hLife最新文献_第3页

Current perspectives on neuroendocrine tumors 神经内分泌肿瘤的当前前景

hLife

Pub Date : 2024-11-01 DOI: 10.1016/j.hlife.2024.07.006

Sunil Kumar Verma , Renu Khare , Devendra Singh

Neoplasms arising from neuroendocrine cells form a heterogeneous group known as neuroendocrine tumors (NETs), which possess both endocrine and neural characteristics. These tumors can occur in various organs throughout the body, with the most prominent sites being the gastrointestinal tract, pancreas, and lungs. Despite their relatively low incidence, NETs have gained significant attention due to their unique biology and clinical behavior. This review intends to provide a widespread gestalt of the present perception of NETs, including their epidemiology, etiology, pathogenesis, classification, clinical presentation, diagnostic modalities, treatment options, and prognosis. Treatment strategies for NETs depend on tumor grade, stage, location, and functional status. Surgical resection remains the pillar of curative treatment for localized disease; on the other hand, systemic therapies take account of targeted therapies like tyrosine kinase inhibitors (TKIs), peptide receptor radionuclide therapy (PRRT), somatostatin analogs, and immunotherapy have shown promising results in advanced cases. In conclusion, this review provides an up-to-date summary of our current knowledge regarding neuroendocrine tumors. Further research is needed to better understand the underlying molecular mechanisms driving tumor development and progression. This will aid in developing novel therapeutic strategies targeting specific pathways involved in NET pathogenesis to improve patient outcomes.

由神经内分泌细胞产生的肿瘤形成了一个异质性的群体，称为神经内分泌肿瘤（NET），它们同时具有内分泌和神经特征。这些肿瘤可发生在全身各个器官，最主要的部位是胃肠道、胰腺和肺部。尽管 NET 的发病率相对较低，但由于其独特的生物学特性和临床表现，已引起了广泛关注。本综述旨在广泛介绍目前对 NET 的认识，包括其流行病学、病因学、发病机制、分类、临床表现、诊断方式、治疗方案和预后。NET的治疗策略取决于肿瘤的分级、分期、位置和功能状态。手术切除仍然是局部疾病治愈治疗的支柱；另一方面，全身治疗包括靶向疗法，如酪氨酸激酶抑制剂（TKIs）、肽受体放射性核素疗法（PRRT）、体生长激素类似物和免疫疗法，这些疗法在晚期病例中显示出良好的疗效。总之，本综述总结了我们目前对神经内分泌肿瘤的最新认识。要更好地了解驱动肿瘤发生和发展的潜在分子机制，还需要进一步的研究。这将有助于开发针对NET发病机制中特定通路的新型治疗策略，从而改善患者的预后。

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引用次数: 0

Targeted protein editing technique in living mammalian cells by peptide-fused PNGase 利用肽融合 PNG 酶在哺乳动物活细胞中开发靶向蛋白质编辑技术

hLife

Pub Date : 2024-11-01 DOI: 10.1016/j.hlife.2024.07.003

Min Wu , Guijie Bai , Ziyi Zhang , Haixia Xiao , Wenliang Sun , Chaoguang Tian

Various precise gene editing techniques at the DNA/RNA level, driven by clustered regularly interspaced short palindrome repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology, have gained significant prominence. Yet, research on targeted protein editing techniques remains limited. Only a few attempts have been made, including the use of specific proteases and de-O-glycosylating enzymes as editing enzymes. Here, we propose direct editing of N-glycosylated proteins using de-N-glycosylating enzymes to modify N-glycosylation and simultaneously alter the relevant asparagine residue to aspartate in living cells. Selective protein deglycosylation editors were developed by fusing high-affinity protein-targeting peptides with active peptide:N-glycanases (PNGases). Three crucial cell membrane proteins, programmed cell death protein-1 (PD-1), programmed cell death-1 ligand 1 (PD-L1), and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein, were chosen to be tested as a proof of concept. N-linked glycans were removed, and the relevant sites were converted from Asn to Asp in living mammalian cells, destabilizing target proteins and accelerating their degradation. Further investigation focused on SARS-CoV-2 spike protein deglycosylation editing. The collaboration of LCB1-PNGase F (PNGF) effectively reduced syncytia formation, inhibited pseudovirus packaging, and significantly hindered virus entry into host cells, which provides insights for coronavirus disease 2019 (COVID-19) treatment. This tool enables editing protein sequences post-de-N-glycosylation in living human cells, shedding light on protein N-glycosylation functions, and Asn to Asp editing in organisms. It also offers the potential for developing protein degradation technologies.

在聚类规则间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9（Cas9）技术的驱动下，DNA/RNA水平上的各种精确基因编辑技术已获得极大的重视。然而，有关靶向蛋白质编辑技术的研究仍然有限。目前只有少数尝试，包括使用特定蛋白酶和去O-糖基化酶作为编辑酶。在此，我们提议使用去 N-糖基化酶直接编辑 N-糖基化蛋白质，以改变 N-糖基化，同时将活细胞中的相关天冬酰胺残基改变为天冬氨酸。通过将高亲和性蛋白质靶向肽与活性肽：N-糖化酶（PNGase）融合，开发出了选择性蛋白质脱糖编辑器。我们选择了三种重要的细胞膜蛋白，即程序性细胞死亡蛋白-1（PD-1）、程序性细胞死亡-1 配体 1（PD-L1）和严重急性呼吸系统综合征冠状病毒-2（SARS-CoV-2）尖峰蛋白，作为概念验证进行测试。在活的哺乳动物细胞中，N-连接的聚糖被移除，相关位点从Asn转化为Asp，从而破坏目标蛋白质的稳定性并加速其降解。进一步研究的重点是 SARS-CoV-2 穗状蛋白质脱糖基化编辑。LCB1-PNGase F（PNGF）的合作有效减少了合胞体的形成，抑制了假病毒的包装，并显著阻碍了病毒进入宿主细胞，这为2019年冠状病毒病（COVID-19）的治疗提供了启示。该工具可在活人体细胞中编辑去N-糖基化后的蛋白质序列，揭示蛋白质N-糖基化的功能，以及生物体中Asn到Asp的编辑。它还为开发蛋白质降解技术提供了潜力。

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引用次数: 0

Regulatory functions and mechanisms of human microbiota in infectious diseases 人类微生物群在传染病中的调节功能和机制

hLife

Pub Date : 2024-10-01 DOI: 10.1016/j.hlife.2024.03.004

The human microbiota, a diverse community of microorganisms living on or within their hosts, play an irreplaceable role in maintaining human health. Dysbiosis of the microbiota is associated with the pathogenesis of diverse human diseases. In recent years, growing evidence has been presented to support the substantial effect of human microbiota on the progression of infectious diseases. In this review, we describe the functional role of human microbiota in infectious diseases by highlighting their Janus-faced effects in the regulation of acute and chronic infections as well as their related co-morbidities. Thereafter, we review the latest advances elucidating the mechanisms underlying tri-directional interactions between the microbiota, hosts, and invading pathogens, with a further discussion on external environmental factors that shape this interconnected regulatory network. A better understanding of the regulatory functions and mechanisms of human microbiota in infectious diseases will facilitate the development of new diagnostic, preventive, and therapeutic approaches for infectious diseases.

人类微生物群是生活在宿主身上或宿主体内的多种微生物群落，在维护人类健康方面发挥着不可替代的作用。微生物群失调与人类多种疾病的发病机制有关。近年来，越来越多的证据表明，人类微生物群对传染病的发展有重大影响。在这篇综述中，我们将介绍人类微生物群在感染性疾病中的功能性作用，强调它们在调节急性和慢性感染及其相关并发症方面的杰纳斯效应。随后，我们回顾了阐明微生物群、宿主和入侵病原体之间三向互动机制的最新进展，并进一步讨论了形成这一相互关联的调控网络的外部环境因素。更好地了解人类微生物群在传染病中的调控功能和机制将有助于开发新的诊断、预防和治疗传染病的方法。

引用次数: 0

Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1 从结构上洞察针对 ZIKV NS1 的人类抗体的独特保护机制

hLife

Pub Date : 2024-10-01 DOI: 10.1016/j.hlife.2024.05.003

Qi Pan , Xiaomin Xing , Jianhai Yu , Qiang Chen , Haizhan Jiao , Wanqin Zhang , Yingfen Wen , Ming Gao , Wei Zhao , Lei Yu , Hongli Hu

Antibodies targeting non-structural protein 1 (NS1) confer protection against Zika virus (ZIKV). Although monoclonal antibodies (MAbs) 3G2 and 4B8 are more potent than MAb 4F10 in suppressing ZIKV infection in neonatal mice models, the epitopes are unclear. Herein, we determined the Cryo-electron microscopy (Cryo-EM) structures of ZIKV NS1 in complex with five human antibodies at 2.6–2.9 Å resolution. Group I antibodies (3G2 and 4B8) recognize the previously unreported epitopes on the outer surface of the NS1 dimer. The unique binding mode of Group I antibodies led to a stronger recognition of the cell surface form of NS1 and completely inhibited secreted form non-structural protein 1 (sNS1)-induced endothelial permeability via their immunoglobulin G (IgG) and Fab. Group II antibodies (4F10, 2E11, and 14G5) recognize common epitopes in the distal end of the β-ladder domain, with a blockade efficiency that may be related to their affinity for the sNS1 protein and the presence of full-length IgG. These findings elucidate the correlation between epitope recognition and protective efficacy of anti-NS1 antibodies and highlight the diagnostic and therapeutic potential of 3G2 and 4B8.

靶向非结构蛋白1（NS1）的抗体可提供针对寨卡病毒（ZIKV）的保护。虽然单克隆抗体（MAbs）3G2和4B8比MAb 4F10更能抑制新生小鼠模型中的ZIKV感染，但其表位尚不清楚。在此，我们以 2.6-2.9 Å 的分辨率测定了 ZIKV NS1 与五种人类抗体复合物的冷冻电子显微镜（Cryo-EM）结构。第一类抗体（3G2 和 4B8）能识别 NS1 二聚体外表面以前未报道过的表位。I 组抗体独特的结合模式能更强地识别细胞表面形式的 NS1，并通过其免疫球蛋白 G（IgG）和 Fab 完全抑制分泌型非结构蛋白 1（sNS1）诱导的内皮通透性。第二类抗体（4F10、2E11 和 14G5）能识别 β 梯形结构域远端的共同表位，其阻断效率可能与它们对 sNS1 蛋白的亲和力和全长 IgG 的存在有关。这些发现阐明了表位识别与抗 NS1 抗体的保护效力之间的相关性，并凸显了 3G2 和 4B8 的诊断和治疗潜力。

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引用次数: 0

Advancements for microbiome research in human health and disease: From composition to functionality 微生物组在人类健康和疾病中的研究进展：从组成到功能

hLife

Pub Date : 2024-10-01 DOI: 10.1016/j.hlife.2024.08.002

Nan Qin , Stanislav Dusko Ehrlich

引用次数: 0

Kha-Ti Lim: Mother of ten thousand infants 卡蒂-林万婴之母

hLife

Pub Date : 2024-10-01 DOI: 10.1016/j.hlife.2024.04.004

引用次数: 0

Construction and investigation of all-in-one microneedles complexed with functionalized polydiacetylene liposomes for improved in situ detection sensitivity 构建和研究与功能化聚二乙烯脂质体复合的一体化微针，提高原位检测灵敏度

hLife

Pub Date : 2024-10-01 DOI: 10.1016/j.hlife.2024.07.005

Jiarui Wang , Weimiao Li , Yan Chen , Meng Wu , Yan Shi , Jumin Lee , Ming Kong

Polydiacetylene (PDA) liposomes have been widely applied for detection due to their distinctive optical properties. However, the liquid phase in which PDA liposomes are dispersed generates several drawbacks, for instance, instability, compromise of detection sensitivity induced by dilution, and separation of target sampling and detection, making it inconvenient for application. In this paper, various functionalized PDA liposomes for detecting target were prepared, which were also immobilized into swelling microneedles to construct a solid-phase detection system. The PDA liposomes-complexed microneedles (PDA/MNs) enable the integration of target sampling and detection in one platform. The effects of the dispersing matrix phase on the detection sensitivity of PDA liposomes were systematically investigated from both environmental and chemical perspectives. PDA/MNs exhibited higher sensitivity than their counterparts in liquid phase. PDA/MNs were optimized and validated for lead ion (Pb²⁺) and sialic acid (SA) detections. For Pb²⁺ detection, the limit of detection (LOD) of the PDA/MNs was 13.7 μM and 2.5 times lower than the liquid phase. For SA detection, the LOD of the PDA/MNs was 0.83 μM and 1.7 times lower than the liquid phase. The results suggested that such PDA/MNs were validated to provide a label-free, stable, sensitive, and convenient tool in an all-in-one manner for physiologic target detection.

聚二乙烯（PDA）脂质体因其独特的光学特性而被广泛应用于检测。然而，PDA 脂质体分散在液相中会产生一些缺点，如不稳定、稀释会影响检测灵敏度、目标取样和检测分离等，给应用带来不便。本文制备了多种用于检测目标物的功能化 PDA 脂质体，并将其固定在膨胀微针中，构建了固相检测系统。PDA 脂质体-复合微针（PDA/MNs）实现了目标物取样和检测在一个平台上的整合。研究人员从环境和化学角度系统研究了分散基质相对 PDA 脂质体检测灵敏度的影响。PDA/MNs 的灵敏度高于液相中的同类产品。针对铅离子（Pb2+）和硅酸（SA）的检测，对 PDA/MNs 进行了优化和验证。对于 Pb2+ 的检测，PDA/MNs 的检测限（LOD）为 13.7 μM，比液相低 2.5 倍。对于 SA 的检测，PDA/MNs 的检测限为 0.83 μM，比液相低 1.7 倍。结果表明，这种 PDA/MNs 经过验证可为生理目标检测提供一种无标记、稳定、灵敏和方便的一体化工具。

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引用次数: 0

Surpassing the natural limits of serological diagnostic tests 超越血清诊断测试的自然极限

hLife

Pub Date : 2024-09-01 DOI: 10.1016/j.hlife.2024.06.001

Serological tests have an important and irreplaceable role in the diagnosis of infectious diseases, both for individual patients and society. They indirectly identify the causative pathogen through the capture of antibodies, which contrasts with the direct detection by antigen and molecular biology tests that are also limited to active infections. Within point-of-care platforms, serodiagnostic assays can support immediate decisions in patient care and contain the spread of disease as they do not require highly trained personnel or dedicated infrastructure. By employing serodiagnosis, health officials can proactively respond and eliminate emerging health risks. Larger sample numbers can be screened in other formats for surveillance as well as securing donated blood supplies. Furthermore, an assay can be designed to detect any immunoglobulin from IgM to IgG and its subclasses, to IgA and IgE. However, most serological assays employ natural proteins as the defining antibody-capturing reagent, which compromises their performance by limiting the two critical parameters of a serodiagnostic test: specificity and sensitivity. To surpass this natural limitation, we have repurposed the β-barrel of fluorescent proteins to receive epitope sequences that dependably produce high-performing designer immunological reagents. Consequently, serodiagnosis can be conducted more accurately at a lower cost.

血清学检测在传染病诊断中具有重要和不可替代的作用，无论是对患者个人还是对社会都是如此。它们通过捕获抗体间接确定致病病原体，这与抗原和分子生物学检测的直接检测不同，后者也仅限于活动性感染。在护理点平台中，血清诊断化验可支持在病人护理中立即做出决定，并遏制疾病的传播，因为它们不需要训练有素的人员或专用基础设施。通过采用血清诊断技术，卫生官员可以积极主动地应对和消除新出现的健康风险。可以通过其他形式筛查更大量的样本，用于监测和确保献血供应。此外，检测方法可用于检测从 IgM 到 IgG 及其亚类，再到 IgA 和 IgE 的任何免疫球蛋白。然而，大多数血清学检测都采用天然蛋白质作为抗体捕获试剂，这就限制了血清诊断检测的两个关键参数：特异性和灵敏度，从而影响了检测效果。为了超越这一天然限制，我们对荧光蛋白的 β 管进行了重新设计，以接收表位序列，从而可靠地生产出高性能的设计型免疫试剂。因此，血清诊断可以更准确、成本更低的方式进行。

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引用次数: 0

Discoidin domain receptor 1 as a potent therapeutic target in solid tumors 作为实体瘤有效治疗靶点的类盘素结构域受体 1

hLife

Pub Date : 2024-09-01 DOI: 10.1016/j.hlife.2024.01.003

Despite significant discoveries in basic cancer research and improvements in treatment options and clinical outcomes, cancer remains a major public health concern worldwide. Today, the main focus of cancer research is the signaling pathways that are crucial for cell survival, cell proliferation, and cell migration. The aberrant expression of proteins involved in these signaling pathways often leads to abnormal cell growth, cell metastasis, and invasion of healthy tissues. One such protein is discoidin domain receptor 1 (DDR1) which belongs to the family of receptor tyrosine kinases (RTKs) and is activated upon collagen binding, as a result, downstream signaling pathways are stimulated which are responsible for cell survival, cell growth, adhesion, extracellular matrix remodeling, and cell migration. DDR1 is found to have abnormally elevated expression in various solid tumors, implying a critical role in cancer progression. Traditional cancer treatment involves the use of cytotoxic drugs, chemotherapy, radiotherapy, and surgery, which do not provide long-term survival and often result in cancer recurrence. Numerous small-molecule kinase inhibitors have been synthesized against RTKs including DDR1 and have been highly efficacious in tumor reduction. More recently, targeting the DDR1 extracellular domain (ECD) has garnered much attention from researchers, as inhibiting the DDR1-collagen binding has been attributed to maximizing the likelihood of the combined cytotoxic effect of both immune cells and targeted drugs. This review focuses on the structure, function, activation, and signaling partners of DDR1, its role in different solid tumors, and finally discusses about designing more DDR1 non-kinase inhibitors as promising therapeutic strategies against DDR1-driven tumors.

尽管癌症基础研究取得了重大发现，治疗方案和临床结果也有所改善，但癌症仍然是全球关注的主要公共卫生问题。如今，癌症研究的重点是对细胞存活、细胞增殖和细胞迁移至关重要的信号通路。参与这些信号通路的蛋白质的异常表达往往会导致细胞异常生长、细胞转移和对健康组织的侵袭。盘状蛋白结构域受体 1（DDR1）就是这样一种蛋白质，它属于受体酪氨酸激酶（RTKs）家族，在与胶原蛋白结合后被激活，从而刺激下游信号通路，这些信号通路负责细胞存活、细胞生长、粘附、细胞外基质重塑和细胞迁移。DDR1 在各种实体瘤中的表达异常升高，这意味着它在癌症进展过程中起着关键作用。传统的癌症治疗方法包括使用细胞毒性药物、化疗、放疗和手术，但这些方法并不能提供长期生存，而且往往会导致癌症复发。针对包括 DDR1 在内的 RTKs 已经合成了许多小分子激酶抑制剂，这些抑制剂在减少肿瘤方面非常有效。最近，以 DDR1 细胞外结构域 (ECD) 为靶点的研究受到了研究人员的广泛关注，因为抑制 DDR1 与胶原蛋白的结合可最大限度地发挥免疫细胞和靶向药物的联合细胞毒性效应。这篇综述重点介绍了 DDR1 的结构、功能、激活和信号传导伙伴，以及它在不同实体瘤中的作用，最后讨论了设计更多的 DDR1 非激酶抑制剂作为针对 DDR1 驱动的肿瘤的有前景的治疗策略。

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引用次数: 0

HiTIP-seq profiles epigenomic reprogramming of patient-derived diffuse midline glioma stem cells to epigenetic therapy HiTIP-seq图谱描绘了患者来源的弥漫中线胶质瘤干细胞在表观遗传学疗法下的表观基因组重编程过程

hLife

Pub Date : 2024-09-01 DOI: 10.1016/j.hlife.2024.07.004

Zhongyao Chen , Qiang Gao , Yukui Shang , Behzad Nasiri Ahmadabadi , Yawei Hu , Wei Zhang , Peng Liu

Diffuse midline glioma (DMG), H3K27-altered, is lethal pediatric-type, high-grade, localized to the midline region of the central nervous system. Effective treatment guidelines are absent, and clinical trials are preferred for primary or recurrent DMG patients. Recently, epigenetic agent-based immunotherapy has exhibited promising therapeutic effects in the clinical setting. However, the underlying mechanisms remain a mystery. The rare DMG tumor samples from biopsy or resection largely impede basic research, by using patient-derived tumor cells which better recapitulate the parental tumor's heterogeneity compared to established cell lines. As an epigenetic reprogramming disease, DMG exhibits a global loss of H3K27 trimethylation (H3K27me3) and a gain of H3K27 acetylation (H3K27ac). Analysis of multiple epigenetic marks is fundamentally necessary. However, traditional techniques cannot allow ultra-low input and high-throughput. Herein we have developed a new method called high-throughput in situ tagged immunoprecipitation sequencing (HiTIP-seq), which uses an integrated superhydrophobic microwell array technology (InSMART). We were able to perform 100 parallel assays from as few as 100 cells per microwell on a single chip. We applied the technology to profile epigenetic alterations of three-dimensional (3D) cell cultures derived from DMG patients. Our HiTIP-seq integrated with RNA sequencing (RNA-seq) analysis revealed that the combination of epigenetic agents (panobinostat and tazemetostat), reprogrammed histone modifications and drove transcriptome changes. Among them, Wnt inhibitory factor 1 (WIF1) has a gain of H3K27ac and a loss of H3K27me3, which leads to the upregulated expression. Altogether, HiTIP-seq is a versatile method for high-throughput analysis of histone modifications, suitable for both DMG research and studying rare 3D models.

弥漫性中线胶质瘤（DMG），H3K27改变，是一种致命的儿科型、高级别、局部位于中枢神经系统中线区域的胶质瘤。目前尚无有效的治疗指南，初治或复发的DMG患者首选临床试验。最近，基于表观遗传制剂的免疫疗法在临床上显示出良好的治疗效果。然而，其潜在机制仍是一个谜。通过活检或切除获得的DMG肿瘤样本非常罕见，这在很大程度上阻碍了基础研究的开展，因为与已建立的细胞系相比，患者来源的肿瘤细胞能更好地再现亲代肿瘤的异质性。作为一种表观遗传重编程疾病，DMG 表现出全球性的 H3K27 三甲基化（H3K27me3）缺失和 H3K27 乙酰化（H3K27ac）增殖。从根本上说，分析多种表观遗传标记是必要的。然而，传统技术无法实现超低输入和高通量。在此，我们开发了一种名为高通量原位标记免疫沉淀测序（HiTIP-seq）的新方法，该方法采用了集成超疏水微孔阵列技术（InSMART）。我们能够在单个芯片上对每个微孔中的100个细胞进行100次平行测定。我们将该技术用于分析来自 DMG 患者的三维（3D）细胞培养物的表观遗传学改变。我们的HiTIP-seq与RNA测序（RNA-seq）相结合的分析表明，表观遗传学药物（panobinostat和tazemetostat）的联合使用，重编程了组蛋白修饰，并推动了转录组的变化。其中，Wnt抑制因子1（WIF1）出现了H3K27ac增益和H3K27me3缺失，从而导致表达上调。总之，HiTIP-seq是一种多用途的组蛋白修饰高通量分析方法，既适用于DMG研究，也适用于罕见三维模型的研究。

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引用次数: 0