships between these variants and an increased CRC risk only in females. Bioinformatics analysis also revealed the putative functions of the selected SNPs. This study demonstrated that rs2856838 could influence the susceptibility to CRC in Chinese Han population from northwest China. IL1A variants rs3783550, rs2856838, rs1609682, and rs3783521 were associated with CRC risk only in females.

The merger of postgraduate education in clinical medicine and resident standardized training is an effective way to cultivate high-quality clinical medical talents. Combined with our own experience, we have made an analysis from the following aspects: training objectives, training methods, tutorial idea renewal, the relationship between the clinical skills and scientific research, the medical humanities education importance and living subsidies, and so on. To explore how to improve the quality system training, perfecting the system of continuing medical education.