A Randomized Open-Label, Multi-Center Pivotal Study of ANG1005 Compared With Physician's Best Choice in HER2-Negative Breast Cancer Patients With Newly Diagnosed Leptomeningeal Carcinomatosis and Previously Treated Brain Metastases (ANGLeD)

This is an open-label Phase 3 study to see if ANG1005 can prolong survival compared to a Physician Best Choice control in HER2-negative breast cancer patients with newly diagnosed leptomeningeal disease and previously treated brain metastases.

开始日期2023-12-01

申办/合作机构

Angiochem, Inc.

ChiCTR2200063734 / Suspended临床2/3期IIT

A Multi-Center, Randomized, Controlled, Open-Label Study of SNG1005 Compared with Physician’s Best Choice in HER2-Negative Breast Cancer Patients with Newly Diagnosed Leptomeningeal Carcinomatosis and Previously Treated Brain Metastases

开始日期2022-09-15

申办/合作机构-

CTR20191654 / Recruiting临床3期

SNG1005对比研究者选择单药化疗治疗既往全脑放疗后脑实质进展的HER2阴性BCBM患者的多中心、随机对照、开放标签临床试验

比较两组的总生存期（OS）；比较两组的颅内、颅外的无进展生存期（PFS）；比较两组颅内、颅外的客观缓解率（ORR）；比较两组的颅内缓解持续时间（DoR）和第3和6个月DCR；比较两组颅外DoR；比较两组整体QoL

开始日期2022-05-24

申办/合作机构

香港欣诺康医药科技有限公司

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100 项与 Tubulin x LRP1 相关的临床结果

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100 项与 Tubulin x LRP1 相关的转化医学

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0 项与 Tubulin x LRP1 相关的专利（医药）

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项与 Tubulin x LRP1 相关的文献（医药）

2020-12-01·Genes and Environment

Using FFPE RNA-Seq with 12 marker genes to evaluate genotoxic and non-genotoxic rat hepatocarcinogens

Article

作者: Ogawa, Kumiko ; Furihata, Chie ; Suzuki, Takayoshi ; Toyoda, Takeshi ; You, Xinyue

AbstractIntroductionVarious challenges have been overcome with regard to applying ‘omics technologies for chemical risk assessments. Previously we published results detailing targeted mRNA sequencing (RNA-Seq) on a next generation sequencer using intact RNA derived from freshly frozen rat liver tissues. We successfully discriminated genotoxic hepatocarcinogens (GTHCs) from non-genotoxic hepatocarcinogens (NGTHCs) using 11 selected marker genes. Based on this, we next attempted to use formalin-fixed paraffin-embedded (FFPE) pathology specimens for RNA-Seq analyses.FindingsIn this study we performed FFPE RNA-Seq to compare a typical GTHC, 2-acetylaminofluorene (AAF) to genotoxicity equivocal p-cresidine (CRE). CRE is used as a synthetic chemical intermediate, and this compound is classified as an IARC 2B carcinogen and is mutagenic in S. typhimurium, which is non-genotoxic to rat livers as assessed by single strand DNA damage analysis. RNA-Seq was used to examine liver FFPE samples obtained from groups of five 10-week-old male F344 rats that were fed with chemicals (AAF: 0.025% and CRE: 1% in food) for 4 weeks or from controls that were fed a basal diet. We extracted RNAs from FFPE samples and RNA-Seq was performed on a MiniSeq (Illumina) using the TruSeq custom RNA panel. AAF induced remarkable differences in the expression of eight genes (Aen, Bax, Btg2, Ccng1, Gdf15, Mbd1, Phlda3 and Tubb4b) from that in the control group, while CRE only induced expression changes in Gdf15, as shown using Tukey’s test. Gene expression profiles for nine genes (Aen, Bax, Btg2, Ccng1, Cdkn1a, Gdf15, Mbd1, Phlda3, and Plk2) differed.between samples treated with AAF and CRE. Finally, principal component analysis (PCA) of 12 genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2, and Tubb4b) using our previous Open TG-GATE data plus FFPE-AAF and FFPE-CRE successfully differentiated FFPE-AAF, as GTHC, from FFPE-CRE, as NGHTC.ConclusionOur results suggest that FFPE RNA-Seq and PCA are useful for evaluating typical rat GTHCs and NGTHCs.

2020-03-01·Physiology & Behavior3区 · 医学

Involvement of chronic unpredictable mild stress-induced hippocampal LRP1 up-regulation in microtubule instability and depressive-like behavior in a depressive-like adult male rat model

3区 · 医学

Article

作者: Xiao, Ling ; Wang, Hui ; Wang, Huiling ; Wang, Gaohua

Low-density lipoprotein receptor-related protein 1 (LRP1) and tau play an important role in developing Alzheimer's disease. This study aimed to explore the involvement of LRP1 in microtubule dynamic and depressive-like behavior in a depressive-like rat model. It also investigated whether fluoxetine blocked the change induced by chronic unpredictable mild stress (CUMS). Sprague-Dawley rats (200-250 g) were exposed to CUMS and fluoxetine for 4 weeks respectively. The body weight was determined, and behavior tests, including sucrose preference test, forced swimming test and open field test were performed. Western blot analysis was conducted to determine the protein levels of LRP1, tubulin, Acet-tub, Tyr-tub and PI3K/Akt/GSK-3β. Real-time quantitative polymerase chain reaction was used for mRNA expression levels of LRP1. Immunohistochemical staining was applied for LRP1 and immunofluorescence staining for the co-location of p-tau (404,262) and Acet-tub. The CUMS group presented a decreased body weight and depressive-like behavior, which was improved by fluoxetine. The protein and mRNA expression levels of LRP1 were elevated in the CUMS group. The levels of Acet-tub increased following CUMS, accompanied by elevated levels of p-tau (404,262). The binding of p-tau and Acet-tub significantly decreased in depressive-like rats, and fluoxetine attenuated microtubule instability. Finally, the inhibition of CUMS-induced PI3K/Akt activated GSK-3β, and fluoxetine reversed the change in the signaling pathway. Hence, LRP1 might impair the microtubule dynamics accompanied by depressive-like behavior via the PI3K/ Akt /GSK3β pathway in adult depressive-like rats, and hippocampal LRP1 might be involved in the development of depression.

2019-02-01·Mutation Research/Genetic Toxicology and Environmental Mutagenesis3区 · 医学

Evaluation of 12 mouse marker genes in rat toxicogenomics public data, Open TG-GATEs: Discrimination of genotoxic from non-genotoxic hepatocarcinogens

3区 · 医学

Article

作者: Suzuki, Takayoshi ; Furihata, Chie

Previously, we proposed 12 marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb4b) to discriminate mouse genotoxic hepatocarcinogens (GTHC) from non-genotoxic hepatocarcinogens (NGTHC). This was determined by qPCR and principal component analysis (PCA), as the aim of an in vivo short-term screening for genotoxic hepatocarcinogens. For this paper, we conducted an application study of the 12 mouse marker genes to rat data, Open TG-GATEs (public data). We analyzed five typical rat GTHC (2-acetamodofluorene, aflatoxin B1, 2-nitrofluorene, N-nitrosodiethylamine and N-nitrosomorpholine), and not only seven typical rat NGTHC (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital and WY-14643) but also 11 non-genotoxic non-hepatocarcinogens (NGTNHC; allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline and tolbutamide) from Open TG-GATEs. The analysis was performed at 3, 6, 9 and 24 h after a single administration and 4, 8, 15 and 29 days after repeated administrations. We transferred Open TG-GATEs DNA microarray data into log₂ data using the "R Project for Statistical Computing". GTHC-specific dose-dependent gene expression changes were observed and significance assessed with the Williams test. Similar significant changes were observed during 3-24 h and 4-29 days, assessed with Welch's t-test, except not for NGTHC or NGTNHC. Significant differential changes in gene expression were observed between GTHC and NGTHC in 11 genes (except not Tubb4b) and between GTHC and NGTNHC in all 12 genes at 24 h and 10 genes (except Ccnf and Mbd1) at 29 days, per Tukey's test. PCA successfully discriminated GTHC from NGTHC and NGTNHC at 24 h and 29 days. The results demonstrate that 12 previously proposed mouse marker genes are useful for discriminating rat GTHC from NGTHC and NGTNHC from Open TG-GATEs.

项与 Tubulin x LRP1 相关的新闻（医药）

2024-03-12

·生物制药小编

LAG-3或搅局阿尔兹海默症

Tau蛋白假说是学术界提出的AD发病机制的另一大主流假说，Tau蛋白聚集导致的神经元纤维缠结被认为是AD另一大主要病理特征。然而一直以来，围绕Tau蛋白的AD药物开发更多是在重复β-淀粉样蛋白假说的失败历程，已经有多家企业（罗氏、渤健、礼来等）接连放弃了靶向Tau蛋白候选药物的开发。围绕Tau蛋白假说的AD新药开发仍然是迷雾重重。Tau蛋白聚集体或具有传染性Tau蛋白是一种微管相关蛋白，广泛存在于神经元（神经细胞）中，起到稳定微管蛋白的作用。而在AD患者脑中，Tau蛋白异常磷酸化，转变为不可溶状态且高度聚集。Tau蛋白的异常磷酸化不但会使其自身微管结构改变，丧失其正常功能，而且会导致突触蛋白失去功能、引起神经纤维缠结(NFTs)，最终导致神经元的死亡。此外，研究发现，Tau蛋白聚集体（tau PFF）似乎还具有类似于朊病毒的“传染性”，在神经元之间可以扩散，使正常的神经元被传染而变性，最终导致认知障碍。然而，介导tau PFF在神经元中传播的机制仍不清楚。目前已知几种Tau蛋白单体的细胞表面受体，如硫酸乙酰肝素蛋白多糖（HSPGs）和低密度脂蛋白受体相关蛋白1(LRP1)，但这些受体对tau PFF或者其他形式的Tau蛋白并不具备特异性。近日，发表在Advanced Science上一篇名为Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission的研究发现，神经元中的Lag-3可以特异性结合Tau PFF，并介导其在神经元中的内吞和传递。敲除神经元中的LAG3或使用LAG3抗体阻断能显著降低Tau PFF在神经元之间的传递，以及其诱导的病理性Tau蛋白产生。Lag-3特异性结合Tau PFF细胞表面结合测定结果显示，Lag-3可与被生物素标记的Tau PFF结合，而非Tau单体（KD值为158nm），并且Lag3对Tau低聚体的结合也相对较弱，KD值1300nm。进一步研发现，Lag-3胞外域的D1结构域对于Lag-3与Tau PFF的结合至关重要。生物素标记的Tau PFF会优先与D1结构域结合，而D1的缺失可以消除Lag3与Tau PFF的结合。不过，D2、D3、D4或胞内结构域的缺失也会在一定程度上削弱这种结合。此外，来自不同Tau蛋白病的Tau PFF与Lag3之间的亲和力也有不同。来自进行性核上性麻痹症（PSP）的Tau PFF与Lag3的KD值为227nm，而来自匹克症（PiD）的KD值为271nm。Lag-3促进Tau PFF的内吞体外内吞实验结果显示，LAG-3能特异性介导Tau PFF的内吞，被生物素标记的Tau PFF能特异性地被原代培养的皮层神经元内吞，而敲除Lag-3可显著抑制其内吞。活细胞成像实验中，被染色的Tau PFF在小鼠皮质神经元中发出红色荧光，而缺乏Lag-3的神经元红色荧光较少，而过表达Lag3的神经元红色荧光增强。Lag-3介导Tau PFF的传递体内外实验皆显示，Lag-3为Tau PFF在神经元间传递所必需的，Lag-3敲除或Lag-3抗体阻断能显著抑制Tau PFF在神经元之间的传递。体外微灌流系统实验显示，在缺乏Lag-3的神经元装置中，不可溶性Tau蛋白含量减少了，而在过表达Lag-3的神经元装置中，不可溶性Tau蛋白含量明显增加了。进一步体内实验显示，Lag-3抗体可以显著阻断神经元Lag3与Tau PFF的结合，并减少Tau PFF在神经元之间的传递。与对照组相比，Lag-3抗体（410C9）显著阻断了Tau PFF与过表达Lag-3神经元的结合，在其他Lag3抗体C9B7W和17B4上也得出了类似结果。此外，410C9降低了Tau PFF诱导的磷酸化Tau蛋白表达水平（p-Tau)）。体内实验中，向神经元Lag-3敲除小鼠背侧海马区定向注射Tau PFF 9个月后，在腹侧海马、内嗅皮层、杏仁核中均观察到p-Tau表达水平的显著下降。总结LAG-3近年来肿瘤免疫治疗方面备受关注的一个靶点，作为PD-1搭档的临床潜力已在多项临床被证实。而除了肿瘤之外，LAG3（在小胶质细胞和神经细胞中表达）亦有可能是神经退行性疾病的一个治疗靶点。在该团队2021发布的一篇研究中，神经元LAG3在帕金森病（PD）的发病机制也扮演重要角色，LAG3可特异性的结合α-突触核蛋白聚集体（一种PD的病理特征），并介导其在神经元中的内吞和传递。参考出处：1.C. Chen, R. Kumbhar, H. Wang, X. Yang, K. Gadhave, C. Rastegar, Y. Kimura, A. Behensky, S. Kotha, G. Kuo, S. Katakam, D. Jeong, L. Wang, A. Wang, R. Chen, S. Zhang, L. Jin, C. J. Workman, D. A. A. Vignali, O. Pletinkova, H. Jia, W. Peng, D. W. Nauen, P. C. Wong, J. Redding-Ochoa, J. C. Troncoso, M. Ying, V. L. Dawson, T. M. Dawson, X. Mao, Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission. Adv. Sci. 2024, 2303775. https://doi.org/10.1002/advs.2023037752.Zhang S, Liu YQ, Jia C, Lim YJ, Feng G, Xu E, Long H, Kimura Y, Tao Y, Zhao C, Wang C, Liu Z, Hu JJ, Ma MR, Liu Z, Jiang L, Li D, Wang R, Dawson VL, Dawson TM, Li YM, Mao X, Liu C. Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson's disease. Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2011196118. doi: 10.1073/pnas.2011196118. LAG3会是帕金森病新药开发潜在突破吗？杂志文摘 | 阿尔茨海默病的发病机制和药物研发进展

临床结果