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Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. 沙门氏菌癌症疗法以 T 细胞免疫的附带代价破坏肿瘤的代谢。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-18 DOI: 10.1038/s44321-024-00159-2
Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (TCM) formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.

细菌癌症疗法(BCT)是一种治疗实体瘤的前景广阔的疗法。在细菌载体中,鼠伤寒沙门氏菌(STm)因其在基因修饰和代谢适应方面的优势而受到广泛研究。一个长期存在的悖论是T细胞对治疗效果的冗余性;相反,STm BCT依赖于先天性吞噬细胞来控制肿瘤。在这里,我们使用远端 T 细胞受体(TCR)和 IFNγ 报告小鼠(Nr4a3-Tocky-Ifnγ-YFP)以及结肠直肠癌(CRC)模型来研究 STm BCT 期间 T 细胞的活性。我们发现结肠肿瘤浸润淋巴细胞(TILs)表现出多种活化缺陷,包括IFN-γ的产生与TCR信号脱钩、多功能性降低和中心记忆(TCM)形成减少。利用肿瘤类器官平台建立的T细胞-肿瘤相互作用模型显示,TCR信号体完好无损,但由于主代谢控制器c-Myc受到抑制,导致代谢重编程瘫痪。通过删除细菌天冬酰胺酶ansB恢复c-Myc可重新激活T细胞,但代价是STm对肿瘤的代谢控制能力下降。这项研究首次表明,T细胞在BCT期间存在代谢缺陷,而且这一现象与细菌载体对肿瘤的内在抑制有着不可分割的联系。
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引用次数: 0
Diagnosis and prognosis prediction of gastric cancer by high-performance serum lipidome fingerprints. 利用高效血清脂质体指纹图谱诊断和预测胃癌预后
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-14 DOI: 10.1038/s44321-024-00169-0
Ze-Rong Cai, Wen Wang, Di Chen, Hao-Jie Chen, Yan Hu, Xiao-Jing Luo, Yi-Ting Wang, Yi-Qian Pan, Hai-Yu Mo, Shu-Yu Luo, Kun Liao, Zhao-Lei Zeng, Shan-Shan Li, Xin-Yuan Guan, Xin-Juan Fan, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju

Early detection is warranted to improve prognosis of gastric cancer (GC) but remains challenging. Liquid biopsy combined with machine learning will provide new insights into diagnostic strategies of GC. Lipid metabolism reprogramming plays a crucial role in the initiation and development of tumors. Here, we integrated the lipidomics data of three cohorts (n = 944) to develop the lipid metabolic landscape of GC. We further constructed the serum lipid metabolic signature (SLMS) by machine learning, which showed great performance in distinguishing GC patients from healthy donors. Notably, the SLMS also held high efficacy in the diagnosis of early-stage GC. Besides, by performing unsupervised consensus clustering analysis on the lipid metabolic matrix of patients with GC, we generated the gastric cancer prognostic subtypes (GCPSs) with significantly different overall survival. Furthermore, the lipid metabolic disturbance in GC tissues was demonstrated by multi-omics analysis, which showed partially consistent with that in GC serums. Collectively, this study revealed an innovative strategy of liquid biopsy for the diagnosis of GC on the basis of the serum lipid metabolic fingerprints.

要改善胃癌(GC)的预后,必须进行早期检测,但这仍是一项挑战。液体活检与机器学习相结合,将为胃癌诊断策略提供新的见解。脂质代谢重编程在肿瘤的发生和发展过程中起着至关重要的作用。在这里,我们整合了三个队列(n = 944)的脂质组学数据,建立了 GC 的脂质代谢图谱。我们通过机器学习进一步构建了血清脂质代谢特征(SLMS),该特征在区分 GC 患者和健康供体方面表现出色。值得注意的是,SLMS 在早期 GC 的诊断中也具有很高的效力。此外,通过对 GC 患者的脂质代谢矩阵进行无监督共识聚类分析,我们得出了总体生存期显著不同的胃癌预后亚型(GCPSs)。此外,多组学分析表明,胃癌组织中的脂质代谢紊乱与胃癌血清中的脂质代谢紊乱部分一致。总之,这项研究揭示了一种基于血清脂质代谢指纹的液体活检诊断 GC 的创新策略。
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引用次数: 0
APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia. 来自星形胶质细胞的 APOE 可恢复阿尔茨海默氏症 Aβ 病理学和 APOE 缺乏症小胶质细胞的 DAM 样反应。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-11 DOI: 10.1038/s44321-024-00162-7
Pranav Preman, Daan Moechars, Emre Fertan, Leen Wolfs, Lutgarde Serneels, Disha Shah, Jochen Lamote, Suresh Poovathingal, An Snellinx, Renzo Mancuso, Sriram Balusu, David Klenerman, Amaia M Arranz, Mark Fiers, Bart De Strooper

The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

阿尔茨海默病(AD)的主要遗传风险因子--APOE4--会加速β-淀粉样蛋白(Aβ)斑块的形成,但这究竟是由小胶质细胞还是星形胶质细胞中表达的APOE引起的还存在争议。在这里,我们在载脂蛋白缺陷型 AD 小鼠模型的星形胶质细胞中表达了人类 APOE 异构体。这不仅足以恢复淀粉样蛋白斑块的病理变化,而且还能诱导斑块周围的载脂蛋白缺陷小胶质细胞产生特征性的转录病理反应。我们发现,来自星形胶质细胞的APOE4和保护性APOE2都会增加纤维斑块的沉积,但对可溶性Aβ聚集体的影响不同。小胶质细胞和星形胶质细胞中表达的 APOE 基因型显示出特定的功能改变。我们的实验表明,星形胶质细胞在 APOE 介导的淀粉样斑块病理学和诱导相关小胶质细胞反应中起着核心作用。
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引用次数: 0
JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia. 将 JAK-STAT1 作为表皮生长因子受体缺乏症相关炎症和瘢痕性脱发的治疗靶点。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-09 DOI: 10.1038/s44321-024-00166-3
Karoline Strobl, Jörg Klufa, Regina Jin, Lena Artner-Gent, Dana Krauß, Philipp Novoszel, Johanna Strobl, Georg Stary, Igor Vujic, Johannes Griss, Martin Holcmann, Matthias Farlik, Bernhard Homey, Maria Sibilia, Thomas Bauer

The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.

毛囊干细胞龛是一种具有免疫特权的微环境,其特点是抗原呈递减少,从而可抵御免疫介导的永久性组织损伤。在这项研究中,我们证实了毛囊特异性表皮生长因子受体(EGFR)对瘢痕性毛囊破坏的保护作用。从机制上讲,表皮生长因子受体信号的中断在JAK-STAT1通路中产生了细胞内在超敏反应,它与表达干扰素γ的CD8 T细胞和NK细胞介导的炎症协同作用,损害了干细胞龛。在表皮和毛囊特异性表皮生长因子受体(EGFR)缺失的小鼠模型中,毛囊特异性基因缺失JAK1/2或STAT1或治疗性抑制JAK1/2可改善炎症,恢复皮肤屏障功能,并激活残余干细胞以恢复毛发生长。表皮生长因子受体抑制剂治疗过的斑秃患者的皮肤活检显示,JAK-STAT1信号特征活跃,抗原呈递上调,表皮生长因子受体通路的关键成分下调。我们的研究结果提供了分子方面的见解,并强调了一种基于机制的治疗策略,可用于治疗与表皮生长因子受体抑制剂抗癌疗法和卡他性脱发相关的慢性毛囊炎。
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引用次数: 0
Hair follicle stem cells and the collapse of self-tolerance in alopecia: the interplay of barrier function, the microbiome, and immunity. 毛囊干细胞与脱发症自我耐受的崩溃:屏障功能、微生物组和免疫的相互作用。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-09 DOI: 10.1038/s44321-024-00170-7
Joseph S Durgin, Sunny Y Wong
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引用次数: 0
Author Correction: Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases. 作者更正:通过假定的小分子抑制剂破坏 TSLP-TSLP 受体的相互作用,可为特应性疾病提供一种新颖高效的治疗方案。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-07 DOI: 10.1038/s44321-024-00165-4
Partho Protim Adhikary, Temilolu Idowu, Zheng Tan, Christopher Hoang, Selina Shanta, Malti Dumbani, Leah Mappalakayil, Bhuwan Awasthi, Marcel Bermudez, January Weiner, Dieter Beule, Gerhard Wolber, Brent D G Page, Sarah Hedtrich
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引用次数: 0
Rett syndrome: interferon-γ to the rescue? 雷特综合征:干扰素-γ能救命吗?
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-04 DOI: 10.1038/s44321-024-00154-7
Richard R Meehan, Sari Pennings
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引用次数: 0
Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches. 败血症诱发的丙酮酸代谢变化:见解和潜在的治疗方法。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-28 DOI: 10.1038/s44321-024-00155-6
Louise Nuyttens, Jolien Vandewalle, Claude Libert

Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival.

败血症是由于宿主对感染的反应失调而导致的一种异质性综合征。它被视为全球主要的健康优先事项。败血症的特点是新陈代谢严重紊乱,导致乳酸等循环代谢物增加。在哺乳动物体内,丙酮酸是产生乳酸的主要底物。丙酮酸在新陈代谢中起着关键作用,它将产生丙酮酸的糖酵解与氧化丙酮酸的线粒体氧化磷酸化途径连接起来。在此,我们概述了参与丙酮酸代谢的所有细胞膜和线粒体酶,以及它们在败血症中的活动是如何被破坏的。根据现有数据,我们还讨论了针对这些丙酮酸相关酶的潜在治疗策略,以提高存活率。
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引用次数: 0
Liver DE(HP)toxification: luteolin as "phthalates-cleaner" to protect from environmental pollution. 肝脏 DE(HP)中毒:叶黄素作为 "邻苯二甲酸盐清洁剂",可防止环境污染。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-29 DOI: 10.1038/s44321-024-00158-3
Federica Cappelli, Alessandro Mengozzi
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引用次数: 0
Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47. 针对遗传性痉挛性截瘫 47 型的 AP4B1 基因替代疗法的临床前开发。
IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-11-01 Epub Date: 2024-10-02 DOI: 10.1038/s44321-024-00148-5
Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz

Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.

痉挛性截瘫47(SPG47)是一种由适配蛋白复合物4 β1亚基(AP4B1)基因突变导致AP-4复合物缺乏引起的神经系统疾病。SPG47 的特征是进行性痉挛性截瘫、全面发育迟缓、智力障碍和癫痫。旨在恢复功能性 AP4B1 蛋白水平的基因疗法是一种改善疾病表型的合理治疗策略。我们在此报告,在 SPG47 小鼠模型中,将表达 hAP4B1 的 9 号血清型腺相关病毒(AAV9/hAP4B1)一次性送入小脑蝶窦,可导致广泛的基因转移,并恢复各种疾病特征,包括 AP-4 货物(ATG9A)错位、小脑深核钙蛋白阳性球、大脑解剖学缺陷和运动功能障碍。此外,基于 AAV9/hAP4B1 的基因疗法显示,治疗小鼠的血浆神经丝光(NfL)水平得到了恢复。在这些临床前概念验证数据的鼓舞下,我们开展了 IND 许可研究,包括免疫原性和 GLP 非人灵长类动物 (NHP) 毒理学研究。重要的是,非人灵长类动物的安全性和生物分布研究表明,治疗干预没有引起明显的不良反应。这些研究结果为治疗效果和安全性提供了证据,为针对 SPG47 患者的临床试验申请 IND 奠定了坚实的基础。
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引用次数: 0
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EMBO Molecular Medicine
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