Aim 1: Primary Prevention of Post-operative Cardiac Arrhythmias
To evaluate the efficacy of dexmedetomidine vs. the combination of Magnesium Sulfate and dexmedetomidine for the prevention of post-operative cardiac arrhythmias in children and young adults undergoing open heart surgical repair for congenital or acquired heart disease using cardiopulmonary bypass. Dexmedetomidine is currently being administered to almost all patients after coming off cardiopulmonary bypass and in the CICU. For this aim, the investigator will be comparing dexmedetomidine administered alone or in combination with Magnesium Sulfate.
To evaluate medication safety based on the frequency of Serious Adverse Events (SAEs) and Adverse Events (AEs)
Aim 2: Secondary treatment of those Patients that develop a clinically significant arrhythmia despite having received either Dexmedetomidine alone or Magnesium Sulfate with Dexmedetomidine at the time of cardiac surgery
To evaluate the efficacy of intravenous (IV) Amiodarone vs. IV Procainamide for the control of postoperative cardiac arrhythmias developing after the failure of Stage 1, Preventative Trial. IV amiodarone and IV procainamide are standardly used treatment agents for the treatment of postoperative cardiac arrhythmias in this setting. The investigator will be assessing the comparative effectiveness of these agents in controlling post-operative cardiac arrhythmias.
To evaluate antiarrhythmic medication safety based on the frequency of SAEs and AEs

开始日期2023-01-01

申办/合作机构

Children's National Research Institute

NCT05343312 / Active, not recruiting临床4期IIT

Monitoring the Therapeutic Efficacy of the Combinations Artemether-Lumefantrine, Amodiaquine-Artesunate, Dihydroartemisinin-Piperaquine, and Pironaridine-Artesunate in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Children Under 5 Years of Age in Five Sentinel Sites in Mozambique

This is a classical in vivo clinical trial, following World Health organization's recommendations, ran as a multisite study within Mozambique trying to assess the efficacy and safety in 5 sites of the four oral ACTS artemether-lumefantrine (AL), Amodiaquine-Artesunate (AQ-AS), Dihydroartemisinin-Piperaquine (DHP) and Pironaridine-Artesunate for the treatment of uncomplicated malaria in children aged<5 years.

开始日期2022-03-16

申办/合作机构-

NCT04485195 / Recruiting临床4期IIT

RAFF4 Trial: Vernakalant vs. Procainamide for Acute Atrial Fibrillation in the Emergency Department

The objective is to compare IV vernakalant to IV procainamide for the ED management of acute AF patients. If vernakalant proves to be more effective, faster, and safer than IV procainamide, this will give clinicians an important alternative for pharmacological cardioversion of acute AF. The investigators propose a pragmatic comparative effectiveness trial entailing an open label, randomized controlled trial at 12 large Canadian EDs. Study subjects will be randomized to 1 of 2 treatment arms: 1) Patients will receive an initial infusion of 3mg/kg of IV vernakalant over 10 minutes, followed by a second dose of 2mg/kg over 10 minutes, if necessary, or 2) Patients will receive a continuous infusion of 15mg/kg of IV procainamide over 60 minutes. The primary aim will be to compare conversion to normal sinus rhythm between the two drugs. The investigators will include stable patients presenting with an episode of acute AF of at least 3 hours duration, where symptoms require urgent management and where immediate cardioversion is a reasonable option. Using the integrated consent model, research assistants will obtain verbal consent from eligible patients.

开始日期2021-06-17

申办/合作机构

Ottawa Hospital Research Institute

100 项与盐酸普鲁卡因胺相关的临床结果

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100 项与盐酸普鲁卡因胺相关的转化医学

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100 项与盐酸普鲁卡因胺相关的专利（医药）

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项与盐酸普鲁卡因胺相关的文献（医药）

2024-02-24·Journal of agricultural and food chemistry

Perception of the Biocontrol Potential and Palmitic Acid Biosynthesis Pathway of Bacillus subtilis H2 through Merging Genome Mining with Chemical Analysis.

Article

作者: Hang Pan ; Longfeng Wei ; Hao Zhao ; Yang Xiao ; Zhu Li ; Haixia Ding

Bacillus has been widely studied for its potential to protect plants from pathogens. Here, we report the whole genome sequence of Bacillus subtilis H2, which was isolated from the tea garden soil of Guiyang Forest Park. Strain H2 showed a broad spectrum of antagonistic activities against many plant fungal pathogens and bacteria pathogens, including the rice blast fungus Magnaporthe oryzae, and showed a good field control effect against rice blast. The complete genome of B. subtilis H2 contained a 4,160,635-bp circular chromosome, with an average G + C content of 43.78%. Through the genome mining of strain H2, we identified 7 known antimicrobial compound biosynthetic gene clusters (BGCs) including sporulation killing factor, surfactin, bacillaene, fengycin, bacillibactin, subtilosin A, and bacilysin. Palmitic acid (PA), a secondary metabolite, was detected and identified in the H2 strain through genome mining analysis and gas chromatography-mass spectrometry (GC-MS). Additionally, we propose, for the first time, that the type II fatty acid synthesis (FAS) pathway in Bacillus is responsible for PA biosynthesis. This finding was confirmed by studying the antimicrobial activity of PA and conducting reverse transcription-quantitative polymerase chain reaction (RT-qPCR) experiments. We also identified numerous genes associated with plant-bacteria interactions in the H2 genome, including more than 94 colonization-related genes, more than 34 antimicrobial genes, and more than 13 plant growth-promoting genes. These findings contribute to our understanding of the biocontrol mechanisms of B. subtilis H2 and have potential applications in crop disease control.

2024-02-22·Haemophilia : the official journal of the World Federation of Hemophilia

Physical activity and factor VIII levels in patients with haemophilia: A real-world prospective observational study.

Article

作者: Fabian Tomschi ; Jamil Hmida ; Steffen Herzig ; Pia Ransmann ; Marius Brühl ; Alexander Schmidt ; Marie Herzig ; Georg Goldmann ; Andreas C Strauß ; Johannes Oldenburg ; Heinrich Richter ; Thomas Hilberg

INTRODUCTION:

Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA.

AIM:

To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH.

METHODS:

In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months.

RESULTS:

795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study.

CONCLUSION:

This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels.

2024-02-21·Journal of dairy science

Effects of saturated fatty acids with lysophospholipids on production and nutrient digestibility in lactating cows.

Article

作者: N H Porter ; K L Clark ; L R Rebelo ; J E Copelin ; I H Kwon ; C Lee

The objective of the experiment was to determine the effects of supplemental saturated fatty acid (SFA) sources, lysophospholipids (LPL), and their interaction on production and nutrient digestibility in lactating dairy cows. The experiment was conducted with 48 cows in a randomized complete block design. Cows were blocked (total 12 blocks) by parity and days in milk and randomly assigned to 4 dietary treatments in each block (2 × 2 factorial arrangement), i.e., 2 sources of fat supplements, C16:0 (palmitic acid, PA)- or C18:0 (stearic acid, SA)-enriched fat, with or without LPL. The experiment was conducted for 6 wk to measure daily dry matter intake and milk yield and weekly milk composition. During the last week of the experiment, spot fecal and urine samples were collected to determine total-tract nutrient digestibility. Milk samples in the last week were also collected to analyze for milk fatty acid (FA) profile. All data were analyzed using the mixed procedure of SAS where block was used as a random effect and FA, LPL, and the interaction of FA by LPL were used as fixed effects. Week and interactions of week by FA or LPL were included for production measures. Different sources of SFA did not affect dry matter intake and milk yield. However, PA increased (39.7 vs. 36.8 kg) energy-corrected milk compared with SA due to increased milk fat yield. No effect of LPL on production measures was observed. Total-tract digestibilities of dry matter, organic matter, crude protein, and total FA were not different between PA and SA, but PA increased (41.4 vs. 38.8%) neutral detergent fiber digestibility compared with SA. Supplementation of LPL increased (64.7 vs. 60.5%) total FA digestibility, especially 18-carbon FA (74.1 vs. 68.2%). An interaction of SFA by LPL was found for 16-carbon FA digestibility. The PA diet increased the concentration of 16-carbon FA in milk fat and SA increased the concentration of preformed FA (≥18 carbons). Supplementation of LPL decreased the concentration of trans-10 C18:1. No difference in N utilization and excretion among treatments was observed. In conclusion, PA was more effective in improving milk fat yield of lactating cows compared with SA. Supplementation of LPL increased digestibility of total FA, especially 18-carbon FA but did not affect production.

项与盐酸普鲁卡因胺相关的新闻（医药）

2024-01-13

·生物探索

Gut | 中山大学郭剑平/匡铭揭示高脂肪饮食通过棕榈酰化和AKT的激活促进肝脏肿瘤的发生

作为代谢稳态的中心节点，PI3K-AKT通路是否以及如何导致高脂肪诱导的非酒精性脂肪性肝炎(NASH)和肝细胞癌(HCC)仍然是一个谜。2024年1月8日，中山大学郭剑平及匡铭共同通讯在Gut（IF=25）在线发表题为“High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT”的研究论文，该研究发现高脂肪饮食通过棕榈酰化和AKT的激活促进肝脏肿瘤的发生。通过筛选代谢物库，该研究发现PA通过促进棕榈酰修饰激活AKT，这是生长因子诱导AKT激活的必要步骤。在生物学上，高脂肪饮食可以促进AKT激酶活性，从而促进NASH和肝癌。从机制上讲，棕榈酰结合以不依赖PIP3的方式将AKT锚定在细胞膜上，部分原因是通过阻止AKT组装成非活性聚合物。棕榈酰转移酶ZDHHC17/24被表征为棕榈酰化AKT发挥致癌作用。有趣的是，抗肥胖药物奥利司他或特异性穿透肽可分别通过限制PA合成或抑制AKT修饰有效减弱AKT棕榈酰化和活化，从而拮抗肝脏肿瘤发生。该研究阐明了PA-ZDHHC17 /24介导的棕榈酰化对AKT的一种新的微调调节，并强调了通过限制PA饮食、限制PA合成或直接靶向AKT棕榈酰化来治疗肿瘤的策略。饮食不仅为肿瘤细胞不受控制的生长提供营养和基础，而且还促进信号转导，影响肿瘤的各个方面，因此饮食改变疗法最近已经实现，包括热量限制和低热量脂肪饮食。值得注意的是，高脂肪饮食(HFDs)主要与代谢性疾病相关，包括肥胖和癌症，其机制多样且尚不清楚。其中，棕榈油是最主要的膳食油来源之一，也是肥胖的主要原因之一，被认为是一种代谢性疾病，倾向于诱发肿瘤。值得注意的是，PA作为棕榈脂和动物脂肪油的主要成分，其代谢功能形成细胞质膜，与口腔肿瘤转移密切相关。同时，PA的活性产物棕榈酰辅酶A已被证明可诱导多种蛋白的棕榈酰修饰，如MC1R对紫外线诱导的黑色素瘤起作用，STAT3对IL-6诱导的Th17分化和抗病毒感染起作用，N-RAS对结肠癌起作用。然而，合成或食物摄取的PA积累是否以及如何参与肿瘤发生，特别是参与代谢稳态的器官，如肝脏，尚不清楚。HFD一直被认为是非酒精性脂肪性肝炎(NASH)的一个不减弱的危险因素，NASH是一种非酒精性脂肪性肝病(NAFLD)的晚期形式，现在也被称为代谢功能障碍相关的脂肪性肝炎。NASH涉及小叶炎症、纤维化和肝细胞膨胀，可发展为HCC。尽管自噬和免疫反应等多种潜在机制与NASH相关，但作为代谢稳态的中心节点，在脂肪生成和HCC进展中发挥重要作用的PI3K-AKT通路是否以及如何导致高脂肪诱导的NASH和HCC仍是一个谜。棕榈酰化增强AKT活性和致癌功能的模型（图源自Gut ）PI3K-AKT通路作为响应细胞外刺激的中心信号，在生理上对细胞生长、存活和代谢稳态起着关键作用，在病理上对糖尿病和肿瘤发生也起着关键作用。因此，AKT的调控，特别是在翻译后水平，已被广泛确立。值得注意的是，AKT PH结构域与PI3K生成的PIP3的结合被认为是通过PDK1介导的T308和mTORC2介导的S473磷酸化完全激活AKT的关键步骤。例如，泛素化、乙酰化和甲基化都有助于AKT与PIP3的结合，从而进一步激活PIP3。因此，PIP3相关酶的遗传改变，包括其激酶PIK3CA、磷酸酶PTEN及其上游调节蛋白，如RAS和EGFR，已在大约50%的不同类型的癌症中被观察到，这在很大程度上有助于PIP3的积累和随后的AKT激活。为此，针对PIK3CA-H1047R突变体的特异性抑制剂已被批准用于乳腺癌干预。然而，除了典型的PI3K-PIP3依赖性AKT激活外，AKT是否以及如何以PIP3独立的方式激活尚不清楚。该研究报道了从HFDs中积累PA或异常合成促进ZDHHC17 /24-以PIP3不依赖的方式催化棕榈酰化和激活AKT，导致NASH和肝脏肿瘤发生，并强调了靶向PA-ZDHHC-AKT轴治疗HCC的策略。参考文献：Bu L, Zhang Z, Chen J, Fan Y, Guo J, Su Y, et al. High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT. Gut. 2024 Jan 8:gutjnl-2023-330826. doi: 10.1136/gutjnl-2023-330826. Epub ahead of print. PMID: 38191266. 责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

ASH会议

2023-11-20

·生物谷

维生素片又致癌啦？！Nature子刊：这种常见的维生素，恐促进肿瘤的生长和增殖！饮食限制即可阻碍

口腔溃疡？吃点维生素B！消化不良？吃点维生素B！神经炎症？吃点维生素B！B族维生素的重要性越来越为人们熟知，是维持人体正常机能与代谢活动不可或缺的物质。由于人体无法自行合成维生素B，需要通过膳食进行补充，因此很多人担心平时生活中吃不够而选择了维生素补充剂。膳食补充维生素B固然重要，但维生素B是个大家族，包括了硫胺素（维生素B1）、核黄素（维生素B2）、烟酸（维生素B3）、泛酸（维生素B5）等等，它们各司其职，发挥着不同的作用。然而，真的有必要“一网打尽”每一种都去补吗？会不会得不偿失，反而对健康造成损害呢？举例来说，维生素B5，又称泛酸，该单词来源于希腊语“无处不在的酸类物质”，在自然界的分布极其广泛。泛酸参与体内多种代谢，促进糖、脂肪、氨基酸中的乙酸分解，同时也是多酶复合物脂肪酸合酶的组成成分。泛酸的重要性不言而喻，但过多的补充反而可能出现“物极必反”的情况。近日，Nature Metabolism上最新刊登的研究显示：高表达的癌症驱动基因MYC的乳腺肿瘤细胞严重依赖维生素B5，进行细胞的生长和存活；相反，饮食限制维生素B5则会逆转MYC介导的代谢变化，阻碍肿瘤生长。因此，这维生素B5，还真不必随意补充。https://doi.org/10.1038/s42255-023-00915-7在人类癌症中，有一种名为MYC的原癌基因——MYC也是一种多效应转录因子，正常情况下，MYC能影响多个基因的表达，调节细胞分化增殖；但在多种肿瘤恶化的过程中，MYC发生突变或多度表达，较高MYC表达水平的克隆往往以亚克隆的形式出现，与癌症分级程度高和生存率低相关。为了找出MYC介导代谢重构的核心代谢物，研究者模拟人类癌症的分析特征构建了一批肿瘤小鼠，从中提取了大量的代谢通路，并分析所有统计学上出现明显变化的代谢物。关联性分析显示，维生素B5与乳腺肿瘤中的MYC水平存在最强的相关性，其化学结构是通过化学标准和肿瘤组织进行串联质谱系统确认得到。同时，这一发现的临床相关性也得到了证实——研究者使用人类患者来源的异种移植物（PDXs），将其皮下移植到免疫功能低下的小鼠体内。结果显示，具有最高MYC水平或强MYC转录特征的PDXs，显示出泛酸水平的显著增加。此外，肿瘤微卫星不稳定性（MSI）检测也明确，肿瘤间和肿瘤内的MYC高表达区域中，泛酸水平明显升高。泛酸与乳腺肿瘤中的MYC表达相关事实上，泛酸（即维生素B5，又称PA）的重要意义在于：PA是辅酶A（CoA）的前体。CoA是一种硫醇，能通过形成硫酯而作为羧基的活化剂。作为PA的活性形式，CoA参与到多种关键代谢途径中，比如：三羧酸循环和脂肪酸的生物合成以及氧化等等。基于上述研究中的发现，即MYC与PA代谢之间的联系存在临床意义和普遍效度，研究者进一步聚焦于“PA-CoA轴参与MYC介导的新陈代谢”的全过程。解吸电流聚焦电离（DEFFI）质谱成像（MSI）和荧光显微镜观察结果显示，具有MYC-ER结构的肿瘤内三羧酸循环活性明显增加。这意味着，MYC活性的增加能够提升PA的吸收和代谢，从而促进三羧酸循环的活跃性，以及代谢产物的摄取，进一步刺激了肿瘤细胞的高速生长。泛酸与高MYC区域有关既然肿瘤生长对维生素B5有着高度依赖性，那么降低体内泛酸的含量是否能有效抑制肿瘤的生长呢？为了证实这一观点，研究者通过饮食控制了乳腺癌小鼠体内的全身PA水平，将小鼠分为无PA饮食或正常对照组饮食。结果不出所料，在正常对照组中，具有MYC-ER结构的乳腺癌小鼠体内的肿瘤细胞保持强烈的增殖趋势；但相反在缺乏PA的情况下，便会丧失这种生长优势，甚至能增加肿瘤细胞的死亡。研究者进一步采用液相色谱与串联质谱联用（LC-MS）分析了两组小鼠的肿瘤组织情况，发现随着PA的减少，CoA的含量也显著下降。不仅如此，大多数糖酵解中间产物、三羧酸循环中间产物、必需氨基酸和非必需氨基酸以及核苷酸均大大减少。不同喂食方式下的肿瘤生长差异机制层面显示，MYC能以细胞自主方式增强PA吸收的能力，而这个过程与多维生素转运载体SLC5A6的存在息息相关。简单来说，MYC可以直接与Slc5a6启动子区域的E-box结合，激活SLC5A6的转录调节。而SLC5A6能控制细胞内的PA水平，即当过表达SLC5A6时，PA的水平急剧增加，进而增强肿瘤细胞的代谢和生长潜力。MYC通过调节SLC5A6表达来控制PA到这里整个影响链路就很清晰了：MYC通过直接上调转运体SLC5A6，提高了肿瘤内的PA水平；而作为CoA的前体，PA的增加又会导致更多的CoA合成，加剧了三羧酸循环活动，诱导癌症细胞的生长和增殖。但相反，如果限制饮食中维生素B5的摄入，则能有效逆转MYC介导的细胞代谢变化，使肿瘤生长受阻。这项研究的重要意义在于，由于化疗会引起一定的胃肠道副作用，从而引发维生素的缺乏，所以临床上往往会给肿瘤患者提供一定的维生素补充剂。但本项研究则给出一记警示，并非所有维生素都需要补充，甚至限制维生素B5的水平将有助于阻碍癌细胞的增殖。因此，补充维生素不一定能与“健康”划上等号，均衡膳食才是王道，切莫“聪明反被聪明误”啦！参考资料：Kreuzaler P, Inglese P, Ghanate A, Gjelaj E, Wu V, Panina Y, Mendez-Lucas A, MacLachlan C, Patani N, Hubert CB, Huang H, Greenidge G, Rueda OM, Taylor AJ, Karali E, Kazanc E, Spicer A, Dexter A, Lin W, Thompson D, Silva Dos Santos M, Calvani E, Legrave N, Ellis JK, Greenwood W, Green M, Nye E, Still E; CRUK Rosetta Grand Challenge Consortium; Barry S, Goodwin RJA, Bruna A, Caldas C, MacRae J, de Carvalho LPS, Poulogiannis G, McMahon G, Takats Z, Bunch J, Yuneva M. Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer. Nat Metab. 2023 Nov 9. doi: 10.1038/s42255-023-00915-7. Epub ahead of print. PMID: 37946084.撰文 | Swagpp编辑 | Swagpp来源 | 梅斯医学精彩推荐：1、感到焦虑抑郁？可能是你的肠道菌群在“作祟”！Nature子刊：产生丁酸盐的肠道菌群丰度降低、促炎菌群丰度增高会加重焦虑抑郁症状2、娃生越多老越快！Nature子刊发现生育多胎可能会增加女性肥胖、患糖尿病的风险，甚至加速衰老！3、久坐伤身不用怕！《英国运动医学杂志》发现每天只需这样运动22分钟即可抵消久坐带来的死亡风险4、易胖体质是因为“胖菌”？Nature Medicine最新研究揭示肠道微生物SNP与宿主BMI的关系5、要想寿命长，还得社交广！50万人数据研究发现孤独会缩短寿命，即使每月一次亲朋好友相聚也能降低死亡风险！本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床结果AACR会议临床1期申请上市

2023-11-15

·奇点网

促癌的MYC让癌细胞狂吸维生素B5~

*仅供医学专业人士阅读参考众所周知，肿瘤是异质性的。近年来，单细胞测序技术和空间基因组学的飞速发展，让我们对肿瘤的异质性有了更清晰的认知。这些进步也让科学家有机会了解肿瘤的进化、分类和耐药等问题。肿瘤的代谢，也是近年来研究的热点领域。既然肿瘤是异质性的，那么肿瘤的代谢必然也是异质性的。不过，目前科学家对于肿瘤代谢异质性的认知还比较少。加深对肿瘤代谢异质性的了解，有望催生新的癌症治疗方法。近日，由弗朗西斯·克里克研究所Mariia Yuneva和Peter Kreuzaler领衔的研究团队，在著名期刊《自然·代谢》发表一项重要研究成果[1]。他们发现，在人类和小鼠三阴性乳腺癌组织中，癌基因MYC高表达的区域，癌细胞中多种维生素转运体SLC5A6表达上调，导致癌细胞对维生素B5的摄取增加，并将其转化为辅酶A，加强三羧酸循环，促进癌细胞的增殖和生长。好消息是，限制维生素B5的摄入，会导致许多由MYC介导的代谢变化发生逆转，并导致肿瘤生长受阻。这意味着，有望从这个角度入手，开发出靶向乳腺癌代谢的抗癌药物。论文首页截图为了探索乳腺癌的代谢异质性，Yuneva团队基于由WNT1驱动的三阴性乳腺细胞系，构建了两个新的细胞系：一个是表达超生理水平MYC的WMhigh（表达红色荧光蛋白tdTomato），另一个正常表达MYC的WMlow（表达绿色荧光蛋白eGFP）。如果将两个细胞系混在一起的话，就是WMmix。在上述两个单细胞系和一个混合细胞系的基础上，他们构建了三个不同类型的乳腺癌小鼠模型。随后，他们检测了三种乳腺癌肿瘤模型的代谢物分布情况。和预期的一样，WMhigh和WMlow单细胞系形成的肿瘤代谢物分布一致性较好，而WMmix形成的肿瘤代谢物与癌细胞克隆一样出现分区情况。三种不同肿瘤模型的代谢和克隆差异在上述数据的基础上，Yuneva团队证实了他们采用的研究方法是稳健可靠的。接下来，他们就开始寻找肿瘤克隆一致性带来的代谢差异。通过对大量代谢通路进行分析，他们发现与WMhigh相关性最强的是泛酸（维生素B5，或者PA）。众所周知，泛酸是辅酶A（CoA）的前体，许多关键的代谢途径都需要辅酶A，包括著名的三羧酸循环以及脂肪酸的生物合成和氧化。因此，他们决定研究泛酸-辅酶A轴与MYC介导的新陈代谢之间的关系。WMhigh与泛酸在空间上重叠为了保险起见，在深入研究之前，Yuneva团队先研究了人体组织样本中WMhigh与泛酸的关系。他们发现，在MYC水平最高或MYC转录特征较强的患者来源异种移植模型（PDXs）中，泛酸水平较高。此外，泛酸水平高也与原发性人类乳腺癌活检组织MYC高表达区域密切相关。这些来自人体的数据，支持他们进一步研究MYC与泛酸代谢之间的联系。在人乳腺癌组织样本中，WMhigh与泛酸在空间上也是重叠的随后，他们使用了一种结合了荧光显微镜、电子显微镜和纳米级二次离子质谱（NanoSIMS）的超高分辨率质谱成像技术，证实在WMhigh区域观察到的泛酸水平升高，是由于细胞自主增加了对泛酸的摄取，然后利用泛酸合成辅酶A等下游代谢产物。成像结果从机制上讲，MYC作为一种转录调控因子，在高表达的情况下会促进多种维生素转运体SLC5A6表达增加，进而促进癌细胞对泛酸的摄取，并将泛酸转化成辅酶A，加强三羧酸循环，促进癌细胞的增殖。Yuneva团队还发现，将乳腺肿瘤细胞系4T1放在缺乏泛酸的条件下培养，它们会停止增殖；而补充辅酶A，可以恢复4T1的增殖。这说明，癌细胞需要泛酸的下游代谢产物辅酶A来维持生长。类似地，小鼠体内的研究也发现，不含泛酸的饮食会限制WMmix肿瘤的生长。泛酸对细胞系和肿瘤生长的影响总的来说，Yuneva团队这项研究发现，在乳腺癌细胞中，MYC通过直接上调转运体SLC5A6的水平，增加了肿瘤内泛酸的水平，而且这是支持MYC调节癌细胞增殖和生物合成程序所必需的。考虑到T细胞的活性也需要高水平的辅酶A，因此Yuneva推测，MYC高表达乳腺癌细胞通过增加对泛酸的吸收，一方面促进自身的增殖，另一方面也限制了免疫细胞的抗癌活性。参考文献：[1].Kreuzaler P, Inglese P, Ghanate A, et al. Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer. Nat Metab. 2023. doi:10.1038/s42255-023-00915-7本文作者丨BioTalker

AACR会议临床结果临床1期

100 项与盐酸普鲁卡因胺相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00477	盐酸普鲁卡因胺	C01BA02	DB01035

研发状态

适应症	最高研发状态	国家/地区	公司
阵发性心动过速	批准上市	日本更多	Alfresa Pharma Corp. 更多
心房颤动	批准上市	日本更多	Alfresa Pharma Corp. 更多
心律失常	批准上市	日本更多	Alfresa Pharma Corp. 更多
心脏早搏	批准上市	日本更多	Alfresa Pharma Corp. 更多
心房扑动	批准上市	日本更多	Alfresa Pharma Corp. 更多

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适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01205529 (CTgov)	N/A	心房颤动	161	Procainamide	簾簾選淵製簾網鑰鑰獵(製廠顧齋獵範願繭憲築) = 願蓋窪築壓淵繭壓願簾鹹糧築齋鬱鑰憲觸艱觸 (觸觸製選鏇齋衊獵醖齋, 範淵築積鹹顧簾製齋窪 ~ 蓋齋膚簾築襯糧憲鑰簾) 更多	-	2018-05-02
ARVO2012	N/A	疱疹性角膜炎	12	Topical prednisolone acetate 1% (PA)	(願膚醖網廠鏇觸簾簾壓) = 醖構鬱顧顧顧廠憲壓鑰網蓋淵簾壓遞廠鹹鬱餘 (顧顧夢鹽獵製觸積觸憲 ) 更多	-	2012-03-01
				PA + Topical cyclosporine A 0.1% (CsA)	(願膚醖網廠鏇觸簾簾壓) = 膚鏇獵淵衊範繭壓鏇鬱網蓋淵簾壓遞廠鹹鬱餘 (顧顧夢鹽獵製觸積觸憲 ) 更多
ESC2022	N/A	室性心动过速	68	Oral procainamide	窪齋範齋願積構餘襯鹹(鑰餘鏇積鏇夢範淵顧衊): HR = 2.54 (95% CI, 1.06 ~ 6.14) 更多	-	2022-04-04
				Mexiletine
ESC2020	N/A	室性早搏	50	Procainamide	憲範糧淵顧網糧憲廠鏇(淵艱淵製願鑰鹹選醖糧) = 製繭鹹蓋艱醖積鬱網觸選壓範窪蓋廠廠夢窪獵 (鬱築鏇鏇鬱範齋窪襯鏇 ) 更多	-	2020-12-11
755 (AUA2011)	N/A	-	50	PA with SHH protein	餘製觸艱鏇艱膚淵製築(蓋夢膚遞衊餘廠鹹製夢) = 鬱齋獵蓋衊網壓範鹹衊壓簾壓襯網鏇願獵窪鏇 (簾膚膚網築齋齋鏇襯夢 )	-	2011-04-01
WCLC2018	N/A	非鳞状非小细胞肺癌一线	164	PC-P	簾網繭遞廠鬱簾鹽窪艱(齋願願鹽製觸鑰衊齋窪) = There was no new occurring intolerant adverse event comparing with other clinical trials 顧顧範廠淵憲願夢衊遞 (獵選築繭襯獵製築壓膚 ) 更多	-	2018-09-24
				PCA-PA
ARVO2018	临床1/2期	非感染性前葡萄膜炎	44	8%-DVX	(壓構襯膚願繭壓觸範繭) = 19 of 44 patients reported 58 AEs of which 54 were ocular. The numbers of reported AEs were 10, 36, and 12 for the 8%-DVX, 15%-DVX and PA groups, respectively. Ten patients among all 3 groups experienced treatment-related AEs which included headache, eye pain, corneal abrasion, conjunctival/corneal staining, conjunctivitis, visual acuity reduction and keratitis. 獵顧壓淵鏇夢衊艱餘憲 (淵繭廠遞製顧艱願廠鹽 )	积极	2018-07-01
				15%-DVX
AACR2015	N/A	前列腺癌 BB2r positive	-	Lu-177-RM2 + PA	(鹽鬱網繭範願遞觸顧齋) = 顧積窪遞壓糧廠廠憲遞製艱壓窪鬱鬱鑰鹽觸餘 (鏇淵壓鑰鑰鏇壓蓋膚廠 )	-	2015-08-01
				Lu-177-RM2 alone	(鹽鬱網繭範願遞觸顧齋) = 淵鏇鑰醖獵膚窪選範蓋製艱壓窪鬱鬱鑰鹽觸餘 (鏇淵壓鑰鑰鏇壓蓋膚廠 )