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The Biological Intersection Between Chemotherapy-Related Cognitive Impairment and Alzheimer Disease. 化疗相关认知障碍与阿尔茨海默病之间的生物学交叉。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-23 DOI: 10.1016/j.ajpath.2024.12.013
Matthew Torre, Camila A Zanella, Mel B Feany

Alzheimer disease (AD) is the most common type of dementia and one of the leading causes of death in elderly patients. The number of patients with AD in the United States is projected to double by 2060. Thus, understanding modifiable risk factors for AD is an urgent public health priority. In parallel with the number of patients with AD, the number of cancer survivors is estimated to increase significantly, and up to 80% of cancer patients treated with chemotherapy will develop cognitive deficits, termed chemotherapy-related cognitive impairment. This review discusses biologically plausible pathways underlying both disorders, with the goal of understanding why a proportion of chemotherapy patients may be at higher risk of developing AD. Highlighted are the E4 allele of the apolipoprotein E gene, neuroinflammation, oxidative stress, DNA damage, mitochondrial dysfunction, neuronal and synaptic loss, cellular senescence, brain-derived neurotrophic factor signaling, white matter damage, blood-brain barrier/vascular dysfunction, tau pathology, and transposable element reactivation.

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引用次数: 0
Brain Connectivity, Neural Networks, and Resilience in Aging and Neurodegeneration.
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-23 DOI: 10.1016/j.ajpath.2024.12.014
Diego Szczupak, Lovisa LjungQvist Brinson, Christi L Kolarcik

The importance of complex systems has become increasingly evident in recent years. The nervous system is one such example, with neural networks sitting at the intersection of complex networks and biology. A particularly exciting feature is the resilience of complex systems. For example, the ability of the nervous system to perform even in the face of challenges that include neuronal loss, neuroinflammation, protein accumulation, axonal disruptions, and metabolic stress is an intriguing and exciting line of investigation. In neurodegenerative diseases, neural network resilience is responsible for the time between the earliest disease-linked changes and clinical symptom onset and disease diagnosis. In this way, connectivity resilience of neurons within the complex network of cells that make up the nervous system has significant implications. This review provides an overview of relevant concepts related to complex systems with a focus on the connectivity of the nervous system. It discusses the development of the neural network and how a delicate balance determines how this complex system responds to injury, with examples illustrating maladaptive plasticity. The review then addresses the implications of these concepts, methods to understand brain connectivity and neural networks, and recent research efforts aimed at understanding neurodegeneration from this perspective. This study aims to provide foundational knowledge and an overview of current research directions in this evolving and exciting area of neuroscience.

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引用次数: 0
Piezo2 Is a Key Mechanoreceptor in Lung Fibrosis that Drives Myofibroblast Differentiation. Piezo2 是肺纤维化过程中的一个关键机械感受器,可驱动肌成纤维细胞分化。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-22 DOI: 10.1016/j.ajpath.2024.12.015
Margaret A T Freeberg, Sarah V Camus, Valentina Robila, Apostolos Perelas, Thomas H Thatcher, Patricia J Sime

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases have limited treatment options. Fibroblasts are key effector cells that sense matrix stiffness through conformation changes in mechanically sensitive receptors, leading to activation of downstream profibrotic pathways. Here, we investigate the role of Piezo2, a mechanosensitive ion channel, in human and mouse lung fibrosis, and its function in myofibroblast differentiation in primary human lung fibroblasts (HLFs). Human samples from patients with IPF and mouse tissue from bleomycin-induced pulmonary fibrosis was assessed. Primary HLFs from nonfibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression is up-regulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, interrogation of published single-cell RNA-sequencing data showed that Piezo2 is expressed in the profibrotic Cthrc1+ fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared with that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression α-smooth muscle actin and fibronectin in HLFs. Piezo2 expression is elevated in fibrotic lung disease in both patients and rodents, and its presence is key in the differentiation of fibroblasts to the profibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and, thus, be a novel therapeutic approach to treat pulmonary fibrosis.

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引用次数: 0
This Month in AJP. 本月在AJP。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-14 DOI: 10.1016/j.ajpath.2025.01.001
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引用次数: 0
Beyond Redox Regulation: Novel Roles of TXNIP in the Pathogenesis and Therapeutic Targeting of Kidney Disease. 超越氧化还原调节:TXNIP在肾脏疾病发病机制和治疗靶向中的新作用。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-13 DOI: 10.1016/j.ajpath.2024.12.011
Chuang Li, Yili Fang, Ying Maggie Chen

Cellular stress conditions, such as oxidative and endoplasmic reticulum (ER) stresses, contribute to the development of various kidney diseases. Oxidative stress is prompted by reactive oxygen species accumulation and delicately mitigated by glutathione and thioredoxin (Trx) antioxidant systems. Initially identified as a Trx-binding partner, Trx-interacting protein (TXNIP) is significantly up-regulated and activated by oxidative and ER stresses. Function of TXNIP is closely linked to its subcellular localizations. Under normal physiological conditions, TXNIP primarily localizes to the nucleus. When exposed to reactive oxygen species or ER stress, TXNIP relocates to mitochondria and binds to mitochondrial Trx2, which releases Trx-tethered apoptosis signal-regulating kinase 1 and activates apoptosis signal-regulating kinase 1-mediated apoptosis. Oxidative and ER stresses are also closely associated with autophagy. TXNIP can promote or inhibit autophagy depending on different contexts. Although recent studies have highlighted the indispensable role of TXNIP in the etiology and progression of kidney disease, TXNIP-targeted therapy is still missing. This review focuses on the following: i) oxidative and ER stresses; ii) regulation and function of TXNIP during cellular stress; iii) TXNIP in stress-regulated autophagy; iv) TXNIP in kidney diseases (nephrotic syndrome, diabetic nephropathy and chronic kidney disease, acute kidney injury, and kidney aging); and v) novel treatment agents targeting TXNIP in kidney disease. Current advances in chemical compounds and RNA-based therapy suppressing TXNIP are also reviewed.

细胞应激条件,如氧化和内质网(ER)应激有助于各种肾脏疾病的发展。氧化应激是由活性氧(ROS)积累引起的,并由谷胱甘肽和硫氧还蛋白(Trx)抗氧化系统微妙地减轻。硫氧还蛋白相互作用蛋白(TXNIP)最初被确定为trx结合伙伴,在氧化和内质网应激下被显著上调和激活。TXNIP的功能与其亚细胞定位密切相关。在正常生理条件下,TXNIP主要定位于细胞核。当暴露于ROS或内质网应激时,TXNIP迁移到线粒体并与线粒体Trx2结合,释放trx拴系的凋亡信号调节激酶1 (ASK1)并激活ASK1介导的细胞凋亡。氧化应激和内质网应激也与自噬密切相关。TXNIP可以根据不同的情况促进或抑制自噬。虽然最近的研究强调了TXNIP在肾脏疾病的病因和进展中不可或缺的作用,但TXNIP靶向治疗仍然缺失。本文将从以下几个方面进行综述:(1)氧化应激和内质网应激;(2)细胞应激过程中TXNIP的调控及功能;(3) TXNIP参与应激调节的自噬;(4) TXNIP在肾病综合征、糖尿病肾病、慢性肾病、急性肾损伤、肾老化等肾脏疾病中的应用;(5)针对TXNIP治疗肾脏疾病的新药物,综述了抑制TXNIP的化合物和基于rna的治疗方法的最新进展。
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引用次数: 0
Cytotoxic T-Lymphocyte-Associated Protein 4 Fused to a Modified Fragment of IgG1 Reduces Muscle Fiber Damage in a Model of Duchenne Muscular Dystrophy by Attenuating Proinflammatory Gene Expression in Myeloid Lineage Cells. CTLA4-Ig通过降低髓系细胞中的促炎基因表达来减轻杜氏肌营养不良模型中的肌纤维损伤。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-13 DOI: 10.1016/j.ajpath.2024.12.012
Michelle Wehling-Henricks, Su-Yin Kok, Haley Gamboa, Pranav Kannan, Connor Thomas, Ivan Flores, Steven S Welc, James G Tidball

Duchenne muscular dystrophy (DMD) is a lethal, muscle-wasting, genetic disease that is greatly amplified by an immune response to the diseased muscles. The mdx mouse model of DMD was used to test whether the pathology can be reduced by treatments with a cytotoxic T-lymphocyte-associated protein 4 fused to a modified fragment of IgG1 (CTLA4-Ig) fusion protein that blocks costimulatory signals required for activation of T cells. CTLA4-Ig treatments reduced mdx sarcolemma lesions and reduced the numbers of activated T cells, macrophages, and antigen-presenting cells in mdx muscle and reduced macrophage invasion into muscle fibers. In vitro data showed that CTLA4-Ig acts directly on bone marrow cells and macrophages to modify their function and gene expression. CTLA4-Ig treatments of mdx bone marrow cells diminished their mobility and chemotactic response to chemokine ligand-2. Treating mdx macrophages with CTLA4-Ig reduced their cytolysis of muscle cells in vitro. RNA-sequencing analysis of mdx macrophages showed that CTLA4-Ig reduced expression of genes associated with leukocyte chemotaxis, migration, and extravasation; >90% of those affected genes were tumor necrosis factor-α target genes. Comparison of mdx and wild-type macrophages by RNA sequencing showed that 46% of the genes down-regulated by CTLA4-Ig were genes up-regulated in macrophages by the presence of muscular dystrophy in mice. These findings show that CTLA4-Ig is a promising immunotherapeutic for DMD, and many of its beneficial effects may result from direct actions on macrophages that modify their expression of proinflammatory genes.

杜氏肌营养不良症(DMD)是一种致命的、肌肉萎缩的遗传性疾病,对患病肌肉的免疫反应极大地放大了这种疾病。使用mdx小鼠DMD模型来测试CTLA4-Ig融合蛋白是否可以通过阻断t细胞激活所需的共刺激信号来减少病理。CTLA4-Ig治疗减少mdx肌膜病变,减少mdx肌中活化的t细胞、巨噬细胞和抗原提呈细胞的数量,减少巨噬细胞对肌纤维的侵袭。体外数据显示,CTLA4-Ig直接作用于骨髓细胞和巨噬细胞,改变其功能和基因表达。CTLA4-Ig治疗mdx BMCs降低了它们的移动性和对趋化因子配体-2的趋化反应。在体外用CTLA4-Ig处理mdx巨噬细胞可减少其对肌肉细胞的细胞溶解。mdx巨噬细胞的RNA-seq分析显示,CTLA4-Ig降低了与白细胞趋化性、迁移和外渗相关基因的表达;>90%的受影响基因为TNFα靶基因。通过RNA-seq对mdx和野生型巨噬细胞的比较发现,CTLA4-Ig下调的基因中有46%是由于小鼠肌营养不良而在巨噬细胞中上调的基因。这些发现表明,CTLA4-Ig是一种很有前景的DMD免疫治疗药物,其许多有益作用可能来自于直接作用于巨噬细胞,改变其促炎基因的表达。
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引用次数: 0
KMeansGraphMIL: A Weakly Supervised Multiple Instance Learning Model for Predicting Colorectal Cancer Tumor Mutational Burden. KMeansGraphMIL:用于预测结直肠癌肿瘤突变负担的弱监督多实例学习模型。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.ajpath.2024.12.008
Linghao Chen, Huiling Xiao, Jiale Jiang, Bing Li, Weixiang Liu, Wensheng Huang

Colorectal cancer (CRC) is one of the top three most lethal malignancies worldwide, posing a significant threat to human health. Recently proposed immunotherapy checkpoint blockade treatments have proven effective for CRC, but their use depends on measuring specific biomarkers in patients. Among these biomarkers, tumor mutational burden (TMB) has emerged as a novel indicator, traditionally requiring next-generation sequencing for measurement, which is time-consuming, labor intensive, and costly. To provide an economical and rapid way to predict patients' TMB, we propose the KMeansGraphMIL model based on weakly supervised multiple-instance learning. Compared with previous weakly supervised multiple-instance learning models, KMeansGraphMIL leverages both the similarity of image patch feature vectors and the spatial relationships between patches. This approach improves the model's area under the receiver operating characteristic curve to 0.8334 and significantly increases the recall to 0.7556. Thus, we present an economical and rapid framework for predicting CRC TMB, offering the potential for physicians to quickly develop treatment plans and saving patients substantial time and money.

结直肠癌(CRC)是全球三大最致命的恶性肿瘤之一,对人类健康构成重大威胁。最近提出的免疫治疗检查点阻断治疗已被证明对结直肠癌有效,但其使用取决于对患者特异性生物标志物的测量。在这些生物标志物中,肿瘤突变负荷(Tumor Mutational Burden, TMB)已成为一种新的指标,传统上需要新一代测序(NGS)来测量,这是耗时、劳动密集型和昂贵的。为了提供一种经济、快速的预测患者TMB的方法,我们提出了基于弱监督多实例学习(WSMIL)的KMeansGraphMIL模型。与以前的WSMIL模型相比,KMeansGraphMIL既利用了图像patch特征向量的相似性,又利用了patch之间的空间关系。该方法将模型的AUC提高到0.8334,并将召回率显著提高到0.7556。因此,我们提出了一个经济快速的预测CRC TMB的框架,为医生提供了快速制定治疗计划的潜力,为患者节省了大量的时间和金钱。
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引用次数: 0
Histopathologic Marks of Tongue in a Mouse Model of Oculopharyngeal Muscular Dystrophy Suggest Biomechanical Defects. 在眼咽肌萎缩症小鼠模型中,舌头的组织病理学标记提示生物力学缺陷。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.ajpath.2024.12.009
Rebecca Kordikowski Boix, Erik Bos, Milad Shademan, Sander Mallon, Sofie van Zanen-Gerhardt, Ngoc Lu-Nguyen, Alberto Malerba, Christina J J Coenen de Roo, Vered Raz

The tongue facilitates vital activities such as swallowing. Difficulty swallowing (dysphagia) is common in the elderly population and in patients with adult-onset neuromuscular disease. In oculopharyngeal muscular dystrophy (OPMD), dysphagia is often the first symptom. OPMD is an autosomal-dominant myopathy caused by a trinucleotide-expansion mutation in the gene encoding nuclear poly(A)-binding protein (PABPN)-1. Expanded-mutant PABPN1 forms insoluble nuclear aggregates that reduce the levels of the soluble form. Clinical tongue involvement in OPMD has been documented but is poorly understood. Histopathologic analysis of the tongue in an OPMD mouse model was done by light and electron microscopy combined with RNA sequencing. PABPN1 nuclear aggregates were found at moderate levels, whereas deposition of insoluble PABPN1 in blood vessels was prominent already at age 4 months. Muscle wasting of the tongue was age associated. RNA signatures of the OPMD tongue were enriched for mitochondrial and cytoskeletal genes. Electron microscopy revealed abnormalities in sarcomere and mitochondria organization in A17/+ mice, suggesting an energy and contractile deficit in OPMD tongue. This detailed analysis of the histopathology of the tongue in the A17/+ mouse model opens new avenues for understanding the mechanisms of dysphagia.

舌头促进吞咽等重要活动。吞咽困难(吞咽困难)在老年人和许多成人发病的神经肌肉疾病中很常见。在眼咽肌营养不良症(OPMD),吞咽困难往往是第一症状。OPMD是一种常染色体显性肌病,由编码PABPN1基因的三核苷酸扩增突变引起。扩展的PABPN1形成不溶性的核聚集体,降低了可溶性形式的水平。临床舌头参与OPMD已被记录,但了解甚少。采用光镜、电镜结合RNA测序技术对OPMD小鼠舌部组织病理学进行研究。在4月龄小鼠中,发现了中等水平的PABPN1核聚集体,而血管中不溶性PABPN1的沉积已经很明显。舌头的肌肉萎缩与年龄有关。OPMD舌的线粒体和细胞骨架基因的RNA特征丰富。电镜显示A17/+组织中肌节和线粒体组织异常,提示OPMD舌部存在能量和收缩缺陷。对A17/+小鼠模型舌组织病理学的详细分析为理解吞咽困难的机制开辟了新的途径。
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引用次数: 0
Deep Learning for Classification of Inflammatory Bowel Disease Activity in Whole Slide Images of Colonic Histopathology. 基于深度学习的炎症性肠病活动在结肠组织病理学整张幻灯片图像中的分类。
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-10 DOI: 10.1016/j.ajpath.2024.12.010
Amit Das, Tanmay Shukla, Naofumi Tomita, Ryland Richards, Laura Vidis, Bing Ren, Saeed Hassanpour

Grading activity of inflammatory bowel disease (IBD) using standardized histopathological scoring systems remains challenging due to limited availability of pathologists with IBD expertise and interobserver variability. In this study, a deep learning model was developed to classify activity grades in hematoxylin and eosin-stained whole slide images (WSIs) from patients with IBD, offering a robust approach for general pathologists. This study utilized 2077 WSIs from 636 patients who visited Dartmouth-Hitchcock Medical Center in 2018 and 2019, scanned at ×40 magnification (0.25 μm/pixel). Board-certified gastrointestinal pathologists categorized the WSIs into four activity classes: inactive, mildly active, moderately active, and severely active. A transformer-based model was developed and validated using five-fold cross-validation to classify IBD activity. Using HoVer-Net, neutrophil distribution across activity grades was examined. Attention maps from the model highlighted areas contributing to its prediction. The model classified IBD activity with weighted averages of 0.871 (95% CI, 0.860-0.883) for the area under the curve, 0.695 (95% CI, 0.674-0.715) for precision, 0.697 (95% CI, 0.678-0.716) for recall, and 0.695 (95% CI, 0.674-0.714) for F1 score. Neutrophil distribution was significantly different across activity classes. Qualitative evaluation of attention maps by a gastrointestinal pathologist suggested their potential for improved interpretability. The model demonstrates robust diagnostic performance and could enhance consistency and efficiency in IBD activity assessment.

使用标准化的组织病理学评分系统对炎症性肠病(IBD)进行分级仍然具有挑战性,因为具有IBD专业知识的病理学家的可用性有限,并且观察者之间的可变性。在这项研究中,开发了一种深度学习模型,用于对IBD患者苏木精和伊红染色的全切片图像(WSIs)的活动等级进行分类,为普通病理学家提供了一种强大的方法。该研究利用2018年和2019年在达特茅斯-希区柯克医疗中心就诊的636名患者的2077张wsi,以40倍放大镜(0.25 μm/像素)扫描。经委员会认证的胃肠病理学家将wsi分为四类:不活动、轻度活动、中度活动和严重活动。开发了一个基于变压器的模型,并使用五次交叉验证来对IBD活动进行分类。使用HoVerNet,检查中性粒细胞在活动等级之间的分布。该模型的注意图突出了有助于其预测的区域。该模型对IBD活动进行分类,曲线下面积的加权平均值为0.871[95%可信区间(CI): 0.860-0.883],精确度为0.695 [95% CI: 0.674-0.715],召回率为0.697 [95% CI: 0.678-0.716], f1评分为0.695 [95% CI: 0.674-0.714]。中性粒细胞分布在不同活动班间差异显著。一位胃肠病理学家对注意图的定性评价表明,注意图的可解释性可能得到改善。该模型具有稳健的诊断性能,可以提高IBD活动性评估的一致性和效率。
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引用次数: 0
Chemokine (C-C Motif) Ligand 2/CCR2/Extracellular Signal-Regulated Kinase Signal Induced through Cancer Cell-Macrophage Interaction Contributes to Hepatocellular Carcinoma Progression. 癌细胞-巨噬细胞相互作用诱导的CCL2/CCR2/Erk信号参与肝癌进展
IF 4.7 2区 医学 Q1 PATHOLOGY Pub Date : 2025-01-03 DOI: 10.1016/j.ajpath.2024.12.007
Nobuaki Ishihara, Yu-Ichiro Koma, Masaki Omori, Shohei Komatsu, Rikuya Torigoe, Hiroki Yokoo, Takashi Nakanishi, Keitaro Yamanaka, Yuki Azumi, Shuichi Tsukamoto, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Hiroshi Yokozaki, Takumi Fukumoto

Tumor-infiltrating macrophages, known as tumor-associated macrophages, play a crucial role in the tumor microenvironment. Immunohistochemistry revealed that intratumoral CD68-positive macrophages are associated with poor prognosis and clinicopathologic factors in patients with hepatocellular carcinoma (HCC). Subsequently, an indirect co-culture system involving HCC cells and peripheral blood-derived macrophages was developed. cDNA microarray analysis revealed that chemokine (C-C motif) ligand 2 (CCL2) was highly expressed in HCC cells co-cultured with macrophages. CCL2 neutralization suppressed proliferation, migration, and phosphorylation of extracellular signal-regulated kinase (Erk) in HCC cells and macrophages enhanced through co-culture. In contrast, recombinant human CCL2 (rhCCL2) addition facilitated these malignant phenotypes and increased Erk phosphorylation levels in HCC cells and macrophages. The primary CCL2 receptor, CCR2, was expressed in HCC cells and macrophages and was up-regulated in co-cultured HCC cells. CCR2 inhibition suppressed malignant phenotypes and reduced phosphorylated levels of Erk enhanced by rhCCL2. Additionally, the inhibition of Erk signal suppressed rhCCL2-enhanced malignant phenotypes. Moreover, serum CCL2 levels were higher in patients with HCC than those in healthy donors. On the basis of immunohistochemistry, CCL2-positive cases with high CCR2 expression and phosphorylated Erk-positive cases exhibited poor survival outcomes. Therefore, CCL2 up-regulation through interactions between HCC cells and macrophages contributed to HCC progression, making the CCL2/CCR2/Erk signal a potential target for HCC treatment.

肿瘤浸润性巨噬细胞(ms),又称肿瘤相关巨噬细胞(tam),在肿瘤微环境中起着至关重要的作用。免疫组化(IHC)结果显示,肝细胞癌(HCC)患者瘤内cd68 - m阳性与预后不良及临床病理因素相关。随后,建立了HCC细胞和外周血源性小鼠的间接共培养系统。互补DNA (cDNA)微阵列分析结果显示,C-C基序趋化因子配体2 (CCL2)在与m圃s共培养的HCC细胞中高表达。CCL2中和可抑制肝癌细胞和小鼠中细胞外信号调节激酶(Erk)的增殖、迁移和磷酸化,并通过共培养增强。相比之下,重组人CCL2 (rhCCL2)的加入促进了这些恶性表型,并增加了HCC细胞和肝癌细胞中Erk磷酸化水平。原代CCL2受体C-C基序趋化因子受体2 (CCR2)在HCC细胞和m中表达,在共培养的HCC细胞中表达上调。CCR2抑制抑制了恶性表型,降低了rhCCL2增强的Erk磷酸化水平。此外,Erk信号的抑制抑制了rhccl2增强的恶性表型。此外,HCC患者的血清CCL2水平高于健康供者。基于免疫组化,高CCR2表达的ccl2阳性病例和磷酸化erk阳性病例表现出较差的生存结果。因此,CCL2通过HCC细胞与m之间的相互作用而上调,促进了HCC的进展,使CCL2/CCR2/Erk信号成为HCC治疗的潜在靶点。
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American Journal of Pathology
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