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Molecular Pathology Methods to Characterize Biodistribution and Pharmacodynamics of the Oncolytic Virus VSV-GP in a Nonclinical Tumor Model.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 DOI: 10.1177/01926233241303904
Andrea Matter, Karol Budzik, Saurin Mehta, Kathleen Hoyt, Richard Dambra, Adam Vigil, Joseph Ashour, Ernest Raymond, Elizabeth Clark, Charles Wood

Replication-competent oncolytic virus (OV) therapies are a promising new modality for cancer treatment. However, they pose unique challenges for preclinical assessment, due in part to their tumor specificity and ability to self-replicate in vivo. Understanding biodistribution, immune cell responses, and potential effects of intratumoral replication on these outcomes are important aspects of the nonclinical profile for OVs. Herein, a single intravenous dose of vesicular stomatitis virus pseudotyped with the glycoprotein of lymphocytic choriomeningitis virus (VSV-GP), or a cargo-expressing variant (VSV-GP-[cargo]), was examined in both tumor-free and CT26.CL25.IFNAR-/- syngeneic tumor-bearing mouse models. Biodistribution and immune cell responses were characterized using different molecular pathology methods, including a strand-specific in situ hybridization method to differentiate administered viral genomes from replicated or transcribed viral anti-genome RNA. We identified distinct patterns of viral biodistribution and replication across tumor and nontumor sites but no major differences in biodistribution, off-tumor cell tropism, or immune cell responses between tumor-free and tumor-bearing mouse models. Our findings characterize key cellular changes following systemic exposure to VSV-GP, provide a better understanding of a nonclinical permissive tumor model for OV assessment, and demonstrate how current molecular pathology methods can provide a bridge between traditional biodistribution and pathology readouts.

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引用次数: 0
Mitigating Nephrotoxicity Risks and Ranking Drug Candidates Using MALDI Mass Spectrometry Imaging: A Case Study.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 DOI: 10.1177/01926233241303905
Bingming Chen, Lisa LaFranco-Scheuch, Shuzhi Dong, Lorraine D Hernandez, Hong Mei, Wendy Zhong, Mark T Cancilla, Marissa Vavrek, Juliann Ehrhart, Thomas Forest, Yu Tao, Yingkai Liang, Takayuki Tsuchiya, Andrew Leithead, Bennett Ma

Drug-induced nephrotoxicity is a major challenge in drug discovery and development, accounting for nearly a quarter of severe adverse effects in current pharmacotherapy. Antimicrobial use may be associated with this problem, with one-third of nephrotoxicity related to these drugs. During the lead optimization stage of our antibacterial programs, nephrotoxicity was observed with renal tubule degeneration and tubular granular casts. To examine the nephrotoxicity mechanisms and triage compounds, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to investigate the compound distribution in rat kidney sections. MALDI-MSI has emerged as a powerful tool allowing for the spatial localization of drugs and metabolites directly from tissue surfaces without the need for labels. By comparing the renal distribution of toxic and non-toxic compounds, a correlation of preferential renal cortex and outer-medullar distribution with positive in vivo nephrotoxicity was discovered for most of the drug candidates being tested. This correlation facilitated the ranking of compounds to aid in the lead optimization process of antimicrobial drug discovery. We envision that MALDI-MSI can be used for drug-induced nephrotoxicity derisking during drug discovery and development when a correlation between tissue distribution and nephrotoxicity can be established.

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引用次数: 0
Applications of Molecular Pathology: An Evolving Approach to Toxicologic Pathology.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-28 DOI: 10.1177/01926233241313371
Ingrid Cornax, Dinesh S Bangari, Vinicius Carreira, Kyathanahalli S Janardhan
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引用次数: 0
Mass Spectrometry Imaging Distinguishes Biliary Toxicants on the Basis of Cellular Distribution. 质谱成像在细胞分布的基础上区分胆道毒物。
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2024-12-12 DOI: 10.1177/01926233241303890
Junhai Yang, Andrew P Bowman, Wayne R Buck, Rebecca Kohnken, Christopher J Good, David S Wagner

Mass spectrometry imaging (MSI) was used to investigate and provide insights into observed biliary pathology found in dogs and rats after administration of two different compounds. Both compounds were associated with peribiliary inflammatory infiltrates and proliferation of the bile duct epithelium. However, MSI revealed very different spatial distribution profiles for the two compounds: Compound A showed significant accumulation within the bile duct epithelium with a much higher concentration than in the parenchymal hepatocytes, while Compound T exhibited only a slight increase in the bile duct epithelium compared to parenchymal hepatocytes. These findings implicate cholangiocyte uptake and accumulation as a key step in the mechanism of biliary toxicity. In both cases, compounds are shown at the site of toxicity in support of a direct mechanism of toxicity on the biliary epithelium. MSI is a powerful tool for localizing small molecules within tissue sections and improvements in sensitivity have enabled localization down to the cellular level in some cases. MSI was also able to identify biomarker candidates of toxicity by differential analysis of ion profiles comparing treated and control cholangiocytes from tissue sections.

质谱成像(MSI)用于研究和提供观察到的胆道病理发现在狗和大鼠给药两种不同的化合物。这两种化合物都与胆管周围炎症浸润和胆管上皮增生有关。然而,MSI显示两种化合物的空间分布特征非常不同:化合物A在胆管上皮内明显积聚,浓度远高于肝实质细胞,而化合物T在胆管上皮内的浓度仅比肝实质细胞轻微增加。这些发现暗示胆管细胞的摄取和积聚是胆道毒性机制的关键步骤。在这两种情况下,化合物都显示在毒性部位,支持胆上皮毒性的直接机制。MSI是一种强大的工具,用于定位组织切片内的小分子,在某些情况下,灵敏度的提高使定位下降到细胞水平。MSI还能够通过比较处理和对照胆管细胞组织切片的离子谱的差异分析来识别毒性的生物标志物候选物。
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引用次数: 0
Integration of Chromogenic RNAscope In Situ Hybridization for Target Validation in Drug Discovery. 整合显色RNAscope原位杂交用于药物发现的靶标验证。
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-19 DOI: 10.1177/01926233241311275
Rosanna Win, Wesley Minto, In Kyoung Mah, Kelli Boyd

Characterizing the expression of novel targets in normal and diseased tissues is a fundamental component of a target validation data package. Often these targets are presented to the pathology team for assessment with bulk or single-cell RNAseq data and limited to no spatial tissue expression data. In situ hybridization to detect mRNA (RNAscope) is a valuable tool to (1) identify cells that may express the target protein and to corroborate protein expression during immunohistochemical (IHC) assay development or (2) to use as surrogate for single-cell expression IHC when antibodies are not available. Chromogenic RNAscope in situ hybridization (CISH) can be performed on frozen or formalin-fixed, paraffin-embedded (FFPE) tissues. This CISH workflow starts with RNA qualification of the tissue (to assess RNA integrity) by measuring the expression of housekeeping genes. RNA-qualified tissues then undergo CISH for the target in question, and positive CISH signals are quantified in VisioPharm by a combination of color deconvolution, size gating, and dot density thresholding. This RNA workflow can complement IHC or standalone in target validation for spatial characterization of novel targets.

表征新靶标在正常和病变组织中的表达是靶标验证数据包的基本组成部分。通常,这些靶标被提交给病理小组,用大量或单细胞RNAseq数据进行评估,并且仅限于没有空间组织表达数据。原位杂交检测mRNA (RNAscope)是一种有价值的工具,可以(1)识别可能表达目标蛋白的细胞,并在免疫组织化学(IHC)检测过程中证实蛋白表达,或者(2)在没有抗体时用作单细胞表达IHC的替代品。显色RNAscope原位杂交(CISH)可以在冷冻或福尔马林固定、石蜡包埋(FFPE)组织上进行。这个CISH工作流程从组织的RNA鉴定(评估RNA完整性)开始,通过测量管家基因的表达。然后,rna合格的组织对目标进行CISH,阳性CISH信号在VisioPharm中通过颜色反褶积、大小门控和点密度阈值的组合进行量化。这种RNA工作流程可以补充IHC或单独用于新靶标的空间表征的靶标验证。
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引用次数: 0
Applications of Cell-Based Protein Array Technology to Preclinical Safety Assessment of Biological Products.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-28 DOI: 10.1177/01926233241311259
Axel Vicart, Cam Holland, Kathryn Fraser, Frederic Gervais, Mark Aspinall-O'Dea, Nick Brown, Kirk Siddals, Géraldine Greiner, Vinicius Carreira, Elizabeth Galbreath, Maggie Willer, Saravanan Kaliyaperumal, Charles Wood, Tim MacLachlan, Elizabeth Clark

Off-target evaluation is essential in preclinical safety assessments of novel biotherapeutics, supporting lead molecule selection, endpoint selection in toxicology studies, and regulatory requirements for first-in-human trials. Off-target interaction of a therapeutic antibody and antibody derivatives has been historically assessed via the Tissue Cross-Reactivity (TCR) study, in which the candidate molecule is used as a reagent in immunohistochemistry (IHC) to assess binding of the candidate molecule to a panel of human tissue sections. The TCR approach is limited by the performance of the therapeutic as an IHC reagent, which is often suboptimal to outright infeasible. Furthermore, binding of the therapeutic in IHC conditions typically has poor in vitro to in vivo translation and lacks qualitative data of the identity of putative off-targets limiting the decisional value of the data. More recently, cell-based protein arrays (CBPA) that allow for screening against a large portion of the human membrane proteome and secretome have emerged as a complement, and likely a higher value alternative, to IHC-based off-target assessment. These arrays identify specific protein interactions and may be useful for testing nontraditional antibody-based therapeutic formats that are unsuitable for TCR studies. This article presents an overview of CBPA technologies in the context of TCR and off-target assessment studies. Selected case examples and strategic considerations covering a range of different modalities are presented.

脱靶评估对于新型生物治疗药物的临床前安全性评估至关重要,它支持先导分子的选择、毒理学研究的终点选择以及首次人体试验的监管要求。治疗性抗体和抗体衍生物的脱靶相互作用历来是通过组织交叉反应(TCR)研究来评估的,在该研究中,候选分子被用作免疫组织化学(IHC)试剂,以评估候选分子与一组人体组织切片的结合情况。TCR 方法受限于治疗药物作为 IHC 试剂的性能,通常不够理想,甚至完全不可行。此外,IHC 条件下的疗法结合通常在体外到体内的转化率较低,而且缺乏关于假定非靶点身份的定性数据,从而限制了数据的决策价值。最近,可针对大部分人类膜蛋白质组和分泌组进行筛选的细胞基蛋白质阵列(CBPA)已成为基于 IHC 的非靶点评估的补充,也可能是价值更高的替代方法。这些阵列可识别特定的蛋白质相互作用,并可用于测试不适合 TCR 研究的非传统抗体疗法。本文概述了 TCR 和脱靶评估研究中的 CBPA 技术。文章介绍了涵盖各种不同模式的精选案例和战略考虑因素。
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引用次数: 0
Thank You to Reviewers.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-30 DOI: 10.1177/01926233251315826
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引用次数: 0
Characterizing Antisense Oligonucleotide-Induced Histopathology Findings in Spinal Cord of Mauritius Cynomolgus Monkeys by Molecular Localization Investigation.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-30 DOI: 10.1177/01926233241311277
Valérie Dubost, Kuno Wuersch, Kelley Penraat, Eric Johnson, Anja Wekkeli, Ramprasad Ramakrishna, Aline Piequet, Géeraldine Greiner, Magali Jivkov, Esther Erard, Regine Hansen, Dominique Brees, Andreas Hartmann, Kamal Kumar Balavenkatraman, Jairo Nunes

The safety of a 2'-O-methoxyethyl antisense oligonucleotide (ASO) was investigated in Mauritius cynomolgus monkeys in a 41-week Good Laboratory Practice (GLP) toxicity study after multiple intrathecal (IT) administrations. Histopathological examination revealed ectopic formation of lymphoid follicles in the spinal cord (SC) at the injection site at all doses and the presence of granular material in neurons of the SC in high-dose animals. The granular material was seen in all the segments of the SC, but mainly in the lumbar segment and persisted at the end of the 26-week recovery period, while the lymphoid follicles showed a reversibility trend. Findings associated with repeated IT administration of ASOs have been described in nonhuman primate (NHP) toxicity studies, specifically in the brain, but findings in the SC are rarely reported. In the present study, we report a high incidence of findings in the SC compared to brain, especially in the lumbar segment in proximity to IT injection sites. An extensive panel of immunohistochemistry markers showed that the ectopic lymphoid follicle formation (LFF) had a cellular composition and organization consistent with tertiary lymphoid structure (TLS) without associated axonal damage in the adjacent nervous tissue. In situ hybridization with an miRNA probe complementary to the ASO revealed that the granular material represented a dose-dependent ASO accumulation in the cytoplasm of neurons without inducing cell death or apoptosis. Glial and ependymal cells in the SC also showed dose-dependent accumulation of the ASO preceding detection of granular material by hematoxylin and eosin (H&E). Based on these molecular localization data, the presence of LFF in SC suggests a chronic local immune activation. Considering the absence of neuronal dysfunction or injury and transient clinical signs previously reported with other 2'-MOE ASOs, the presence of TLS and ASO was considered non-adverse.

在一项为期41周的良好实验室规范(GLP)毒性研究中,研究人员对毛里求斯绒猴进行了多次鞘内给药后的2'-O-甲氧基乙基反义寡核苷酸(ASO)安全性研究。组织病理学检查显示,在所有剂量下,注射部位的脊髓(SC)中都有异位淋巴滤泡形成,高剂量动物的脊髓神经元中存在颗粒状物质。颗粒状物质出现在脊髓的所有节段,但主要出现在腰椎节段,并且在26周的恢复期结束时仍然存在,而淋巴滤泡则呈现出可逆性趋势。在非人灵长类动物(NHP)的毒性研究中,已经描述了与反复 IT 给药 ASO 相关的结果,特别是在大脑中,但在 SC 中的结果却鲜有报道。在本研究中,我们报告了与脑部相比,腹腔积液的发病率较高,尤其是在靠近 IT 注射部位的腰部。大量免疫组化标记物显示,异位淋巴滤泡形成(LFF)的细胞组成和组织结构与三级淋巴结构(TLS)一致,但邻近神经组织没有相关的轴突损伤。与ASO互补的miRNA探针原位杂交显示,颗粒状物质是神经元胞质中ASO的剂量依赖性积累,不会诱导细胞死亡或凋亡。在苏木精和伊红(H&E)检测到颗粒状物质之前,SC 中的胶质细胞和上皮细胞也显示出剂量依赖性的 ASO 聚集。根据这些分子定位数据,SC 中 LFF 的存在表明存在慢性局部免疫激活。考虑到没有神经元功能障碍或损伤,以及之前报道的其他 2'-MOE ASO 的短暂临床症状,TLS 和 ASO 的存在被认为是非不良反应。
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引用次数: 0
European Society of Toxicologic Pathology-Pathology 2.0 Mass Spectrometry Imaging Special Interest Group: Mass Spectrometry Imaging in Diagnostic and Toxicologic Pathology for Label-Free Detection of Molecules-From Basics to Practical Applications.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2025-02-04 DOI: 10.1177/01926233241311269
Enrico Vezzali, Michael Becker, Fernando Romero-Palomo, Marjolein van Heerden, Caroline Chipeaux, Gregory Hamm, Dinesh S Bangari, Thomas Lemarchand, Barbara Lenz, Bogdan Munteanu, Bhanu Singh, Celine Thuilliez, Seong-Wook Yun, Andrew Smith, Rob Vreeken

Mass Spectrometry Imaging (MSI) is a powerful tool to understand molecular pathophysiology and therapeutic and toxicity mechanisms, as well as for patient stratification and precision medicine. MSI, a label-free technique offering detailed spatial information on a large number of molecules in different tissues, encompasses various techniques including Matrix-Assisted Laser Desorption Ionization (MALDI), Desorption Electrospray Ionization (DESI), and Secondary Ion Mass Spectrometry (SIMS) that can be applied in diagnostic and toxicologic pathology. Given the utmost importance of high-quality samples, pathologists play a pivotal role in providing comprehensive pathobiology and histopathology knowledge, as well as information on tissue sampling, orientation, morphology, endogenous biomarkers, and pathogenesis, which are crucial for the correct interpretation of targeted experiments. This article introduces MSI and its fundamentals, and reports on case examples, determining the best suited technology to address research questions. High-level principles and characteristics of the most used modalities for spatial metabolomics, lipidomics and proteomics, sensitivity and specific requirements for sample procurement and preparation are discussed. MSI applications for projects focused on drug metabolism, nonclinical safety assessment, and pharmacokinetics/pharmacodynamics and various diagnostic pathology cases from nonclinical and clinical settings are showcased.

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引用次数: 0
Points to Consider From the ESTP Pathology 2.0 Working Group: Overview on Spatial Omics Technologies Supporting Drug Discovery and Development.
IF 1.4 4区 医学 Q3 PATHOLOGY Pub Date : 2025-01-01 Epub Date: 2025-02-10 DOI: 10.1177/01926233241311258
Kerstin Hahn, Bettina Amberg, Josep M Monné Rodriguez, Mieke Verslegers, Byunghak Kang, Hans Wils, Chandra Saravanan, Dinesh S Bangari, Simon Y Long, Sameh A Youssef, Benedek Pesti, Johanna Schaffenrath, Alberto Valdeolivas, Nadine Kumpesa, José A Galván, Marion Richardson, Nicolas Giroud, Leo Kunz, Inês Berenguer Veiga, Michael Bscheider, Precious Cramer, Sizun Jiang, Robert Kreutzer, Enrico Vezzali, Seong-Wook Yun, Sven Rottenberg, Bjoern Jacobsen

Recent advances in bioanalytical and imaging technologies have revolutionized our ability to assess complex biological and pathological changes within tissue samples. Spatial omics, a rapidly evolving technology, enables the simultaneous detection of multiple biomolecules in tissue sections, allowing for high-dimensional molecular profiling within tissue microanatomical contexts. This offers a powerful opportunity for precise, multidimensional exploration of complex disease pathophysiology. The Pathology 2.0 working group within the European Society of Toxicologic Pathology (ESTP) includes a subgroup dedicated to spatial omics technologies. Their primary goal is to raise awareness about these emerging technologies and their potential applications in discovery and toxicologic pathology. This review provides an overview of commonly used, commercially available platforms for transcriptomic, proteomic, and multiomic analysis, discussing technical aspects and illustrative examples of their applications. To harness the power of spatial omics for translational drug discovery and human safety risk assessment, we emphasize the important role of pathologists at every stage of the workflow-from hypothesis generation to sample preparation, data analysis, and interpretation. Spatial omics technologies offer novel opportunities in target discovery, lead selection, preclinical assessment, and clinical development in compound development.

生物分析和成像技术的最新进展彻底改变了我们评估组织样本中复杂的生物和病理变化的能力。空间全息技术(Spatial omics)是一种快速发展的技术,可同时检测组织切片中的多种生物分子,从而在组织微观解剖环境中进行高维分子剖析。这为精确、多维地探索复杂的疾病病理生理学提供了有力的机会。欧洲毒理学病理学学会(ESTP)的病理学 2.0 工作组包括一个专门研究空间 omics 技术的分组。他们的主要目标是提高人们对这些新兴技术及其在发现和毒理病理学中潜在应用的认识。本综述概述了转录组学、蛋白质组学和多组学分析的常用商用平台,讨论了其应用的技术方面和示例。为了将空间全息技术的力量用于转化药物发现和人类安全风险评估,我们强调病理学家在工作流程的每个阶段--从假设生成到样本制备、数据分析和解释--都扮演着重要角色。空间全息技术为化合物开发中的目标发现、先导选择、临床前评估和临床开发提供了新的机遇。
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引用次数: 0
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