The main aim of this study is to assess how the human body of adults with advanced or metastatic solid tumors absorbs, distributes, metabolizes and excretes subasumstat following a single 1 hour infusion of subasumstat.
The study consists of two parts. In Part A, participants will receive a single infusion of C14 radiolabeled subasumstat. In Part B, participants will receive subasumstat treatment for up to 1 year.

开始日期2023-11-14

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

CTR20221395 / Active, not recruiting临床1/2期

一项在患有选定晚期或转移性实体瘤的患者中评价TAK-981与帕博利珠单抗联合治疗的安全性、耐受性和抗肿瘤活性的Ib/II期研究

在患有选定实体瘤适应症的患者中评价II期推荐剂量下TAK-981与帕博利珠单抗联合治疗的初步疗效

开始日期2022-08-31

申办/合作机构

Lyophilization Services of New England, Inc.

[+2]

CTR20213021 / Terminated临床2期

一项在晚期或转移性实体瘤或复发性/难治性血液学恶性肿瘤成年患者中评价TAK-981安全性、耐受性、初步疗效和药代动力学的开放性、剂量递增、1/2期研究

评价TAK-981在特定实体瘤或复发性/难治性CD20+ NHL患者中的初步疗效和安全性。

开始日期2022-07-08

申办/合作机构

Lyophilization Services of New England, Inc.

[+2]

100 项与 SAE 相关的临床结果

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100 项与 SAE 相关的转化医学

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0 项与 SAE 相关的专利（医药）

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673

项与 SAE 相关的文献（医药）

2025-01-01·Applied Ergonomics

User comfort and naturalness of automated driving: The effect of vehicle kinematic and proxemic factors on subjective response

Article

作者: Merat, Natasha ; Hagenzieker, Marjan ; Peng, Chen ; Wei, Chongfeng ; Solernou, Albert

User comfort in higher-level Automated Vehicles (AVs, SAE Level 4+) is crucial for public acceptance. AV driving styles, characterised by vehicle kinematic and proxemic factors, affect user comfort, with "human-like" driving styles expected to provide natural feelings. We investigated a) how the kinematic and proxemic factors of an AV's driving style affect users' evaluation of comfort and naturalness, and b) how the similarities between automated and users' manual driving styles affect user evaluation. Using a motion-based driving simulator, participants experienced three Level 4 automated driving styles: two human-like (defensive, aggressive) and one machine-like. They also manually drove the same route. Participants rated their comfort and naturalness of each automated controller, across twenty-four varied UK road sections. We calculated maximum absolute values of the kinematic and proxemic factors affecting the AV's driving styles in longitudinal, lateral, and vertical directions, for each road section, to characterise the automated driving styles. The Euclidean distance between AV and manual driving styles, in terms of kinematic and proxemic factors, was calculated to characterise the human-like driving style of the AV. We used mixed-effects models to examine a) the effect of AV's kinematic and proxemic factors on the evaluation of comfort and naturalness, and b) how similarities between manual and automated driving styles affected the evaluation. Results showed significant effects of lateral and rotational kinematic factors on comfort and naturalness, with longitudinal kinematic factors having a less prominent effect. Similarities in vehicle metrics, such as speed, longitudinal jerk, lateral offset, and yaw, between manual and automated driving styles, enhanced user comfort and naturalness. This research facilitates an understanding of how control features of AVs affect user experience, contributing to the design of user-centred controllers and better acceptance of higher-level AVs.

2024-12-01·Cellular and Molecular Life Sciences

Rhes, a striatal enriched protein, regulates post-translational small-ubiquitin-like-modifier (SUMO) modification of nuclear proteins and alters gene expression

Article

作者: Rivera, Oscar ; Karunadharma, Pabalu ; Ramĺrez-Jarquĺn, Uri Nimrod ; McManus, Francis ; Crynen, Gogce ; Bonneil, Eric ; Pierre, Thibault ; Subramaniam, Srinivasa ; Sharma, Manish ; Shahani, Neelam ; Dagar, Sunayana

AbstractRhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to cell via the formation of tunneling-like nanotubes (TNTs). However, the mechanisms by which Rhes mediates diverse functions remain unclear. Rhes is a small GTPase family member which contains a unique C-terminal Small Ubiquitin-like Modifier (SUMO) E3-like domain that promotes SUMO post-translational modification of proteins (SUMOylation) by promoting “cross-SUMOylation” of the SUMO enzyme SUMO E1 (Aos1/Uba2) and SUMO E2 ligase (Ubc-9). Nevertheless, the identity of the SUMO substrates of Rhes remains largely unknown. Here, by combining high throughput interactome and SUMO proteomics, we report that Rhes regulates the SUMOylation of nuclear proteins that are involved in the regulation of gene expression. Rhes increased the SUMOylation of histone deacetylase 1 (HDAC1) and histone 2B, while decreasing SUMOylation of heterogeneous nuclear ribonucleoprotein M (HNRNPM), protein polybromo-1 (PBRM1) and E3 SUMO-protein ligase (PIASy). We also found that Rhes itself is SUMOylated at 6 different lysine residues (K32, K110, K114, K120, K124, and K245). Furthermore, Rhes regulated the expression of genes involved in cellular morphogenesis and differentiation in the striatum, in a SUMO-dependent manner. Our findings thus provide evidence for a previously undescribed role for Rhes in regulating the SUMOylation of nuclear targets and in orchestrating striatal gene expression via SUMOylation.

2024-10-01·Experimental Neurology

ADSC-derived exosomes provide neuroprotection in sepsis-associated encephalopathy by regulating hippocampal pyroptosis

Article

作者: Tian, Mi ; Chen, Jiu ; Zhang, Li ; Zhan, Yunliang ; Yao, Hao ; Sun, Jie

AIMSAdipose-derived stem cell (ADSC)-derived exosomes have been recognized for their neuroprotective effects in various neurological diseases. This study investigates the potential neuroprotective effects of ADSC-derived exosomes in sepsis-associated encephalopathy (SAE).METHODSBehavioral cognitive functions were evaluated using the open field test, Y-maze test, and novel object recognition test. Brain activity was assessed through functional magnetic resonance imaging (fMRI). Pyroptosis was measured using immunofluorescence staining and western blotting.RESULTSOur findings indicate that ADSC-derived exosomes mitigate cognitive impairment, improve survival rates, and prevent weight loss in SAE mice. Additionally, exosomes protect hippocampal function in SAE mice, as demonstrated by fMRI evaluations. Furthermore, SAE mice exhibit neuronal damage and infiltration of inflammatory cells in the hippocampus, conditions which are reversed by exosome treatment. Moreover, our study highlights the downstream regulatory role of the NLRP3/caspase-1/GSDMD signaling pathway as a crucial mechanism in alleviating hippocampal inflammation.CONCLUSIONADSC-derived exosomes confer neuroprotection in SAE models by mediating the NLRP3/caspase-1/GSDMD pathway, thereby ameliorating cognitive impairment.

项与 SAE 相关的新闻（医药）

2022-07-27

·生物谷

J Clin Invest: KRAS基因突变是胰腺癌细胞外小泡淋巴管生成的重要启动子

该研究提供了对癌症淋巴管生成的机制洞察，具有开发生物标记物和RAS途径疗法的潜力。胰腺癌是最致命的胃肠道恶性肿瘤，是癌症相关死亡的第四大原因，五年生存率最低，仅为11%。由于缺乏筛查方法和早期症状的缺乏，胰腺癌最常在晚期被发现-当时几乎没有可用的治疗选择。主要的组织学类型是胰腺导管腺癌(PDAC)，90%以上的病例携带KRAS基因突变作为分子标志。作为胰腺癌的驱动基因，KRAS基因改变促进了胰腺上皮异型增生、胰腺上皮内瘤变和胰腺粘液瘤的发生发展。直到最近，由于设计特定抑制剂的结构困难，KRAS突变被认为是不可药物的靶点。图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1172/JCI161454. 近日，来自罗马尼亚的研究者们在J Clin Invest杂志上发表了题为“KRAS mutations as essential promoters of lymphangiogenesis via extracellular vesicles in pancreatic cancer”的文章，该研究提供了对癌症淋巴管生成的机制洞察，具有开发生物标记物和RAS途径疗法的潜力。柯尔斯滕鼠肉瘤病毒(KRAS)基因突变存在于90%以上的胰腺导管腺癌(PDAC)中。KrasG12D是最常见的改变，促进癌前病变，并与更具侵袭性的表型相关。这些肿瘤具有瘤内淋巴管网络增多和频繁的淋巴转移。罗、李等人探讨了KrasG12D突变与PDAC淋巴管生成的关系。作者使用体外和体内模型和一种优雅的机制方法来描述促进淋巴管生成的另一种途径。KrasG12D通过SAE1和SUMO2的激活诱导异源核糖核蛋白A1(HnRNPA1)的SUMO化。 SUMOylated hnRNPA1被负载到细胞外小泡(EVS)中，并被人内皮淋巴细胞(HLEC)内化。此外，SUMOylated hnRNPA1通过稳定PROX1的mRNA，促进淋巴管生成和LN转移。 KrasG12D诱导PDAC淋巴管生成的可能机制图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1172/JCI161454. 综上所述，本研究揭示了KrasG12D PDAC中肿瘤诱导淋巴管发育和早期LN转移的分子机制。作者发现KrasG12D蛋白是血管内皮生长因子-C非依赖性诱导淋巴管生成的重要因素。在机制上，KrasG12D在激活依赖于SAE1的hnRNPA1的SUMO化和随后的EV负载方面发挥了作用，从而进一步诱导了HLEC中PROX1的激活。（生物谷 Bioon.com）参考文献 Radu Pirlog et al. KRAS mutations as essential promoters of lymphangiogenesis via extracellular vesicles in pancreatic cancer. J Clin Invest. 2022 Jul 15;132(14):e161454. doi: 10.1172/JCI161454.