考虑CAV自主停车行为的混合交通均衡配流模型

为了评估网联自动驾驶汽车(CAV)的自主停车行为对交通系统效率的影响,建立了CAV通勤流、人工驾驶汽车(HDV)通勤流、CAV自主停车流3类交通流混行下的交通均衡配流模型.通过引入CAV停车需求内生变量,考虑CAV对路段通行能力的提升效应,从而定量描述CAV停车需求分布以及3类交通流在路段上混行的拥挤效应.分别采用用户均衡、随机用户均衡原则描述CAV、HDV出行者的路径选择行为,采用Logit离散选择模型描述自主停车CAV的停车场选择行为,由此建立多用户混合交通均衡条件以及等价的变分不等式(VI)模型.由于模型中CAV自主停车需求为未知的内生变量,提出一种改进的相继加权平均法求解该模型.最后,通过算例验证了混合交通均衡配流模型及求解算法的有效性.

面向混合编队领航CAVs的博弈换道决策模型

以CAVs为领航车的混合编队有助于实现更顺畅和安全的道路交通,但当前研究较少关注于具有多车道分布特征的混合编队形成问题。对此,本文提出了一种面向混合编队领航CAVs的博弈换道决策模型。该模型建立数学优化与博弈论相结合的换道决策机制,建立以最小化CAVs换道次数为目标的领航CAVs目标车道初始化流程,并依据CAVs博弈换道收益,更新领航CAVs目标车道,实现混合编队多车道分布。同时,基于博弈论建立CAVs与HDVs非合作博弈矩阵,综合考虑换道效率和安全性,分别设计时间和安全收益函数,量化CAVs换道风险,并使用交通软件SUMO建立微观仿真。实验结果表明,与基准模型相比,本文提出的博弈换道策略在不同混合交通量下混合编队完成率维持在97%以上,每组领航CAVs换道时间平均缩短约40%,每组领航CAV换道次数保持较低水平。

Comparative Study on the Immunogenicity and Efficacy of Different Post-exposure Intramuscular Rabies Vaccination Regimens in China

Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in terms of their safety,efficacy,and protection.Methods Mice were vaccinated according to different immunization schedules,and blood was collected for detection of rabies virus neutralizing antibodies(RVNAs)on days 14,21,28,35,and 120after the first immunization.Additionally,different groups of mice were injected with lethal doses of the CVS-11 virus on day 0,subjected to different rabies immunization schedules,and assessed for morbidity and death status.In a clinical trial,185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule,and blood was collected for RVNAs detection on days 28and 42 after the first immunization.Results A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day(P<0.05).The groups 0-3-7-14,0-3-7-21,and 0-3-7-28 showed no statistically significant difference(P>0.05)in RVNAs levels at any time point.The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%,whereas that in the immunization groups was 40%.In the clinical trial,the RVNAs positive conversion rates on days 28(14 days after 4 doses)and 42(14 days after 5 doses)were both 100%,and no significant difference in RVNAs levels was observed(P>0.05).Conclusion The simple 4-dose schedule can produce sufficient RVNAs levels,with no significant effect of a delayed fourth vaccine dose(14–28 d)on the immunization potential.

CAV1在消化道肿瘤中的研究进展

消化道肿瘤是目前全球最常见的癌症之一,包括食管癌、胃癌、肝癌、胰腺癌和结直肠癌等,其预后不佳,治疗方法仍需进一步改进。小窝蛋白-1(caveolin⁃1,CAV1)在消化道肿瘤中具有双重调节作用,既是肿瘤抑制因子又是致癌因子。CAV1对消化道肿瘤的细胞增殖、侵袭、转移、血管生成和药物耐受性等方面具有重要作用,调节CAV1蛋白及其相关信号通路可能成为治疗消化道肿瘤的策略之一。因此,本综述就CAV1的结构、功能、表达调控以及调节消化道肿瘤上皮-间充质转换(epithelial⁃mesenchymal transition,EMT)及其耐药性等方面分析CAV1与消化道肿瘤的关系,以期为临床消化道肿瘤的诊疗提供新的思路。

Autologous hematopoietic stem cell transplantation conditioning regimens and chimeric antigen receptor T cell therapy in various diseases

Conditioning regimens employed in autologous stem cell transplantation have been proven useful in various hematological disorders and underlying malignancies;however,despite being efficacious in various instances,negative consequences have also been recorded.Multiple conditioning regimens were extracted from various literature searches from databases like PubMed,Google scholar,EMBASE,and Cochrane.Conditioning regimens for each disease were compared by using various end points such as overall survival(OS),progression free survival(PFS),and leukemia free survival(LFS).Variables were presented on graphs and analyzed to conclude a more efficacious conditioning regimen.In multiple myeloma,the most effective regimen was high dose melphalan(MEL)given at a dose of 200/mg/m2.The comparative results of acute myeloid leukemia were presented and the regimens that proved to be at an admirable position were busulfan(BU)+MEL regarding OS and BU+VP16 regarding LFS.In case of acute lymphoblastic leukemia(ALL),BU,fludarabine,and etoposide(BuFluVP)conferred good disease control not only with a paramount improvement in survival rate but also low risk of recurrence.However,for ALL,chimeric antigen receptor(CAR)T cell therapy was preferred in the context of better OS and LFS.With respect to Hodgkin’s lymphoma,mitoxantrone(MITO)/MEL overtook carmustine,VP16,cytarabine,and MEL in view of PFS and vice versa regarding OS.Non-Hodgkin’s lymphoma patients were administered MITO(60 mg/m2)and MEL(180 mg/m2)which showed promising results.Lastly,amyloidosis was considered,and the regimen that proved to be competent was MEL 200(200 mg/m2).This review article demonstrates a comparison between various conditioning regimens employed in different diseases.

CAV1和CAV2在头颈部鳞状细胞癌组织中的表达及其对生存、免疫的影响

目的:基于生物信息学方法筛选出头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)的关键生物标记物CAV1和CAV2,并探究其在HNSCC中的表达情况以及临床预后价值。方法:本研究中,我们首先基于GEPIA数据库比较了caveolins及cavins在HNSCC的差异表达情况,随后同时在Ualcan平台分析了caveolins及cavins家族中差异基因与临床表型的关系;比较与临床表型相关的差异基因与HNSCC生存的关系;此外还进行了CAV1与CAV2的富集分析及免疫浸润分析。结果:GEPIA数据库分析显示CAV1、CAV2、CAVIN2、CAVIN3等存在显著相关性,其中CAV1、CAV2与临床表型显著相关且能显著影响HNSCC患者生存预后。GSEA富集分析显示CAV1主要上调IL-17 signaling pathway、PI3K-Akt signaling pathway、NOD-like receptor signaling pathway;CAV2主要上调NOD-like receptor signaling pathway、PI3K-Akt signaling pathway。免疫浸润分析表明CAV1及CAV2能显著改变HNSCC肿瘤免疫微环境,与多种免疫细胞浸润存在相关性。结论:CAV1与CAV2在HNSCC中高表达,是与免疫侵袭相关的独立预后因素,可作为确定HNSCC患者的免疫侵袭相关预后的候选预后标志物。

Cav3.2 channel regulates cerebral ischemia/reperfusion injury:a promising target for intervention

Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.

SETD2 in cancer:functions,molecular mechanisms,and therapeutic regimens

In recent years,the histone methyltransferase SET domain containing 2(SETD2)has garnered significant attention for its involvement in carcinogenesis.Herein we aim to summarize the research advances regarding SETD2 in tumors,elucidate the role in global epigenetic regulation,highlight potential therapeutic regimens for patients with SETD2 deficiency,and outline future research directions.

CAV1在肿瘤化疗敏感性和耐药性中的研究进展

陷窝蛋白(caveolin-1,CAV1)是细胞膜上陷窝的基本成分之一,是一种完整的膜蛋白,与CAV1相关的信号转导可调节细胞增殖、侵袭、细胞死亡和脂质代谢,并与多种免疫相关信号有关。化疗是临床上治疗肿瘤、预防肿瘤复发的重要手段,但其在治疗过程中时常发生药物耐药及敏感性降低,这在很大程度上削弱了化疗的治疗效果,而CAV1与肿瘤化疗的耐药性及敏感性关系密切。该文围绕相关机制及研究进展进行综述,并对这一领域未来的发展方向进行讨论,以期为基于肿瘤化疗治疗的临床试验及机制研究提供帮助。

Effect of cetuximab plus FOLFOX4 regimen on clinical outcomes in advanced gastric carcinoma patients receiving evidence-based care

BACKGROUND Although chemotherapy is effective for treating advanced gastric carcinoma(aGC),it may lead to an adverse prognosis.Establishing a highly effective and low-toxicity chemotherapy regimen is necessary for improving efficacy and outcomes in aGC patients.AIM To determine the efficacy and safety of cetuximab(CET)combined with the FOLFOX4 regimen(infusional fluorouracil,folinic acid,and oxaliplatin)as firstline therapy for patients with aGC,who received evidence-based care(EBC).METHODS A total of 117 aGC patients who received EBC from March 2019 to March 2022 were enrolled.Of these,60 in the research group(RG)received CET+FOLFOX4 as first-line therapy,whereas 57 in the control group(CG)received FOLFOX4.The efficacy[clinical response rate(RR)and disease control rate(DCR)],safety(liver and kidney dysfunction,leukopenia,thrombocytopenia,rash,and diarrhea),serum tumor marker expression[STMs;carbohydrate antigen(CA)19-9,CA72-4,and carcinoembryonic antigen(CEA)],inflammatory indicators[interleukin(IL)-2 and IL-10],and quality of life(QOL)of the two groups were compared.RESULTS A markedly higher RR and DCR were observed in the RG compared with the CG,with an equivalent safety profile between the two groups.RG exhibited notably reduced CA19-9,CA72-4,CEA,and IL-2 levels following treatment,which were lower than the pre-treatment levels and those in the CG.Post-treatment IL-10 was statistically increased in RG,higher than the pre-treatment level and the CG.Moreover,a significantly improved QOL was evident in the RG.CONCLUSION The CET+FOLFOX4 regimen is highly effective as first-line treatment for aGC patients receiving EBC.It facilitates the suppression of STMs,ameliorates the serum inflammatory microenvironment,and enhances QOL,without increased adverse drug effects.

Correlation between postoperative chemotherapy regimen and survival in patients with resectable gastric adenocarcinoma accompanied with vascular cancer thrombus

BACKGROUND Patients with resectable gastric adenocarcinoma accompanied by vascular cancer thrombus(RGAVCT)have a poor prognosis,with a 5-year survival rate ranging from 18.42%-53.57%.These patients need a reasonable postoperative treatment plan to improve their prognosis.AIM To determine the most effective postoperative chemotherapy regimen for patients with RGAVCT.METHODS We retrospectively collected the clinicopathological data of 530 patients who un-derwent radical resection for gastric cancer between January 2017 and January 2022 and who were pathologically diagnosed with gastric adenocarcinoma with a choroidal cancer embolus.Fur-thermore,we identified the high-risk variables that can influence the prognosis of patients with RGAVCT by asse-ssing the clinical and pathological features of the patients who met the inclusion criteria.We also assessed the significance of survival outcomes using Mantel-Cox univariate and multivariate analyses.The subgroups of pa-tients with stages Ⅰ,Ⅱ,and Ⅲ disease who received single-,dual-,or triple-drug regimens following surgery were analyzed using SPSS 25.0 and the ggplot2 package in R 4.3.0.RESULTS In all,530 eligible individuals with RGAVCT were enrolled in this study.The median overall survival(OS)of patients with RGAVCT was 24 months,and the survival rates were 80.2%,62.5%,and 42.3%at 12,24,and 59 months,respectively.Preoperative complications,tumor size,T stage,and postoperative chemotherapy were identified as independent factors that influenced OS in patients with RGAVCT according to the Cox multivariate analysis model.A Kaplan-Meier analysis revealed that chemotherapy had no effect on OS of patients with stage Ⅰ or Ⅱ RGAVCT;however,chemotherapy did have an effect on OS of stage Ⅲ patients.Stage Ⅲ patients who were treated with chemotherapy consisting of dual-or triple-agent regimens had better survival than those treated with single-agent regimens,and no significant difference was observed in the survival of patients treated with chemo-therapy consisting of dual-or triple-agent regimens.CONCLUSION For patients with stage Ⅲ RGAVCT,a dual-agent regimen of postoperative chemotherapy should be recom-mended rather than a triple-agent treatment,as the latter is associated with increased frequency of adverse events.

Clinical Effects of the Follicular Phase Long Regimen and Luteal Phase Long Regimen on Ovulation Induction in IVF-ET Treatment: A Meta-Analysis

Objective:To systematically evaluate the clinical effects of the follicular phase long regimen and the luteal phase long regimen on ovulation induction in IVF-ET treatment.Methods:Databases including PubMed,Embase,Cochrane Library,CNKI,Chinese Biomedical Literature(CBM),VIP,Wanfang,and others were searched up to January 2021.Clinical studies on ovulation induction using the follicular phase long regimen and luteal phase long regimen in IVF-ET treatment were identified.Literature screening,data extraction,and quality evaluation were conducted based on inclusion and exclusion criteria.Meta-analysis was performed using RevMan 5.3 software.Results:After screening,a total of 11 studies were included,comprising 21,544 patients:9,974 in the follicular phase long regimen group and 11,570 in the luteal phase long regimen group.The meta-analysis results were as follows:(1)The number of Gn days and the total amount of Gn in the follicular phase long regimen were higher than those in the luteal phase long regimen(P<0.05);(2)The number of eggs obtained in the follicular phase long regimen was higher than that in the luteal phase long regimen(P<0.05).There were no significant differences in the rate of embryo optimization and cycle cancellation between the two groups(P>0.05);(3)The embryo implantation rate and clinical pregnancy rate in the follicular phase long regimen were higher than those in the luteal phase long regimen(P<0.05),while the abortion rate in the follicular phase long regimen was lower than that in the luteal phase long regimen(P<0.05).Conclusion:Compared to the luteal phase long regimen,the follicular phase long regimen involves more Gn days and a higher total amount of Gn.The optimal embryo rate and cycle cancellation rate were similar between the regimens,but the follicular phase long regimen resulted in more eggs,significantly improved the implantation and clinical pregnancy rates,and reduced the abortion rate.However,these conclusions require further validation through more multicenter,large-sample RCT studies.

Cav3.2基因在盆底电刺激治疗小鼠压力性尿失禁中的作用及其机制

目的:探讨Cav 3.2基因在盆底电刺激(PES)治疗小鼠压力性尿失禁(SUI)中的作用,并阐明其相关机制。方法:30只C57BL/6小鼠按干预措施随机分为对照组[未进行阴道扩张(VD)造模]、VD组(VD造模)和VD+PES组(VD造模联合PES),每组10只;按照基因型和干预措施将小鼠分为WT-VD组(野生型VD造模)、WT-VD+PES组(野生型VD造模联合PES)、KO-VD组(Cav 3.2敲除型VD造模)和KO-VD+PES组(Cav 3.2敲除型VD造模联合PES)。Masson染色观察各组小鼠尿道和阴道前壁组织中Ⅰ型胶原(ColⅠ)和Ⅲ型胶原(ColⅢ)的胶原纤维沉积情况和胶原纤维表达水平,测定各组小鼠尿动力学参数最大膀胱容积(MBC)和漏尿点压力(LPP),Western blotting法检测各组小鼠尿道和阴道前壁组织中整合素β1、钙蛋白酶2、ColⅠ和ColⅢ蛋白表达水平。结果:与VD组比较,VD+PES组小鼠尿道和阴道前壁组织中ColⅠ和ColⅢ胶原纤维表达水平明显升高(P<0.01);与WT-VD组比较,WT-VD+PES组小鼠尿道和阴道前壁组织中ColⅠ及ColⅢ胶原纤维表达水平明显升高(P<0.01);与WT-VD+PES组比较,KO-VD组和KO-VD+PES组小鼠尿道和阴道前壁组织中ColⅠ及ColⅢ胶原纤维表达水平明显降低(P<0.01)。与对照组比较,VD组小鼠MBC和LPP均降低(P<0.05);与VD组比较,VD+PES组小鼠MBC和LPP均升高(P<0.05)。Western blotting法检测,与VD组比较,VD+PES组小鼠尿道和阴道前壁组织中ColⅠ及ColⅢ蛋白表达水平均明显升高(P<0.01);与WT-VD组比较,WT-VD+PES组小鼠尿道和阴道前壁组织中ColⅠ及ColⅢ蛋白表达水平明显升高(P<0.01);与WT-VD+PES组比较,KOVD组和KO-VD+PES组小鼠尿道和阴道前壁组织中ColⅠ及ColⅢ蛋白表达水平明显降低(P<0.01)。与WT-VD组比较,WT-VD+PES组小鼠尿道和阴道前壁组织中整合素β1及钙蛋白酶2蛋白表达水平明显升高(P<0.01)。结论:PES可改善小鼠尿动力学功能,并通过Cav 3.2基因及其下游整合素β1和钙蛋白酶2促进盆底胶原的生成,促进盆底修复。

补阳还五汤对Cav-1^(-/-)小鼠脑缺血后m^(6)A修饰和血管新生的影响

目的观察补阳还五汤对小窝蛋白1基因敲除(Cav-1^(-/-))小鼠脑缺血后N6-甲基腺苷(m^(6)A)修饰和血管新生的影响,探讨其可能的作用机制。方法将72只雄性野生型(WT)小鼠及Cav-1^(-/-)(KO)小鼠分别随机分为对照组、模型组和补阳还五汤组,采用大脑中动脉栓塞法制备脑缺血模型,补阳还五汤组予补阳还五汤(18.5 g/kg)灌胃,对照组和模型组予等体积蒸馏水灌胃,连续7 d。对小鼠进行神经行为学评分,试剂盒检测缺血侧皮质m^(6)A水平,HE染色观察缺血侧皮质病理变化,免疫荧光双标法检测缺血侧皮质血管新生情况,RT-qPCR检测缺血侧皮质甲基转移酶样3(METTL3)、甲基转移酶样14(METTL14)、肾母细胞瘤1相关蛋白(WTAP)、肥胖相关蛋白(FTO)及AlkB同系物5(ALKBH5)mRNA表达。结果与同基因型对照组比较,WT、KO模型组小鼠神经行为学评分及缺血侧皮质m^(6)A水平明显升高(P<0.01),缺血侧皮质出现病理形态损伤,血管性血友病因子(VWF)/Ki-67双标阳性细胞数明显增加(P<0.01),KO模型组小鼠缺血侧皮质WTAP mRNA表达明显升高(P<0.01),FTO和ALKBH5 mRNA表达明显下降(P<0.01);与同基因型模型组比较,WT、KO补阳还五汤组小鼠神经行为学评分及m^(6)A水平明显降低(P<0.01,P<0.05),缺血侧皮质病理形态损伤改善,VWF/Ki-67双标阳性细胞数目明显增加(P<0.05),KO补阳还五汤组小鼠缺血侧皮质WTAP mRNA表达明显降低(P<0.01),FTO和ALKBH5 mRNA表达明显升高(P<0.01,P<0.05)。WT模型组和WT补阳还五汤组各项指标优于KO组(P<0.01,P<0.05)。结论补阳还五汤可能通过Cav-1调控脑缺血小鼠m^(6)A修饰和血管新生,从而发挥保护脑缺血损伤作用。

LINC00662通过调控miR⁃106a⁃5p/CAV1轴影响肝癌细胞对索拉非尼药物的敏感性

目的:探究长链非编码RNA⁃LINC00662对诱导肝细胞癌(HCC)细胞索拉非尼耐药的机制。方法:以HCC细胞(HepG2、HCCLM3),索拉非尼耐药肝癌细胞HCC⁃SR(HepG2⁃SR、HCCLM3⁃SR)为研究对象,通过实时荧光定量聚合酶链反应(RT⁃qPCR)和Western blotting检测各组细胞中LINC00662、miR⁃106a⁃5p和小窝蛋白⁃1(CAV1)表达水平。将si⁃LINC00662、miR⁃106a⁃5p模拟物分别转染HCC⁃SR细胞,通过细胞活性试剂盒(CCK⁃8)检测细胞对索拉非尼药物敏感性。且进一步通过双荧光素酶报告实验、RT⁃qPCR、Western blotting确定LINC00662与miR⁃106a⁃5p、miR⁃106a⁃5p与CAV1之间的靶向关系。结果:HCC⁃SR细胞中LINC00662和CAV1相对表达显著升高,miR⁃106a⁃5p表达显著降低(P<0.01,P<0.001);干扰LINC00662表达或过表达miR⁃106a⁃5p,HCC⁃SR细胞对索拉非尼药物敏感性显著升高(P<0.05,P<0.01)。且LINC00662靶向负性调控miR⁃106a⁃5p表达,miR⁃106a⁃5p靶向负性调控CAV1表达(P<0.05)。结论:LINC00662可以作为miR⁃106a⁃5p的竞争性内源性RNA(ceRNA)促进CAV1的表达,介导HCC细胞索拉菲尼的耐药性,干扰LINC00662表达可抑制HCC细胞索拉非尼耐药,增加索拉非尼的敏感性。

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.

基于CAV1.2/CaM/CaMKⅡ通路探讨祛痰化瘀中药复治疗心房颤动的作用机制

目的探讨祛痰化瘀中药复方治疗心房颤动的作用机制。方法将60只雄性SD大鼠随机分为空白组和造模组,连续7天尾静脉注射Ach(66μg·mL^(-1))-CaCl_(2)(10 mg·mL^(-1))建立大鼠AF模型。将造模成功的大鼠随机分为模型组、中药复方高、中、低剂量组和维拉帕米组,中药复方高、中、低剂量组给予12.38 mg·kg^(-1)·d^(-1)、6.18 mg·kg^(-1)·d^(-1)、3.10 mg·kg^(-1)·d^(-1)祛痰化瘀中药复方溶液灌胃、维拉帕米组给予维拉帕米溶液8.31 mg·kg^(-1)·d^(-1)灌胃,空白组、模型组给予等体积蒸馏水灌胃,期间仍持续尾静脉注射,连续14天。电生理记录仪测量大鼠Ⅱ导联房颤持续时间,透射电镜观察大鼠心房肌超微结构变化,RT-PCR法检测大鼠心房肌CAV1.2、CaM、CaMKⅡmRNA相对表达量,Western blot法检测大鼠心房肌CAV1.2、CaM、CaMKⅡ及下游蛋白RyR2、P-RyR2蛋白表达情况。结果与空白组相比,模型组大鼠均出现典型房颤心电图(P<0.01),心房肌细胞肌丝排列絮乱、线粒体嵴断裂、呈“空泡样”改变,CAV1.2 mRNA及蛋白表达显著降低(P<0.01),CaM、CaMKⅡmRNA及蛋白表达显著升高(P<0.01),P-RyR2蛋白表达显著升高(P<0.01),RyR2蛋白表达无差异(P>0.05)。与模型组相比,中药复方组房颤持续时间降低(P<0.05);肌丝排列相对整齐,线粒体结构相对完整;CAV1.2 mRNA及蛋白表达升高(P<0.05),CaM、CaMKⅡmRNA及蛋白表达下降(P<0.01),下游蛋白P-RyR2表达降低(P<0.01),RyR2蛋白表达无差异(P>0.05)。结论祛痰化瘀中药复方可缩短大鼠房颤持续时间,抑制心房肌细胞超微结构损伤,其作用机制可能与调控CAV1.2/CaM/CaMKⅡ信号通路表达,改善钙调控紊乱有关。

Treatment outcomes and adverse drug reactions among patients with drug-resistant tuberculosis receiving all-oral,long-term regimens:First record viewing report from Pakistan

Objective:To assess the effectiveness and adverse drug reactions of all-oral regimens for patients with multidrug-resistant tuberculosis.Methods:This retrospective study was conducted at 10 Programmatic Management of Drug Resistant Tuberculosis sites in Punjab province of Pakistan.Patients receiving treatment for drug resistant tuberculosis from July 2019 to December 2020 with at least interim result i.e.6th month culture conversion or final outcomes(cured,complete,lost to follow-up,failure,death)available,were included in the study.Data was extracted from electronic data management system.For the reporting and management of adverse drug events,active tuberculosis drug safety monitoring and management was implemented across all sites.All the data was analyzed using SPSS version 22.Results:Out of 947 drug resistant tuberculosis patients included in this study,579(68%)of the patients had final outcomes available.Of these,384(67.9%)successfully completed their treatment.Out of 368(32%)patients who had their interim results available,all had their 6th month culture negative.Combining new medications was thought to result in serious adverse outcomes such as QT prolongation.However,this study did not record any severe adverse events among patients.Conclusions:All-oral regimens formulation guided by overall treatment effectiveness resulted in treatment outcomes comparable to those obtained with traditional injectable treatment.

苯妥英抑制心脏Cav1.2通道合成与转运的机制研究

目的:探讨抗癫痫药物苯妥英(PHT)对心肌细胞(CMs)中L型钙通道(Cav1.2)蛋白合成和转运的影响。方法:对无特定病原体(SPF)级雄性Sprague-Dawley(SD)乳鼠的原代CMs分别使用不同浓度的PHT(0μg/mL、0.0001μg/mL、0.001μg/mL、0.01μg/mL、0.1μg/mL、1μg/mL、10μg/mL、100μg/mL)干预24 h和48 h,采用CellTiter-Glo法检测细胞活性。采用蛋白免疫印迹法(Western Blot)和激光扫描共聚焦显微镜分别观察PHT对原代CMs中Cav1.2通道蛋白合成和转运的影响。结果:在CellTiter-Glo细胞活性检测中,随着苯妥英浓度的增加,除100μg/mL组干预48 h后细胞存活率降低至85.23%(P<0.05)外,其余各组间细胞活性比较,差异均无统计学意义(P>0.05)。Western Blot结果显示,100μg/mL苯妥英干预原代CMs时Cav1.2合成明显受到抑制,然而激光扫描共聚焦显微镜结果提示在10μg/mL苯妥英干预原代CMs时已出现Cav1.2转运障碍。结论:苯妥英可抑制心脏Cav1.2的合成和转运,可能与其可致心律失常作用相关,临床上在应用苯妥英时应仔细评估病人情况,尽可能减少副作用的产生。

Adjusting phosphate feeding regimen according to daily rhythm increases eggshell quality via enhancing medullary bone remodeling in laying hens

Background Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle.The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms.There is lack of information about the impact of adjusting phosphate feeding regimen according to daily rhythm on the phosphorus homeostasis and bone remodeling of laying hens.Methods and results Two experiments were conducted.In Exp.1,Hy-Line Brown laying hens(n=45)were sampled according the oviposition cycle(at 0,6,12,and 18 h post-oviposition,and at the next oviposition,respectively;n=9 at each time point).Diurnal rhythms of body calcium/phosphorus ingestions and excretions,serum calcium/phosphorus levels,oviduct uterus calcium transporter expressions,and medullary bone(MB)remodeling were illustrated.In Exp.2,two diets with different phosphorus levels(0.32%and 0.14%non-phytate phosphorus(NPP),respectively)were alternately presented to the laying hens.Briefly,four phosphorus feeding regimens in total(each included 6 replicates of 5 hens):(1)fed 0.32%NPP at both 09:00 and 17:00;(2)fed 0.32%NPP at 09:00 and 0.14%NPP at 17:00;(3)fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00;(4)fed 0.14%NPP at both 09:00 and 17:00.As a result,the regimen fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00,which was designed to strengthen intrinsic phosphate circadian rhythms according to the findings in Exp.1,enhanced(P<0.05)MB remodeling(indicated by histological images,serum markers and bone mineralization gene expressions),elevated(P<0.05)oviduct uterus calcium transportation(indicated by transient receptor potential vanilloid 6 protein expression),and subsequently increased(P<0.05)eggshell thickness,eggshell strength,egg specific gravity and eggshell index in laying hens.Conclusions These results underscore the importance of manipulating the sequence of daily phosphorus ingestion,instead of simply controlling dietary phosphate concentrations,in modifying the bone remodeling process.Body phosphorus rhythms will need to be maintained during the daily eggshell calcification cycle.