American Journal of Pathology最新文献_第7页

Improving Colorectal Cancer Screening and Risk Assessment through Predictive Modeling on Medical Images and Records 基于医学影像和记录的预测建模改进结直肠癌筛查和风险评估。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.016

Shuai Jiang , Christina Robinson , Joseph Anderson , William Hisey , Lynn Butterly , Arief Suriawinata , Saeed Hassanpour

Colonoscopy screening effectively identifies and removes polyps before they progress to colorectal cancer (CRC), but current follow-up guidelines rely primarily on histopathologic features, overlooking other important CRC risk factors. Variability in polyp characterization among pathologists also hinders consistent surveillance decisions. Advances in digital pathology and deep learning enable the integration of pathology slides and medical records for more accurate progression risk prediction. Using data from the New Hampshire Colonoscopy Registry, including longitudinal follow-up, a transformer-based model for histopathology image analysis was adapted to predict 5-year progression risk. Multi-modal fusion strategies were further explored to combine clinical records with deep learning–derived image features. Training the model to predict intermediate clinical variables improved 5-year progression risk prediction [area under the receiver-operating characteristic curve (AUC), 0.630] compared with direct prediction (AUC, 0.615; P = 0.013). Integrating whole-slide imaging–based model predictions with nonimaging features further improved performance (AUC, 0.672), significantly outperforming the nonimaging-only approach (AUC, 0.666; P = 0.002). These results highlight the value of integrating diverse data modalities with computational methods to enhance progression risk stratification.

结肠镜筛查可以有效地在息肉发展为结直肠癌（CRC）之前识别并切除息肉，但目前的随访指南主要依赖于组织病理学特征，忽略了其他重要的CRC危险因素。病理学家之间息肉特征的差异也阻碍了一致的监测决策。数字病理学和深度学习的进步使病理切片和医疗记录的整合能够更准确地预测进展风险。利用新罕布什尔结肠镜登记中心的数据，包括纵向随访，采用基于变压器的组织病理学图像分析模型来预测5年进展风险。进一步探索多模式融合策略，将临床记录与深度学习衍生的图像特征相结合。与直接预测（AUC = 0.615, p = 0.013）相比，训练模型预测中间临床变量可提高5年进展风险预测（AUC = 0.630）。将基于wsi的模型预测与非成像特征相结合进一步提高了性能（AUC = 0.672），显著优于仅非成像方法（AUC = 0.666, p = 0.002）。这些结果强调了将不同数据模式与计算方法相结合以增强进展风险分层的价值。

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引用次数: 0

Inactivation of Atp7b Copper Transporter in Intestinal Epithelial Cells Is Associated with Altered Lipid Processing and Cell Growth Machinery Independent from Hepatic Copper Accumulation and Severity of Liver Histology 肠上皮细胞中Atp7b铜转运体的失活与脂质加工和细胞生长机制的改变有关，与肝铜积累和肝脏组织学的严重程度无关。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.015

Amanda Caceres , Noreene M. Shibata , Christian D. Davalos-Gutierrez , Gaurav V. Sarode , Hisham Hussan , Margarida Bettencourt , Adriana Fontes , Hans Zischka , Svetlana Lutsenko , Marie C. Heffern , Valentina Medici

The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and brain, but little is known about the role of other organs expressing the ATP7B copper transporter on metabolic and ultrastructural changes characterizing WD. To examine the consequences of intestinal Atp7b inactivation in the absence of hepatic copper accumulation, a new mouse model (Atp7b^ΔIEC) characterized by enterocyte-specific Atp7b inactivation was generated. Atp7b^ΔIEC mice were compared with wild-type mice with the same genetic background (iWT). The Atp7b global knockout (Atp7b^–/–) model of WD on a C57Bl/6 background was previously generated and compared with its respective wild type (WT). Hepatic copper, lipid metabolism, liver and intestine histology, and electron microscopy were assessed over time up to 30 weeks of age. Although there was no evidence of intestine copper accumulation in Atp7b^ΔIEC mice, transcriptome analysis in Atp7b^ΔIEC mice revealed changes in genes involved in AMP-activated protein kinase signaling, fatty acid metabolism, and cell cycle both with partial overlap between the intestinal epithelial cells and the liver. Mitochondrial and other ultrastructural changes were observed in the intestinal epithelial cells of both Atp7b^–/– and Atp7b^ΔIEC mice. Intestine-specific Atp7b deficit affects systemic metabolic pathways and intestine morphology, and hepatic metabolic perturbations are associated with intestinal dysfunction, independently from hepatic copper accumulation, providing evidence that the WD phenotype is at least partially influenced by organ-specific ATP7B variants.

Wilson病（WD）的临床表现与铜在肝脏和大脑的积累有关，但对其他器官表达ATP7B铜转运体在WD代谢和超微结构变化中的作用知之甚少。为了研究在没有肝铜积累的情况下肠道Atp7b失活的后果，我们建立了一个以肠细胞特异性Atp7b失活为特征的新小鼠模型（Atp7bΔIEC）。将Atp7bΔIEC小鼠与具有相同遗传背景（iWT）的野生型小鼠进行比较。在C57Bl/6背景下，WD的Atp7b全基因敲除（Atp7b-/-）模型之前已被生成，并与各自的WT进行了比较。肝铜、脂质代谢、肝脏和肠道组织学以及电子显微镜在30周龄时进行了评估。虽然在Atp7bΔIEC小鼠中没有肠道铜积累的证据，但在Atp7bΔIEC小鼠中进行的转录组分析显示，参与AMPK信号、脂肪酸代谢和细胞周期的基因发生了变化，并且在肠上皮细胞和肝脏之间存在部分重叠。Atp7b-/-和Atp7bΔIEC小鼠肠上皮细胞均观察到线粒体和其他超微结构的改变。肠道特异性Atp7b缺陷影响全身代谢途径和肠道形态，肝脏代谢紊乱与肠道功能障碍相关，独立于肝铜积累，提供了WD表型至少部分受器官特异性Atp7b变异影响的证据。

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引用次数: 0

Transforming Growth Factor-β Signaling in Alcohol-Associated Liver Disease 转化生长因子-β信号在酒精相关肝病中的作用：多细胞视角

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.017

Huihui Zou , Sai Wang , Chenjun Huang , Steven Dooley , Nadja M. Meindl-Beinker

Transforming growth factor-β (TGF-β) signaling exerts broad regulatory effects on alcohol-associated liver disease (ALD) progression, influencing processes such as hepatocellular injury, regeneration, inflammation, fibrogenesis, cirrhosis, carcinogenesis, and hepatic failure. TGF-β modifies alcohol-induced signals in multiple liver-resident cell types, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells, and immune populations, particularly macrophages. To delineate its context-specific roles in ALD, 154 of 421 PubMed-listed publications (2000 to 2025; search terms TGF-β and alcohol and liver disease) were reviewed, supplemented by 19 foundational studies published earlier. In hepatocytes, TGF-β promotes oxidative stress, apoptosis, metabolic reprogramming, and epithelial-to-mesenchymal transition. In hepatic stellate cells and Kupffer cells, gut-derived endotoxins, ethanol, and unsaturated fatty acids induce TGF-β alongside proinflammatory cytokines. Ethanol metabolism generates acetaldehyde, which drives TGF-β and receptor expression, enhances canonical and noncanonical signaling, and engages epigenetic regulators to promote extracellular matrix deposition. In liver sinusoidal endothelial cells, alcohol-induced TGF-β suppresses proliferation, contributing to sinusoidal capillarization, impaired endothelial regeneration, and fibrogenesis. TGF-β dampens clearance of damaged hepatocytes and perpetuating chronic injury by suppressing natural killer cell cytotoxicity and promoting regulatory T-cell differentiation. At end-stage disease, TGF-β promotes expansion and fate switching of cholangiocyte-derived liver progenitor cells to replenish lost hepatocytes. Despite its central role in ALD, therapeutic exploitation of TGF-β signaling remains underexplored. Future studies should define cell type–specific signaling nodes to enable precision therapies.

转化生长因子-β (TGF-β)信号在酒精相关性肝病（ALD）进展中发挥广泛的调节作用，影响肝细胞损伤、再生、炎症、纤维化、肝硬化、癌变和肝功能衰竭等过程。TGF-β改变多种肝驻留细胞类型中酒精诱导的信号，包括肝细胞、肝星状细胞（hsc）、肝窦内皮细胞（LSECs）和免疫群体，特别是巨噬细胞。为了描述其在ALD中的具体作用，我们回顾了421篇pubmed列出的出版物中的172篇（2000年至2025年，搜索词“TGF-β”和“酒精”和“肝脏疾病”），并补充了之前发表的18篇基础研究。在肝细胞中，TGF-β促进氧化应激、细胞凋亡、代谢重编程和上皮到间质转化。在造血干细胞和库普弗细胞（KCs）中，肠道来源的内毒素、乙醇和不饱和脂肪酸与促炎细胞因子一起诱导TGF-β。乙醇代谢产生乙醛，驱动TGF-β和受体表达，增强典型和非典型信号传导，并参与表观遗传调节因子促进细胞外基质沉积。在LSECs中，酒精诱导的TGF-β抑制增殖，促进窦状毛细血管形成，内皮再生受损和纤维形成。TGF-β通过抑制自然杀伤细胞的细胞毒性和促进调节性T细胞分化，抑制受损肝细胞的清除和慢性损伤的延续。在终末期疾病中，TGF-β促进胆管细胞来源的肝祖细胞的扩张和命运转换，以补充失去的肝细胞。尽管TGF-β在ALD中发挥核心作用，但TGF-β信号的治疗利用仍未得到充分探索。未来的研究应确定细胞类型特异性信号节点，以实现精确治疗。

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引用次数: 0

Intrahost Genomic Variation of Haemophilus influenzae Isolates from Asymptomatic Nasopharyngeal Carriers Involves Genes Encoding Proteins with Diverse Inferred Functions 从无症状鼻咽病毒携带者分离的流感嗜血杆菌的宿主内基因组变异涉及编码具有多种推断功能的蛋白质的基因。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-15 DOI: 10.1016/j.ajpath.2025.09.014

Randall J. Olsen , S. Wesley Long , Yuvanesh Vedaraju , Sandra Tomasdottir , Helga Erlendsdottir , Ásgeir Haraldsson , Karl G. Kristinsson , James M. Musser , Gunnsteinn Haraldsson

Haemophilus influenzae is a human-specific pathogen that causes infections, ranging in severity from otitis media to potentially fatal meningitis. It also asymptomatically colonizes the upper respiratory tract. Although intrahost genomic variation of H. influenzae has been investigated in some anatomic sites, the genes most frequently acquiring nonsynonymous (amino acid–changing) or nonsense (protein-truncating) single-nucleotide polymorphisms (SNPs) during human carriage remain largely unidentified. To study intrahost genomic variation of H. influenzae during human asymptomatic carriage in the nasopharynx, the genomes of 805 isolates recovered from 24 healthy Icelandic children were sequenced. Most children were colonized with isolates with a single multilocus sequence type, although some were concurrently colonized with isolates with multiple multilocus sequence types. Intrahost genomic variation was discovered, with 120 genes acquiring SNPs in at least one isolate. Among them, 69 genes were recurrently polymorphic in isolates recovered from multiple children, and 72 SNPs occurred in multiple isolates recovered from the same child. The polymorphic genes encode proteins with diverse inferred functions, including transcription regulators and putative virulence factors. Many of the proteins likely play roles in bacterial fitness, virulence, and host-pathogen molecular interactions. This intrahost variation study provides a model for understanding the genomic diversity acquired by H. influenzae during human asymptomatic carriage in the nasopharynx.

流感嗜血杆菌是一种人类特有的病原体，可引起从中耳炎到可能致命的脑膜炎等严重程度的感染。它也在上呼吸道无症状地定植。虽然流感嗜血杆菌的宿主内基因组变异已经在一些解剖位点进行了研究，但在人类携带过程中最常获得非同义（氨基酸改变）或无义（蛋白质截断）单核苷酸多态性（snp）的基因在很大程度上仍未确定。为了研究人类无症状携带流感嗜血杆菌在鼻咽部宿主内的基因组变异，对从24名健康冰岛儿童中分离的805株流感嗜血杆菌进行了基因组测序。大多数儿童定植的分离株为单一多位点序列型（MLST），尽管有些儿童同时定植的分离株为多个MLST。发现宿主内基因组变异，在至少一个分离物中有120个基因获得snp。其中69个基因在多个患儿分离株中重复多态性，72个snp出现在同一患儿分离株中。多态基因编码具有多种推断功能的蛋白质，包括转录调节因子和推定的毒力因子。许多蛋白质可能在细菌适应性、毒力和宿主-病原体分子相互作用中发挥作用。这项宿主内变异研究为理解流感嗜血杆菌在人类无症状携带期间在鼻咽获得的基因组多样性提供了一个模型。

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引用次数: 0

This Month in AJP 本月在AJP。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-10 DOI: 10.1016/j.ajpath.2025.09.011

引用次数: 0

Meeting Abstracts 会议摘要

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-01 DOI: 10.1016/j.ajpath.2025.10.001

引用次数: 0

Title Page 标题页

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-01 DOI: 10.1016/S0002-9440(25)00369-4

引用次数: 0

Periostin Deletion Reduces Corneal Opacity and the Infiltration of Immune Cells 骨膜蛋白缺失可减少角膜混浊和免疫细胞浸润。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.007

Hyemin Seong , Chieun Song , Mingyo Kim , Woong-Sun Yoo , Mee-Young Choi , Réka Dorottya Varga , Yong-Ho Choe , Bina Lee , Seung Pil Yun , Young-Sik Yoo , Youngsub Eom , Choun-Ki Joo , Jinsung Yang , Seong-Jae Kim

Corneal opacity resulting from corneal injury is a leading cause of blindness. The interaction of extracellular matrix (ECM) proteins, cytokines, and immune cells induces corneal opacity after corneal injury. Periostin, which is secreted into the ECM, is involved in wound healing and is associated with immune cell infiltration. The function of periostin in corneal wound healing and in the development of corneal opacity was investigated. Wild-type (WT) and Postn knockout (KO) mice underwent central corneal incision. Periostin expression level was significantly increased after the incision in WT mice, correlating with higher levels of wound healing markers, such as fibronectin and α-smooth muscle actin, and increased corneal opacity. However, Postn KO mice showed reduced corneal opacity and immune cell infiltration, particularly from myeloid lineage cells after incision. In addition, pro-inflammatory cytokine levels (IL-1β, IL-6, and C1q) were not significantly changed in Postn KO mice. The results suggest that periostin deletion impairs corneal wound healing and reduces opacity by regulating cytokine expression and immune cell recruitment. The findings indicate that periostin can be a potential therapeutic target for reducing corneal opacity.

角膜损伤引起的角膜混浊是导致失明的主要原因。细胞外基质（ECM）蛋白、细胞因子和免疫细胞的相互作用诱导角膜损伤后角膜混浊。骨膜蛋白分泌到ECM中，参与伤口愈合并与免疫细胞浸润有关。探讨了骨膜素在角膜创面愈合和角膜混浊形成中的作用。野生型（WT）和Postn敲除（KO）小鼠进行角膜中央切口。WT小鼠切口后骨膜蛋白表达水平显著升高，与纤维连接蛋白、α-SMA等创面愈合标志物水平升高、角膜混浊增加相关。然而，术后KO小鼠显示角膜混浊和免疫细胞浸润减少，尤其是骨髓系细胞。此外，促炎细胞因子（IL-1β、IL-6、C1q）水平在KO后小鼠中没有显著变化。结果表明，骨膜蛋白缺失通过调节细胞因子表达和免疫细胞募集，影响角膜创面愈合，减少角膜不透明。研究结果表明，骨膜蛋白可作为降低角膜混浊的潜在治疗靶点。

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引用次数: 0

Targeting RORγ to Boost Regulatory T cells and Ameliorate Diabetic Retinopathy in Mice 靶向RORγ促进调节性T细胞和改善小鼠糖尿病视网膜病变。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.006

Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L. Wilkinson-Berka

Diabetic retinopathy, a leading cause of blindness, features damage to the retinal vasculature, where T-cell–mediated inflammation is increasingly recognized as an important contributor. Retinoic acid receptor-related orphan receptor gamma (RORγ) plays a key role in regulating the balance between anti-inflammatory regulatory T cells (Tregs) expressing the transcription factor Foxp3 and proinflammatory Th17 cells. It was hypothesized that inhibiting RORγ with SR2211, targeting both RORγ and its isoform RORγt, increases Tregs and reduces Th17 cells, resulting in reduced inflammation and vasculopathy in a streptozotocin-induced model of diabetic retinopathy. Mice expressing Foxp3 as a red fluorescent protein were treated with SR2211 for 26 weeks of diabetes, and comparisons made to diabetic mice administered vehicle and non-diabetic control mice. In blood and lymphoid tissues of diabetic mice, treatment with SR2211 restored the number of Tregs and reduced Th17 cells to the levels of diabetic mice + vehicle. In the retina of diabetic mice, treatment with SR2211 increased Tregs and reduced the activation of microglia cells, the expression of proinflammatory factors including IL-17A, IL-6 and tumor necrosis factor, vascular leakage, vascular endothelial growth factor, and acellular capillaries, compared with diabetic mice + vehicle. These findings indicate the ability of RORγ/RORγt inhibition to modulate specific T-cell responses and suppress microglia activation to reduce inflammation and vascular damage in diabetic retinopathy.

糖尿病视网膜病变是导致失明的主要原因之一，其特征是视网膜脉管系统受损，其中T细胞介导的炎症越来越被认为是一个重要的因素。视黄酸受体相关孤儿受体γ (RORγ)在调节表达转录因子Foxp3的抗炎调节性T细胞（Tregs）和促炎Th17细胞之间的平衡中起关键作用。我们假设SR2211抑制RORγ，同时靶向RORγ及其亚型RORγ γt，可以增加Tregs并减少Th17细胞，从而减少链佐菌素诱导的糖尿病视网膜病变模型中的炎症和血管病变。将表达Foxp3为红色荧光蛋白的小鼠用SR2211治疗糖尿病26周，并与糖尿病小鼠和非糖尿病对照组小鼠进行比较。在糖尿病小鼠的血液和淋巴组织中，用SR2211治疗可以恢复treg的数量，并将Th17细胞降低到糖尿病小鼠+对照体的水平。在糖尿病小鼠的视网膜中，与糖尿病小鼠+对照体相比，SR2211处理增加了Tregs，降低了小胶质细胞的活化，降低了促炎因子（包括白细胞介素- 17a、白细胞介素-6和肿瘤坏死因子）的表达，降低了血管渗漏、血管内皮生长因子和脱细胞毛细血管的表达。这些发现表明，RORγ/RORγ γt抑制能够调节特异性t细胞反应，抑制小胶质细胞激活，从而减少糖尿病视网膜病变的炎症和血管损伤。

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引用次数: 0

Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice 肝细胞特异性MET缺失加剧对乙酰氨基酚诱导的小鼠肝毒性。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.010

Siddhi Jain , Ranjan Mukherjee , Gillian Williams , Jia-Jun Liu , Lanuza A.P. Faccioli , Zhiping Hu , Rodrigo M. Florentino , George K. Michalopoulos , Alejandro Soto-Gutierrez , Silvia Liu , Joseph Locker , Bharat Bhushan

Despite the well-known role of MET in liver regeneration after partial hepatectomy, its role in the clinically relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from partial hepatectomy because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET knockout (MET KO) mice were administered a toxic dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated the initial hepatotoxicity and consequentially impaired the compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative damage, releasing apoptosis-inducing factor into cytosol. Excess JNK activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET signaling. Pharmacologic activation of AKT reduced JNK activation and hepatotoxicity in MET KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling but also activation of cell death/senescence pathways along with an impaired unfolded protein response in MET KO mice. Analysis of published single-nucleus RNA-sequencing data showed that proliferation in livers from patients with APAP-induced acute liver failure was associated with strong activation of hepatocyte growth factor/MET signaling in hepatocytes, with spatial transcriptomics showing striking induction of hepatocyte growth factor surrounding the necrotic zones. Interestingly, 35% of the genes altered in human acute liver failure were regulated by MET in the mouse AILI model. The current study shows that MET is crucial for restraining hepatotoxicity after APAP overdose via inhibition of the mitochondrial cell death signaling pathway.

尽管MET在部分肝切除术（PHx）后肝脏再生中的作用众所周知，但其在临床相关的对乙酰氨基酚（APAP）诱导的肝损伤（AILI）模型中的作用仍未被探索。aii明显不同于PHx，因为它与大量肝坏死有关。本研究旨在明确MET在AILI中的作用。给肝细胞特异性MET-KO小鼠注射毒性剂量的APAP，并评估肝损伤/再生参数。MET缺失显著加剧了最初的肝毒性，并因此损害了代偿性增殖反应，最终导致显著的死亡率。在机制上，MET缺失增强了jnk活化及其线粒体易位，导致线粒体过度氧化损伤，将细胞死亡诱导剂AIF释放到细胞质中。过量的JNK激活归因于AKT在缺乏met信号的情况下对JNK的抑制活性降低。AKT的药理激活降低了MET-KO小鼠的jnk激活和肝毒性。rna测序/免疫印迹不仅显示MET-KO小鼠的增殖/生存信号被抑制，而且细胞死亡/衰老途径被激活，同时未折叠蛋白反应受损。对已发表的单核rna测序数据的分析显示，apap诱导的ALF患者肝脏中的增殖与肝细胞中HGF/MET信号的强烈激活有关，空间转录组学显示坏死区周围HGF的显著诱导。有趣的是，在小鼠aili模型中，人类alf中35%的基因改变受到MET的调节。总之，本研究表明MET通过抑制线粒体细胞死亡信号通路，对抑制APAP过量后的肝毒性至关重要。

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引用次数: 0