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Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging 对衰老相关细胞状态进行有针对性的部分重编程可改善衰老小鼠模型的健康指标
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-11 DOI: 10.1126/scitranslmed.adg1777
Sanjeeb Kumar Sahu, Pradeep Reddy, Jinlong Lu, Yanjiao Shao, Chao Wang, Mako Tsuji, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (cMyc) (OSKM) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a-OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A-OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.
衰老是一个复杂的多因素过程,与表观基因组失调、细胞衰老加剧和再生能力下降有关。在野生型小鼠体内短期循环表达八聚体结合转录因子 4(Oct4)、性别决定区 Y-box 2(Sox2)、Kruppel 样因子 4(Klf4)和细胞髓母细胞瘤病癌基因(cMyc)(OSKM)可改善健康状况,但无法区分细胞状态,从而给健康细胞带来风险。在这里,我们在细胞周期蛋白依赖性激酶抑制剂2a(Cdkn2a)启动子的控制下释放了单剂量的携带OSK的腺相关病毒(AAV),在哈钦森-吉尔福特早衰综合征(HGPS)小鼠模型中特异性地对衰老和受压细胞进行了部分重编程。老化细胞特异性 OSK 表达后,小鼠促炎细胞因子的表达减少,寿命延长。尤其是骨髓和脾脏的基因表达发生了明显变化,老年 HGPS 小鼠的部分重编程导致造血干细胞区的细胞组成向年轻小鼠的细胞组成转变。给自然衰老的野生型小鼠注射携带Cdkn2a-OSK的AAV也能延缓衰老表型,延长寿命,但不会改变肿瘤的发病率。此外,皮内注射携带 Cdkn2a-OSK 的 AAV 还能改善老年野生型小鼠的伤口愈合。在衰老或受压的人类原代成纤维细胞中表达 CDKN2A-OSK 可减少炎症相关基因的表达,但不会改变细胞周期相关基因的表达。因此,这种有针对性的部分重编程方法可能有助于开发改善老年人健康和寿命以及增强复原力的策略。
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引用次数: 0
Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models 罗库溴铵特异性抗体会导致围手术期过敏性休克,但在临床前模型中也能起到逆转作用
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-11 DOI: 10.1126/scitranslmed.ado4463
Alice Dejoux, Qianqian Zhu, Christelle Ganneau, Odile Richard-Le Goff, Ophélie Godon, Julien Lemaitre, Francis Relouzat, François Huetz, Aurélien Sokal, Alexis Vandenberghe, Cyprien Pecalvel, Lise Hunault, Thomas Derenne, Caitlin M. Gillis, Bruno Iannascoli, Yidan Wang, Thierry Rose, Christel Mertens, Pascale Nicaise-Roland, NASA Study Group, Patrick England, Matthieu Mahévas, Luc de Chaisemartin, Roger Le Grand, Hélène Letscher, Frederick Saul, Cédric Pissis, Ahmed Haouz, Laurent L. Reber, Pascal Chappert, Friederike Jönsson, Didier G. Ebo, Gaël A. Millot, Sylvie Bay, Sylvie Chollet-Martin, Aurélie Gouel-Chéron, Pierre Bruhns
Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.
神经肌肉阻滞剂(NMBA)可放松骨骼肌,从而促进手术并方便插管,但也可能导致不良反应,包括术后残留神经肌肉阻滞(rNMB)引起的并发症,以及极少数情况下的过敏性休克。这两种不良反应因 NMBA 类型而异,其中罗库溴铵是一种广泛使用的非去极化 NMBA,可诱导最长的 rNMB 持续时间和最高的过敏性休克发生率。然而,在极少数情况下,苏甘麦得可引发过敏性休克。因此,还需要其他治疗方案。有人提出,罗库溴铵诱发的过敏性休克依赖于预先存在的罗库溴铵结合抗体。为了了解罗库溴铵诱发过敏性休克的发病机理并确定潜在的治疗方法,我们研究了疑似对罗库溴铵过敏的患者的记忆 B 细胞抗体复合物。我们发现多克隆抗体复合物在 V(D)J 基因间具有高度多样性,但没有克隆群的迹象。重组表达时,这些抗体对罗库溴铵表现出特异性和低亲和性,而对其他 NMBAs 没有交叉反应。此外,当这些抗体表达为人类免疫球蛋白 E(IgE)时,它们会引发转基因小鼠的人类肥大细胞活化和被动性全身过敏性休克,尽管它们的亲和力不足以作为逆转剂。因此,我们从免疫了罗库溴铵的小鼠体内分离出了罗库溴铵特异性高亲和力抗体。亲和力最高的抗体能够逆转非人灵长类动物中洛库铵诱导的神经肌肉阻滞,其动力学与苏加麦克斯相当。这些数据共同支持了抗体导致罗库溴铵过敏反应的假设,并为改进诊断和神经肌肉阻滞逆转剂铺平了道路。
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引用次数: 0
BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML BATF 是急性髓细胞性白血病中 NK 细胞表观遗传重编程和功能障碍的主要驱动因素
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-11 DOI: 10.1126/scitranslmed.adp0004
Bijender Kumar, Anand Singh, Rafet Basar, Nadima Uprety, Ye Li, Huihui Fan, Ana Karen Nunez Cortes, Mecit Kaplan, Sunil Acharya, Hila Shaim, Anna C Xu, Manrong Wu, Emily Ensley, Dexing Fang, Pinaki P. Banerjee, Luciana Melo Garcia, Silvia Tiberti, Paul Lin, Hind Rafei, Maliha Nuzhat Munir, Madison Moore, Mayra Shanley, Mayela Mendt, Lucila N. Kerbauy, Bin Liu, Alexander Biederstädt, Elif Gokdemir, Susmita Ghosh, Kiran Kundu, Francia Reyes-Silva, Xin Ru Jiang, Xinhai Wan, April L. Gilbert, Merve Dede, Vakul Mohanty, Jinzhuang Dou, Patrick Zhang, Enli Liu, Luis Muniz-Feliciano, Gary M. Deyter, Abhinav K. Jain, Juan Jose Rodriguez-Sevilla, Simona Colla, Guillermo Garcia-Manero, Elizabeth J. Shpall, Ken Chen, Hussein A. Abbas, Kunal Rai, Katayoun Rezvani, May Daher
Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.
骨髓增生异常综合征和急性髓性白血病(AML)属于髓系恶性肿瘤的一种连续性疾病谱,在复发/难治的情况下预后较差,需要采用新型疗法。髓系恶性肿瘤患者的自然杀伤(NK)细胞表现出整体功能障碍,杀伤能力受损,新陈代谢改变,在单细胞转录组和蛋白质组水平上表现出衰竭表型。在这项研究中,我们发现这种功能障碍是通过 NK 细胞和髓样细胞之间的交叉对话介导的,而这种交叉对话需要细胞与细胞之间的接触。NK细胞功能障碍可通过靶向αvβ-整合素/TGF-β/SMAD通路来预防,但一旦形成,就会因深刻的表观遗传重编程而持续存在。我们发现 BATF 是一种核心转录因子,也是导致 AML 中 NK 细胞功能障碍的主要介质。从机理上讲,我们发现BATF直接受SMAD2/3调控和诱导,进而与NK细胞衰竭相关的关键基因结合,如HAVCR2、LAG3、TIGIT和CTLA4。删除 BATF 可增强 NK 细胞在体外和体内抗 AML 的功能。总之,我们的研究结果揭示了一种之前未被发现的NK免疫在AML中的逃避机制,这种机制表现为NK细胞的表观遗传重排和髓细胞瘤的失活。这项工作强调了使用健康的异体NK细胞作为治疗髓系恶性肿瘤患者的采纳性细胞疗法的重要性,同时还强调了通过靶向TGF-β途径或BATF来预防功能障碍的策略的重要性。
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引用次数: 0
A spatially resolved single-cell lung atlas integrated with clinical and blood signatures distinguishes COVID-19 disease trajectories 结合临床和血液特征的空间分辨单细胞肺图谱可区分 COVID-19 疾病轨迹
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-11 DOI: 10.1126/scitranslmed.adk9149
João Da Silva Filho, Vanessa Herder, Matthew P. Gibbins, Monique Freire dos Reis, Gisely Cardoso Melo, Michael J. Haley, Carla Cristina Judice, Fernando Fonseca Almeida Val, Mayla Borba, Tatyana Almeida Tavella, Vanderson de Sousa Sampaio, Charalampos Attipa, Fiona McMonagle, Derek Wright, Marcus Vinicius Guimaraes de Lacerda, Fabio Trindade Maranhão Costa, Kevin N. Couper, Wuelton Marcelo Monteiro, Luiz Carlos de Lima Ferreira, Christopher Alan Moxon, Massimo Palmarini, Matthias Marti
COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: “early death” (<15 days until death) and “late death” (>15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2+ macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2+ epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (TH17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, TH2 responses, and anti-inflammatory–mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes.
COVID-19 的特点是症状和疾病轨迹多种多样。了解急性 COVID-19 期间临床生物标志物与肺部病理之间的相关性对于了解其多样化的发病机制和提供更有效的治疗方法非常必要。在此,我们对 142 名巴西 COVID-19 住院患者的纵向临床参数、外周血标志物和肺部病理进行了综合分析。我们发现了核心临床和外周血特征,这些特征区分了重症康复患者和死亡患者的疾病进展。死亡病例的特征不尽相同,但可分为两组:"早期死亡"(15 天内死亡)和 "晚期死亡"(15 天内死亡)。在全身和肺组织病理学样本中,早期死亡的特征是内皮细胞和髓细胞迅速活化,并出现与 SARS-CoV-2+ 巨噬细胞相关的血栓。与此相反,晚期死亡的进展与纤维化、凋亡和死后肺组织中的 SARS-CoV-2+ 上皮细胞有关。在晚期死亡病例中,只有在住院两周后才能在外周血中检测到细胞毒性、干扰素和T辅助细胞17(TH17)特征。恢复期的进展与较高的淋巴细胞计数、TH2 反应和抗炎介导的反应有关。通过整合死前纵向血液特征和死后肺样本的空间单细胞肺特征,我们定义了可用于帮助预测 COVID-19 结果的临床参数。
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引用次数: 0
HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis 在非酒精性脂肪性肝炎中,HIF-2α 驱动肝 Kupffer 细胞死亡和促炎性招募的巨噬细胞活化
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-11 DOI: 10.1126/scitranslmed.adi0284
Ishtiaq Jeelani, Jae-Su Moon, Flavia Franco da Cunha, Chanond A. Nasamran, Seokhyun Jeon, Xinhang Zhang, Gautam K. Bandyopadhyay, Katarzyna Dobaczewska, Zbigniew Mikulski, Mojgan Hosseini, Xiao Liu, Tatiana Kisseleva, David A. Brenner, Seema Singh, Rohit Loomba, Minkyu Kim, Yun Sok Lee
Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow–derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)– and extracellular signal–regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2α–dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage–specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α–specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype–specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.
促炎性肝巨噬细胞活化在非酒精性脂肪性肝炎(NASH)的发病过程中起着关键作用。这涉及胚胎肝 Kupffer 细胞(KC)死亡的增加,促进了骨髓来源的高表达促炎基因的招募肝巨噬细胞(RHM)对 KC 的替代。此外,在 NASH 中,KCs 的噬细胞/吞噬细胞活性减弱,从而加剧了肝脏炎症。然而,KCs 发生这些变化的分子机制尚不清楚。在这里,我们发现低氧诱导因子2α(HIF-2α)通过增强溶酶体应激介导了NASH相关的KC生长和排泄减少。在分子水平上,HIF-2α刺激哺乳动物雷帕霉素靶标(mTOR)和细胞外信号调节激酶依赖性抑制转录因子EB(TFEB)磷酸化,导致溶酶体和吞噬基因表达减少。随着 NASH 代谢应激和噬血细胞/吞噬细胞负担的增加,这些变化足以增加溶酶体应激,导致渗出细胞减少和溶酶体细胞死亡。值得注意的是,依赖于 HIF-2α 的 TFEB 调节只发生在 KCs 中,而不是 RHMs 中。相反,在 RHMs 中,HIF-2α 通过增加 ANT2 的表达和线粒体通透性转换,促进线粒体活性氧的产生和促炎激活。因此,髓系特异性或 KC 特异性 HIF-2α 消耗或使用反义寡核苷酸抑制依赖于 mTOR 的 TFEB 抑制可防止小鼠发生 NASH。此外,HIF-2α特异性抑制剂还能减少在类似NASH条件下培养的人肝球细胞中炎症和纤维化基因的表达。总之,我们的研究结果表明,HIF-2α对巨噬细胞亚型的特异性作用共同促成了肝脏巨噬细胞的促炎激活,从而导致了NASH的发生。
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引用次数: 0
A skin-interfaced microfluidic platform supports dynamic sweat biochemical analysis during human exercise 皮肤界面微流控平台支持人体运动过程中的动态汗液生化分析。
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-04 DOI: 10.1126/scitranslmed.ado5366
Soongwon Cho, Samy M. Shaban, Ruihao Song, Haohui Zhang, Dasom Yang, Min-Jae Kim, Yirui Xiong, Xiuyuan Li, Kenneth Madsen, Sarena Wapnick, Shifan Zhang, Ziyu Chen, Jiwon Kim, Gianna Guinto, Michelle Li, Minkyu Lee, Ravi F. Nuxoll, Shaghayegh Shajari, Jin Wang, Seongeun Son, Jihoon Shin, Alexander J. Aranyosi, Donald E. Wright, Tae-il Kim, Roozbeh Ghaffari, Yonggang Huang, Dong-Hwan Kim, John A. Rogers
Blood lactate concentration is an established circulating biomarker for measuring muscle acidity and can be evaluated for monitoring endurance, training routines, or athletic performance. Sweat is an alternative biofluid that may serve similar purposes and offers the advantage of noninvasive collection and continuous monitoring. The relationship between blood lactate and dynamic sweat biochemistry for wearable engineering applications in physiological fitness remains poorly defined. Here, we developed a microfluidic wearable band with an integrated colorimetric timer and biochemical assays that temporally captures sweat and measures pH and lactate concentration. A colorimetric silver nanoplasmonic assay was used to measure the concentration of lactate, and dye-conjugated SiO2 nanoparticle–agarose composite materials supported dynamic pH analysis. We evaluated these sweat biomarkers in relation to blood lactate in human participant studies during cycling exercise of varying intensity. Iontophoresis-generated sweat pH from regions of actively working muscles decreased with increasing heart rate during exercise and was negatively correlated with blood lactate concentration. In contrast, sweat pH from nonworking muscles did not correlate with blood lactate concentration. Changes in sweat pH and blood lactate were observed in participants who did not regularly exercise but not in individuals who regularly exercised, suggesting a relationship to physical fitness and supporting further development for noninvasive, biochemical fitness evaluations.
血液乳酸浓度是一种公认的测量肌肉酸度的循环生物标志物,可用于监测耐力、训练程序或运动表现。汗液是一种可用于类似目的的替代生物流体,具有无创采集和连续监测的优点。血液乳酸与动态汗液生物化学之间的关系在生理健身的可穿戴工程应用中仍未得到很好的界定。在这里,我们开发了一种微流体可穿戴带,它集成了比色计时器和生化检测装置,可实时采集汗液并测量 pH 值和乳酸盐浓度。比色银纳米质谱检测法用于测量乳酸盐浓度,染料共轭二氧化硅纳米粒子-琼脂糖复合材料支持动态 pH 值分析。在不同强度的自行车运动中,我们评估了这些汗液生物标志物与血液乳酸盐的关系。在运动过程中,随着心率的增加,积极工作肌肉区域的汗液 pH 值随之降低,并且与血液乳酸浓度呈负相关。相反,非工作肌肉的汗液 pH 值与血液乳酸浓度无关。在不经常运动的参与者身上观察到了汗液 pH 值和血液乳酸盐的变化,而在经常运动的人身上却没有观察到,这表明汗液 pH 值和血液乳酸盐与体能有关,并支持进一步开发无创生化体能评估。
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引用次数: 0
Precision adjuvants for pediatric vaccines 用于小儿疫苗的精确佐剂。
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-04 DOI: 10.1126/scitranslmed.abq7378
Anjali Singh, César Boggiano, Dwight E. Yin, Laura Polakowski, Sai P. Majji, Wolfgang W. Leitner, Ofer Levy, Kristina De Paris
Elucidating optimal vaccine adjuvants for harnessing age-specific immune pathways to enhance magnitude, breadth, and durability of immunogenicity remains a key gap area in pediatric vaccine design. A better understanding of age-specific adjuvants will inform precision discovery and development of safe and effective vaccines for protecting children from preventable infectious diseases.
阐明利用年龄特异性免疫途径的最佳疫苗佐剂,以提高免疫原性的强度、广度和持久性,仍然是儿科疫苗设计的一个关键空白领域。更好地了解年龄特异性佐剂将有助于精准发现和开发安全有效的疫苗,保护儿童免受可预防传染病的侵害。
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引用次数: 0
PTPRT loss enhances anti–PD-1 therapy efficacy by regulation of STING pathway in non–small cell lung cancer PTPRT缺失可通过调节STING通路增强非小细胞肺癌抗PD-1疗法的疗效。
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-04 DOI: 10.1126/scitranslmed.adl3598
Zhuo Chen, Wenxiang Ji, Wenxin Feng, Jingchuan Cui, Yuchen Wang, Fan Li, Jiachen Chen, Ziheng Guo, Liliang Xia, Xiaokuan Zhu, Xiaomin Niu, Yanshuang Zhang, Ziming Li, Alice S. T. Wong, Shun Lu, Weiliang Xia
With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.
随着免疫检查点抑制剂(ICIs)在非小细胞肺癌领域取得革命性进展,确定哪些癌症患者可从 ICIs 中获益已变得至关重要且刻不容缓。在此,我们报告了蛋白酪氨酸磷酸酶受体T型(PTPRT)缺失作为一种独立于PD-L1表达的精确、便捷的预测指标,可用于抗PD-1/PD-L1轴治疗。抗PD-1/PD-L1轴治疗显著提高了PTPRT缺失肿瘤患者的无进展生存期。PTPRT缺陷型肿瘤显示出累积性DNA损伤、细胞膜DNA释放增加以及更高的肿瘤突变负荷。此外,STING 的酪氨酸残基 240 被确定为 PTPRT 的直接底物。PTPRT的缺失会增加STING在Y240处的磷酸化,从而抑制蛋白酶体介导的降解。PTPRT 缺失的肿瘤通过激活 STING 通路释放出更多的 IFN-β、CCL5 和 CXCL10,并增加了免疫细胞的浸润,尤其是 CD8 T 细胞和自然杀伤细胞,最终提高了抗 PD-1 治疗在多种皮下和正位肿瘤小鼠模型中的疗效。PTPRT缺陷肿瘤对抗PD-1疗法的反应取决于肿瘤内在STING通路。总之,我们的研究结果揭示了PTPRT缺陷肿瘤如何对抗PD-1治疗变得敏感的机制,并强调了PTPRT在先天免疫中的生物学功能。考虑到PTPRT突变和阴性表达的普遍性,本研究对患者分层和临床决策具有重要价值。
{"title":"PTPRT loss enhances anti–PD-1 therapy efficacy by regulation of STING pathway in non–small cell lung cancer","authors":"Zhuo Chen,&nbsp;Wenxiang Ji,&nbsp;Wenxin Feng,&nbsp;Jingchuan Cui,&nbsp;Yuchen Wang,&nbsp;Fan Li,&nbsp;Jiachen Chen,&nbsp;Ziheng Guo,&nbsp;Liliang Xia,&nbsp;Xiaokuan Zhu,&nbsp;Xiaomin Niu,&nbsp;Yanshuang Zhang,&nbsp;Ziming Li,&nbsp;Alice S. T. Wong,&nbsp;Shun Lu,&nbsp;Weiliang Xia","doi":"10.1126/scitranslmed.adl3598","DOIUrl":"10.1126/scitranslmed.adl3598","url":null,"abstract":"<div >With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adl3598","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adaptive cognitive control circuit changes associated with problem-solving ability and depression symptom outcomes over 24 months 适应性认知控制回路的变化与问题解决能力和抑郁症状的24个月结果有关。
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-04 DOI: 10.1126/scitranslmed.adh3172
Xue Zhang, Adam Pines, Patrick Stetz, Andrea N. Goldstein-Piekarski, Lan Xiao, Nan Lv, Leonardo Tozzi, Philip W. Lavori, Mark B. Snowden, Elizabeth M. Venditti, Joshua M. Smyth, Trisha Suppes, Olusola Ajilore, Jun Ma, Leanne M. Williams
Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.
有针对性的机制行为干预是改善抑郁症治疗效果的一种亟需的策略,尤其是对肥胖等合并症的弱势群体而言。此类干预可能会通过改变潜在的神经回路功能来改变行为和结果。然而,这些神经回路层面的改变是如何随着干预而展开的,早期神经回路层面改变的个体差异又是如何解释治疗效果的异质性的,这些都是未知数。我们在一项针对有抑郁症状和合并肥胖症的参与者的问题解决疗法临床试验中满足了这一需求,并将重点放在认知控制回路这一可能的神经作用机制上。该研究采用功能磁共振成像技术,在 24 个月内的五个时间点测量认知控制回路的活动。与接受常规治疗的参与者相比,接受问题解决疗法的参与者显示认知控制回路活动的减弱与问题解决能力的增强有关,这表明该回路在问题解决疗法的机制中起着关键作用。认知控制回路活动的减弱也与抑郁症状的改善有关。2个月时认知控制回路活动的变化能更好地预测6、12和24个月时问题解决能力和抑郁症状的变化,预测改善率从17.8%到104.0%不等,超过了基线人口统计学和症状特征。我们的研究结果表明,以回路作用机制为目标可以提高对治疗结果的预测能力,因此未来有必要对模型进行完善和改进,为其临床应用铺平道路。
{"title":"Adaptive cognitive control circuit changes associated with problem-solving ability and depression symptom outcomes over 24 months","authors":"Xue Zhang,&nbsp;Adam Pines,&nbsp;Patrick Stetz,&nbsp;Andrea N. Goldstein-Piekarski,&nbsp;Lan Xiao,&nbsp;Nan Lv,&nbsp;Leonardo Tozzi,&nbsp;Philip W. Lavori,&nbsp;Mark B. Snowden,&nbsp;Elizabeth M. Venditti,&nbsp;Joshua M. Smyth,&nbsp;Trisha Suppes,&nbsp;Olusola Ajilore,&nbsp;Jun Ma,&nbsp;Leanne M. Williams","doi":"10.1126/scitranslmed.adh3172","DOIUrl":"10.1126/scitranslmed.adh3172","url":null,"abstract":"<div >Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of CCL7 improves endothelial dysfunction and vasculopathy in mouse models of diabetes mellitus 抑制 CCL7 可改善糖尿病小鼠模型的内皮功能障碍和血管病变。
IF 15.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-04 DOI: 10.1126/scitranslmed.adn1507
Ting-Ting Chang, You-Zhen Li, Hsiao-Wei Mo, Ching Chen, Liang-Yu Lin, Chia-Chi Chang, Jaw-Wen Chen
Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific Ccl7-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.
糖尿病血管疾病是糖尿病(DM)的主要并发症。趋化因子 C-C motif 配体 7(CCL7)会吸引巨噬细胞和单核细胞,从而扩大血管中的炎症过程。我们假设 CCL7 在糖尿病血管病变中起着因果作用。2 型糖尿病患者血浆及其内皮祖细胞(EPCs)上清液中的 CCL7 浓度较高。高血糖刺激通过 c-Fos 和 c-Jun 信号通路增加了人真皮微血管内皮细胞(HDMECs)的 CCL7 分泌。使用基因敲除或中和抗体抑制 CCL7 可逆转高糖诱导的 EPCs、人主动脉内皮细胞、人冠状动脉内皮细胞和 HDMECs 管形成和迁移能力受损。通过下调内皮细胞中的AKT-内皮一氧化氮合酶和AKT/核因子红细胞2相关因子2/血红素氧合酶-1/血管内皮生长因子/基质细胞衍生因子-1通路,以及通过CC趋化因子受体3上调ERK/磷酸化p65/白细胞介素-1β/白细胞介素-6/肿瘤坏死因子-α通路,服用重组人CCL7蛋白会损害管形成和迁移能力。在链脲佐菌素处理的小鼠中敲除 Ccl7 后,缺血肢体的新血管生成得到改善,伤口修复加快,循环中的 EPC 和毛细血管密度增加。CCL7 抗体治疗 db/db 小鼠和高脂饮食诱导的高血糖小鼠显示,缺血肢体和伤口区域的新血管生成得到改善,同时血管生成蛋白上调,炎症蛋白下调。内皮细胞特异性 Ccl7 基因敲除小鼠在链脲佐菌素诱导的 DM 中表现出糖尿病血管病变的改善。这项研究强调了 CCL7 作为糖尿病血管病变治疗靶点的潜力。
{"title":"Inhibition of CCL7 improves endothelial dysfunction and vasculopathy in mouse models of diabetes mellitus","authors":"Ting-Ting Chang,&nbsp;You-Zhen Li,&nbsp;Hsiao-Wei Mo,&nbsp;Ching Chen,&nbsp;Liang-Yu Lin,&nbsp;Chia-Chi Chang,&nbsp;Jaw-Wen Chen","doi":"10.1126/scitranslmed.adn1507","DOIUrl":"10.1126/scitranslmed.adn1507","url":null,"abstract":"<div >Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. <i>Ccl7</i> knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in <i>db/db</i> mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific <i>Ccl7</i>-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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