A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study Using a Bayesian Adaptive Design to Assess the Efficacy, Safety, Tolerability, and Serum Exposure of Multiple Doses of BG00010 (Neublastin) in Subjects With Painful Lumbar Radiculopathy

The primary objective of the study is to assess the efficacy of Intravenous (IV) BG00010 (Neublastin) in improving pain in painful lumbar radiculopathy participants when administered 3 times per week for 1 week.
The secondary objectives of this study in this study population are as follows: To explore the duration of the effect of BG00010 in improving pain; To explore the dose response curve on pain reduction; To assess the safety and tolerability of BG00010; To assess the serum exposure to BG00010.

开始日期2013-06-01

申办/合作机构

Biogen, Inc.

NL-OMON40320

/ CompletedN/A

Study of Safety, Tolerability, and Pharmacokinetics of BG00010 (Neublastin) Intravenous and Subcutaneous Single Ascending Doses in Healthy Volunteers, and Subcutaneous Multiple Ascending Doses in Subjects with Painful Lumbar Radiculopathy - SC and IV doses SAD/MAD study BG00010

开始日期2013-04-15

申办/合作机构

Biogen, Inc.

NCT01842126

/ Completed临床1期

The primary objective of the study is to evaluate the safety and tolerability of a range of single intravenous (IV) and subcutaneous (SC) doses of BG00010 in healthy volunteers, and a range of multiple SC doses of BG00010 in participants with painful lumbar radiculopathy. Secondary objectives of this study are to determine the single IV and SC dose pharmacokinetics (PK) profile of BG00010 in healthy volunteers including assessment of bioavailability by comparing SC exposure to IV exposure in each participant, to determine the multiple SC dose PK profiles of BG00010 in participants with painful lumbar radiculopathy, to assess the single IV and SC dose immunogenicity of BG00010 in healthy volunteers, to assess the multiple SC dose immunogenicity of BG00010 in participants with painful lumbar radiculopathy, and to assess the potential of BG00010 to reduce pain following multiple SC administrations in participants with painful lumbar radiculopathy.

开始日期2013-04-01

申办/合作机构

Biogen, Inc.

100 项与 Neublastin 相关的临床结果

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100 项与 Neublastin 相关的转化医学

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100 项与 Neublastin 相关的专利（医药）

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180

项与 Neublastin 相关的文献（医药）

2024-11-01·CEPHALALGIA

The neurotrophic factor artemin and its receptor GFRα3 mediate migraine-like pain via the ion channel TRPM8

Article

作者: Yang, Chenyu ; Alam, Sanaa ; McKemy, David D. ; Wei, Chao ; Chen, Xunyang

Background:

Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous genetic variants linked with migraine risk. Surprisingly, some of the most common mutations are associated with transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel that is the primary sensor of cold temperatures in cutaneous primary afferents of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 is relevant in migraine-related tissues, such as the meninges, suggesting other activation mechanisms underly its role in migraine pathogenesis. Thus, to define the basis of the channel's involvement, we reasoned that cellular processes that increase cold sensitivity in the skin, such as the neurotrophic factor artemin, via its receptor glial cell-line derived neurotrophic factor family receptor alpha-3 (GFRα3), also mediate TRPM8-associated migraine-like pain in the meninges.

Methods:

To investigate the role of artemin and GFRα3 in preclinical rodent migraine models, we infused nitroglycerin acutely and chronically, and measured changes in periorbital and hind paw mechanical sensitivity in male and female mice lacking GFRα3, after neutralization of free artemin with specific monoclonal antibodies, or by systemic treatment with a TRPM8-specific antagonist. Further, in mice lacking GFRα3 we tested the effects of supradural infusions of a mix of inflammatory mediators, as well as tested if dura stimulation with artemin or a TRPM8-specific agonist induce migraine-related pain in mice.

Results:

We find that mechanical allodynia induced by systemic nitroglycerin, or supradural infusion of inflammatory mediators, involves GFRα3. In addition, neutralization of circulating artemin reduces the nitroglycerin phenotype, demonstrating the importance of this neurotrophic pathway in headaches. Further, we show TRPM8 expression in the meninges, and that direct supradural infusion of either a TRPM8-specific agonist or artemin itself produces mechanical allodynia, with the latter dependent on TRPM8 and ameliorated by concurrent treatment with sumatriptan.

Conclusions:

These results indicate that neuroinflammatory events in the meninges can produce migraine-like pain in mice via artemin and GFRα3, likely acting upstream of TRPM8, providing a novel pathway that may contribute to headaches or migraine pathogenesis.

2024-08-01·The Journal of investigative dermatology

The EGR1–Artemin Axis in Keratinocytes Enhances the Innervation of Epidermal Sensory Neurons during Skin Inflammation Induced by House Dust Mite Extract from Dermatophagoides farinae

Article

作者: Yun, Sook Jung ; Lee, Young Han ; Lim, Yoongho ; Yeo, Hyunjin ; Koh, Dongsoo ; Shin, Soon Young ; Ahn, Sung Shin ; Ou, Sukjin

Epidermal hyperinnervation is a critical feature of pruritus during skin inflammation. However, the mechanisms underlying epidermal hyperinnervation are unclear. This study investigates the role of the transcription factor EGR1 in epidermal innervation by utilizing wild-type (Egr1^+/+) and Egr1-null (Egr1^‒/‒) mice topically applied Dermatophagoides farinae extract from dust mite. Our findings revealed that Egr1^‒/‒ mice exhibited reduced scratching behaviors and decreased density of epidermal innervation compared with Egr1^+/+ mice. Furthermore, we identified artemin, a neurotrophic factor, as an EGR1 target responsible for Dermatophagoides farinae extract-induced hyperinnervation. It has been demonstrated that Dermatophagoides farinae extract stimulates toll-like receptors in keratinocytes. To elucidate the cellular mechanism, we stimulated keratinocytes with Pam3CSK4, a toll-like receptor 1/2 ligand. Pam3CSK4 triggered a toll-like receptor 1/2-mediated signaling cascade involving IRAK4, IκB kinase, MAPKs, ELK1, EGR1, and artemin, leading to increased neurite outgrowth and neuronal migration. In addition, increased expression of EGR1 and artemin was observed in the skin tissues of patients with atopic dermatitis. These findings highlight the significance of the EGR1-artemin axis in keratinocytes, promoting the process of epidermal innervation and suggesting it as a potential therapeutic target for alleviating itch and pain associated with house dust mite-induced skin inflammation.

2024-07-01·JOURNAL OF AUTOIMMUNITY

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome

Article

作者: Bozorgmehr, Najmeh ; Sligl, Wendy ; Redmond, Desiree ; Lam, Grace ; Osman, Mohammed ; Rosychuk, Rhonda J ; Cohen Tervaert, Jan Willem ; Elahi, Shokrollah ; Saito, Suguru ; Shahbaz, Shima

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC. The expansion of immunosuppressive CD71⁺ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4⁺CD160⁺ and TIM3⁺CD160⁺ CD8⁺ T cells completely separated LC patients from the R group. Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

项与 Neublastin 相关的新闻（医药）

2024-10-10

·生物探索

Dev Cell | 范衡宇实验室揭示RNA解旋酶MTR4介导的RNA监管机制决定小鼠卵母细胞体积增长的机制

引言成熟的卵母细胞（oocyte）是哺乳动物体内最大的细胞类型。与体细胞（somatic cell）有限的体积增长不同，卵母细胞从原始卵泡激活发育到生长完成，体积增长近500倍。但卵母细胞如何生长成为最大的细胞，还存在诸多未解之谜。卵巢中储存的原始卵泡激活以后，卵泡中的卵母细胞要经历为期数周的生长期，伴随着持续活跃的转录和转录后加工、核质运输等活动，并在卵胞质中积累了大量转录加工成熟的mRNA，为后续转录沉默的减数分裂、排卵和受精时期提供重要的物质基础【1,2】。但卵母细胞如何确保这一过程中RNA的正确加工与储存，及其对卵母细胞发育潜能的影响还尚未清晰。 2024年10月7日，浙江大学生命科学研究院范衡宇团队（博士生吴韵雯（已毕业）为本文第一作者）在Developmental Cell发表题为RNA Surveillance by the RNA Helicase MTR4 Determines Volume of Mouse Oocytes的研究论文，报道了RNA解旋酶MTR4参与的RNA外切体复合物（RNA exosome）作为一种RNA监管机制，是卵母细胞生长过程中的一个关键检查点，允许卵母细胞生长到巨大的体积，经历细胞核和细胞质的成熟并最终获得发育潜能。此外，该研究还发现了MTR4介导的RNA监管机制对于维持卵母细胞正常核环境的新功能。研究团队在卵母细胞中首次使用细胞核与细胞质分离后进行转录组测序的方法，定量统计了卵母细胞在生长过程中整体 mRNA 水平及细胞核和细胞质这两种亚细胞组分中 mRNA 分布比例的变化，并鉴定出细胞核和细胞质中转录物的不同剪接加工特征，提出 RNA 监管机制可能在其中发挥重要功能。通过对 RNA 外切体复合物的前期调研，该研究采用在卵母细胞中条件性敲除 Mtr4 这一基因来实现对卵母细胞中RNA监管机制的破坏。基于基因敲除鼠的表型分析和回补实验证实了MTR4缺失会给小鼠卵母细胞造成无法逆转的严重的成熟障碍，包括卵母细胞体积明显减小，无法完成卵子成熟所必须的核构象转变、基因组转录沉默和减数分裂恢复。通过荧光原位杂交实验和核质分离测序等实验，该研究证明了 MTR4 缺失后 RNA 监管机制失效，导致大量未成熟RNA滞留在细胞核中，与此同时细胞质中的成熟mRNA 储量也大幅下降。生信分析表明，MTR4 缺失后核中滞留的转录本多为加工不完全的废物 RNA，部分内含子异常保留的转录本甚至被进一步运输到胞质中。通过在 Mtr4 敲除的卵母细胞中显微注射回补 MTR4，检测到异常累积的转录本含量明显减少，证实了 MTR4 介导的 RNA 监管机制在监管 RNA质量和维持 RNA 正常的核质分布比例中发挥直接作用。 Mtr4敲除小鼠卵母细胞RNA 监管机制失效后，卵母细胞发育过程中核构象由NSN向SN转变失败。通过进一步的表型鉴定及染色质开放性分析（ATAC-seq），发现核中异常累积的RNA造成了染色质开放程度增加，染色质无法正常凝集并转录沉默；CUT&Tag测序分析也揭示了与转录密切相关的组蛋白修饰H3K4me3在染色质上分布异常。除影响染色质结构外，核中异常累积的RNA还造成了细胞核区室化结构的异常，包括核斑点和核仁无法正常组装。以上实验结果揭示了MTR4 介导的RNA 监管机制在维持卵母细胞健康的核环境及促进细胞核成熟方面的重要功能，也进一步发现RNA稳态负反馈调节染色质构象、组蛋白修饰建立和核内区室化结构的形成。图1: RNA监管机制失效后卵母细胞的细胞核环境紊乱。A: MTR4缺失后卵母细胞核构象由NSN向SN转变失败。B: MTR4缺失后卵母细胞无法转录沉默。C: MTR4缺失后PABPN1介导的NPAD结构和nuclear speckles无法正常形成（Credit: Developmental Cell）此外，该研究还提出RNA 监管机制通过以下两个方面影响卵母细胞的生长和胞质成熟。（1）维持健康的核环境，保证了卵母细胞生长过程中的转录及转录后加工活动，在胞质中累积足量的正常转录本。（2）保证了核仁正常的组装与功能，为细胞质的蛋白翻译提供核糖体机器。综上，MTR4介导的RNA监管机制确保了细胞核和细胞质中丰富的mRNA积累和有序储存，对于决定卵母细胞的体积和发育潜能具有重要生理意义。图2: RNA监管机制确保小鼠卵母细胞生长成熟的模式图（Credit: Developmental Cell）该课题组在先前的研究中发现，Poly(A)结合蛋白PABPN1具有对新生RNA进行剪切、加尾、保护和储存的重要功能【3】。PABPN1通过介导液-液相分离形成细胞核内的特定功能区域nuclear poly(A) domain (NPAD)，调控卵子发生过程中mRNA的转录后加工。MTR4和PABPN1同属于RNA外切体复合物，两者的敲除小鼠卵母细胞在分子水平上均存在RNA加工异常、不能有效建立起母源mRNA储备等问题，并具有卵母细胞体积减小、发育成熟障碍等相似的表型。这一系列研究揭示了卵母细胞生长过程中的mRNA转录后加工调控和监管对于建立卵母细胞发育潜能的重要作用，为解析卵母细胞如何生长成为体内最大的细胞提供了新的理论。参考文献 1. Rong, Y., Ji, S.Y., Zhu, Y.Z., Wu, Y.W., Shen, L., and Fan, H.Y. (2019). ZAR1 and ZAR2 are required for oocyte meiotic maturation by regulating the maternal transcriptome and mRNA translational activation. Nucleic Acids Res 47, 11387-11402. 10.1093/nar/gkz863. 2. Cheng, S.Y., Altmeppen, G., So, C., Welp, L.M., Penir, S., Ruhwedel, T., Menelaou, K., Harasimov, K., Stützer, A., Blayney, M., et al. (2022). Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment. Science 378. ARTN eabq4835 97210.1126/science.abq4835. 3. Dai, X.X., Pi, S.B., Zhao, L.W., Wu, Y.W., Shen, J.L., Zhang, S.Y., Sha, Q.Q., and Fan, H.Y. (2022). PABPN1 functions as a hub in the assembly of nuclear poly(A) domains that are essential for mouse oocyte development. Sci Adv 8. 10.1126/sciadv.abn9016. https://www.cell.com/developmental-cell/abstract/S1534-5807(24)00537-9 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

信使RNA

2024-08-09

·生物谷

Cell｜北京大学张泽民团队通过泛癌种单细胞整合分析揭示表型各异的肿瘤浸润B细胞亚类

2024年7月23日，北京大学生物医学前沿创新中心（BIOPIC）张泽民课题组在Cell发表了题为Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtype的研究论文。该研究整合了来自19种癌症类型患者的大规模单细胞转录组测序数据，描绘了肿瘤浸润B细胞在泛癌种水平上丰度和构成的异质性，发现了能够与CD4 T细胞进行互作并具有预后潜力的肿瘤相关非典型B细胞（tumor-associated atypical B cell, TAAB）。近些年来，肿瘤免疫治疗的成功激发了对肿瘤微环境，特别是肿瘤免疫微环境全面深入的探究[1]。此前，张泽民课题组的研究系统刻画了肿瘤浸润髓系细胞、T细胞和NK细胞的泛癌种单细胞图谱[2–4]，为肿瘤治疗策略的研发提供了新的思路。然而，尽管B细胞在免疫中发挥着重要作用，它们受到的关注相对较少。本研究通过整合来自19种主要癌症类型的649名患者的单细胞RNA测序数据，构建了包含511,857个B细胞的泛癌种B细胞单细胞表达谱图谱，鉴定出5个B细胞大类和20个B细胞亚类。研究人员还利用算法重建了部分细胞的BCR序列，并对80例患者样本进行了肿瘤浸润B细胞相关的免疫组化或多色免疫组化染色。基于整合的数据资源，研究人员发现肿瘤浸润B细胞的丰度和亚群组成在不同癌症类型间表现出了明显的偏好性。研究人员还观察到在肿瘤中存在B细胞分化阶段中重要的过渡亚群，例如，肿瘤中的生发中心B细胞前体（pre-germinal center B cell）和浆母细胞（plasmablast）。通过BCR序列分析，研究人员在肿瘤内观察到BCR序列演化的进程，以及伴随此演化过程中出现的从生发中心B细胞（germinal center B cell）向记忆B细胞（memory B cell）和抗体分泌细胞（antibody-secreting cell）的转化，这与二级淋巴器官生发中心反应的过程相类似。此外，研究人员关注到肿瘤浸润抗体分泌细胞的免疫球蛋白类型倾向于IgG型，尤其是IgG1亚型。除此以外，研究人员还鉴定出了两群在泛癌种水平上广泛存在、在肿瘤中富集且具有预后潜力的亚群：应激反应记忆B细胞（stress-response memory B cell）和肿瘤相关非典型B细胞（TAAB），它们分别与癌症患者更短和更长的生存期相关。应激反应记忆B细胞高表达应激反应相关基因，与之前报道的肿瘤相关功能失调NK细胞（tumor-associated dysfunctional NK cell）和应激反应T细胞（stress-response T cell）相类似[4,5]，这两类细胞的应激反应特征被报道与病人的不良预后或免疫治疗不响应相关。在尝试寻找与患者的不良预后相关的TIB亚群时，研究人员发现调节B细胞（regulatory B cell），或者说IL10+ B细胞，在单细胞聚类分析中并不能单独成群，这些细胞很可能源自B细胞分化的不同阶段。肿瘤富集的肿瘤相关非典型B细胞（TAAB）在肿瘤组织中具有高克隆扩增水平和增殖能力，并呈现高度激活的转录状态。CD4 T细胞，尤其是CXCL13+ CD4 T细胞，可能与肿瘤相关非典型B细胞（TAAB）在其激活和向浆细胞分化的过程中产生相互作用。重要的是，肿瘤相关非典型B细胞（TAAB）的特征与患者预后存在癌症类型依赖性关联，并且也是多种免疫治疗响应的预测指标。图1. 泛癌种B细胞单细胞图谱的摘要图综上所述，该研究拓展了在泛癌种视角对肿瘤浸润B细胞的了解，为B细胞的异质性及其抗肿瘤免疫反应提供了新的见解，并为未来进一步探索B细胞在癌症中功能的共性和多样性奠定了基础。北京大学前沿交叉学科研究院CLS项目博士生杨雨、北京大学BIOPIC/生命科学学院博士生陈雪雁为该论文的并列第一作者，北京大学BIOPIC张泽民院士、深圳湾实验室陈敏敏副研究员、北京大学BIOPIC王东方副研究员为该论文的共同通讯作者。深圳湾实验室盘洁莹、宁慧恒在本研究的免疫组化染色和细胞诱导等实验中提供了重要协助。研究得到了国家重点研发计划，国家自然科学基金、北京市科学技术委员会、深圳湾实验室重大项目和深圳湾实验室开放基金的资助。论文链接： https://www.cell.com/cell/fulltext/S0092-8674(24)00712-8 原文链接： https://mp.weixin.qq.com/s/FLCjmkY55lCM99QbscmXVQ 参考文献： 1.Wang, D.F., Liu, B.L., and Zhang, Z.M. (2023). Accelerating the understanding of cancer biology through the lens of genomics. Cell 186, 1755–1771. https://doi.org/10.1016/j.cell.2023.02.015. 2.Zheng, L., Qin, S., Si, W., Wang, A., Xing, B., Gao, R., Ren, X., Wang, L., Wu, X., Zhang, J., et al. (2021). Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474. https://doi.org/ARTN eabe6474 10.1126/science.abe6474. 3.Cheng, S., Li, Z., Gao, R., Xing, B., Gao, Y., Yang, Y., Qin, S., Zhang, L., Ouyang, H., Du, P., et al. (2021). A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 184, 792-809.e23. https://doi.org/10.1016/j.cell.2021.01.010. 4.Tang, F., Li, J., Qi, L., Liu, D., Bo, Y., Qin, S., Miao, Y., Yu, K., Hou, W., Li, J., et al. (2023). A pan-cancer single-cell panorama of human natural killer cells. Cell 186, 4235-4251.e20. https://doi.org/10.1016/j.cell.2023.07.034. 5.Chu, Y., Dai, E., Li, Y., Han, G., Pei, G., Ingram, D.R., Thakkar, K., Qin, J.-J., Dang, M., Le, X., et al. (2023). Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat Med 29, 1550–1562. https://doi.org/10.1038/s41591-023-02371-y. 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！

免疫疗法细胞疗法

2024-07-24

·生物探索

Cell｜张泽民团队通过泛癌种单细胞整合分析揭示表型各异的肿瘤浸润B细胞亚类

引言近些年来，肿瘤免疫治疗的成功激发了对肿瘤微环境，特别是肿瘤免疫微环境全面深入的探究【1】。此前，北京大学生物医学前沿创新中心（BIOPIC）张泽民课题组的研究系统刻画了肿瘤浸润髓系细胞、T细胞和NK细胞的泛癌种单细胞图谱【2-4】，为肿瘤治疗策略的研发提供了新的思路。然而，尽管B细胞在免疫中发挥着重要作用，它们受到的关注相对较少。 2024年7月23日，张泽民课题组在Cell发表了题为Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtype的研究论文。该研究整合了来自19种癌症类型患者的大规模单细胞转录组测序数据，描绘了肿瘤浸润B细胞在泛癌种水平上丰度和构成的异质性，发现了能够与CD4 T细胞进行互作并具有预后潜力的肿瘤相关非典型B细胞（tumor-associated atypical B cell, TAAB）。本研究通过整合来自19种主要癌症类型的649名患者的单细胞RNA测序数据，构建了包含511,857个B细胞的泛癌种B细胞单细胞表达谱图谱，鉴定出5个B细胞大类和20个B细胞亚类。研究人员还利用算法重建了部分细胞的BCR序列，并对80例患者样本进行了肿瘤浸润B细胞相关的免疫组化或多色免疫组化染色。基于整合的数据资源，研究人员发现肿瘤浸润B细胞的丰度和亚群组成在不同癌症类型间表现出了明显的偏好性。研究人员还观察到在肿瘤中存在B细胞分化阶段中重要的过渡亚群，例如，肿瘤中的生发中心B细胞前体（pre-germinal center B cell）和浆母细胞（plasmablast）。通过BCR序列分析，研究人员在肿瘤内观察到BCR序列演化的进程，以及伴随此演化过程中出现的从生发中心B细胞（germinal center B cell）向记忆B细胞（memory B cell）和抗体分泌细胞（antibody-secreting cell）的转化，这与二级淋巴器官生发中心反应的过程相类似。此外，研究人员关注到肿瘤浸润抗体分泌细胞的免疫球蛋白类型倾向于IgG型，尤其是IgG1亚型。除此以外，研究人员还鉴定出了两群在泛癌种水平上广泛存在、在肿瘤中富集且具有预后潜力的亚群：应激反应记忆B细胞（stress-response memory B cell）和肿瘤相关非典型B细胞（TAAB），它们分别与癌症患者更短和更长的生存期相关。应激反应记忆B细胞高表达应激反应相关基因，与之前报道的肿瘤相关功能失调NK细胞（tumor-associated dysfunctional NK cell）和应激反应T细胞（stress-response T cell）相类似【4,5】，这两类细胞的应激反应特征被报道与病人的不良预后或免疫治疗不响应相关。在尝试寻找与患者的不良预后相关的TIB亚群时，研究人员发现调节B细胞（regulatory B cell），或者说IL10+ B细胞，在单细胞聚类分析中并不能单独成群，这些细胞很可能源自B细胞分化的不同阶段。肿瘤富集的肿瘤相关非典型B细胞（TAAB）在肿瘤组织中具有高克隆扩增水平和增殖能力，并呈现高度激活的转录状态。CD4 T细胞，尤其是CXCL13+ CD4 T细胞，可能与肿瘤相关非典型B细胞（TAAB）在其激活和向浆细胞分化的过程中产生相互作用。重要的是，肿瘤相关非典型B细胞（TAAB）的特征与患者预后存在癌症类型依赖性关联，并且也是多种免疫治疗响应的预测指标。图1. 泛癌种B细胞单细胞图谱的摘要图（Credit: Cell）综上所述，该研究拓展了在泛癌种视角对肿瘤浸润B细胞的了解，为B细胞的异质性及其抗肿瘤免疫反应提供了新的见解，并为未来进一步探索B细胞在癌症中功能的共性和多样性奠定了基础。参考文献 1. Wang, D.F., Liu, B.L., and Zhang, Z.M. (2023). Accelerating the understanding of cancer biology through the lens of genomics. Cell 186, 1755–1771. https://doi.org/10.1016/j.cell.2023.02.015. 2. Zheng, L., Qin, S., Si, W., Wang, A., Xing, B., Gao, R., Ren, X., Wang, L., Wu, X., Zhang, J., et al. (2021). Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474. https://doi.org/ARTN eabe6474 10.1126/science.abe6474. 3. Cheng, S., Li, Z., Gao, R., Xing, B., Gao, Y., Yang, Y., Qin, S., Zhang, L., Ouyang, H., Du, P., et al. (2021). A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 184, 792-809.e23. https://doi.org/10.1016/j.cell.2021.01.010. 4. Tang, F., Li, J., Qi, L., Liu, D., Bo, Y., Qin, S., Miao, Y., Yu, K., Hou, W., Li, J., et al. (2023). A pan-cancer single-cell panorama of human natural killer cells. Cell 186, 4235-4251.e20. https://doi.org/10.1016/j.cell.2023.07.034. 5. Chu, Y., Dai, E., Li, Y., Han, G., Pei, G., Ingram, D.R., Thakkar, K., Qin, J.-J., Dang, M., Le, X., et al. (2023). Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat Med 29, 1550–1562. https://doi.org/10.1038/s41591-023-02371-y. https://doi.org/10.1016/j.cell.2024.06.038 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法细胞疗法

100 项与 Neublastin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15438

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
椎间盘疾病	临床2期	美国	Biogen, Inc.	2013-06-01
腰椎神经根病	临床2期	美国	Biogen, Inc.	2013-06-01
坐骨神经痛	临床2期	美国	Biogen, Inc.	2013-06-01
神经痛	临床1期	丹麦	NsGene A/S	-

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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


EASL2021	N/A	肝细胞癌 serum ARTN concentration	56	artemin (High ARTN)	襯齋壓獵膚選膚鹹願製(鏇簾鑰衊願網齋簾選鏇) = 憲獵襯範範積築膚壓壓製糧蓋淵選網鑰製願齋 (壓簾齋壓積齋願鏇構獵 )	不佳	2021-06-23
				artemin (Low ARTN)	襯齋壓獵膚選膚鹹願製(鏇簾鑰衊願網齋簾選鏇) = 鹽蓋網鏇鏇餘糧壓鹹憲製糧蓋淵選網鑰製願齋 (壓簾齋壓積齋願鏇構獵 )
NCT01873404 (SPRINT, Pubmed \| Pain Physician) 人工标引	临床2期	腰骶神经根病变	176	Neublastin	繭範蓋鏇獵鑰蓋顧簾鹹(築構壓構廠襯遞鏇獵積): difference = -0.75 (95% CI, -1.59 ~ 0.08) 更多	积极	2017-09-01
				Placebo
NCT01405833 (Pubmed \| Br J Clin Pharmacol) 人工标引	临床1期	坐骨神经痛	28	BG00010 (In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ))	醖構繭選壓遞壓壓醖鏇(構衊鏇廠襯鬱襯膚選壓) = Most AEs were mild 淵製範餘築廠衊餘窪遞 (願齋壓壓鏇製餘糧夢鏇 ) 更多	积极	2016-07-01
				BG00010 (in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ).)
NCT00961766 (Pubmed \| J Biol Chem \| PLoS One) 人工标引	临床1期	坐骨神经痛	48	BG00010	膚窪簾製鏇網糧憲繭壓(築選鏇獵繭壓廠艱製襯) = the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache 襯簾糧淵淵夢築廠憲淵 (淵鹹醖餘齋築艱選顧鹽 )	积极	2015-05-11
				Placebo