Laboratory Investigation最新文献

{"title":"Real-World Performance of Integrative Clinical Genomics in Pediatric Precision Oncology","authors":"Petra Pokorna ,&nbsp;Hana Palova ,&nbsp;Sona Adamcova ,&nbsp;Robin Jugas ,&nbsp;Dagmar Al Tukmachi ,&nbsp;Michal Kyr ,&nbsp;Dana Knoflickova ,&nbsp;Katerina Kozelkova ,&nbsp;Vojtech Bystry ,&nbsp;Sona Mejstrikova ,&nbsp;Tomas Merta ,&nbsp;Karolina Trachtova ,&nbsp;Eliska Podlipna ,&nbsp;Peter Mudry ,&nbsp;Zdenek Pavelka ,&nbsp;Viera Bajciova ,&nbsp;Pavel Tinka ,&nbsp;Marie Jarosova ,&nbsp;Tina Catela Ivkovic ,&nbsp;Sibylle Madlener ,&nbsp;Ondrej Slaby","doi":"10.1016/j.labinv.2024.102161","DOIUrl":"10.1016/j.labinv.2024.102161","url":null,"abstract":"<div><div>Despite significant improvement in the survival of pediatric patients with cancer, treatment outcomes for high-risk, relapsed, and refractory cancers remain unsatisfactory. Moreover, prolonged survival is frequently associated with long-term adverse effects due to intensive multimodal treatments. Accelerating the progress of pediatric oncology requires both therapeutic advances and strategies to mitigate the long-term cytotoxic side effects, potentially through targeting specific molecular drivers of pediatric malignancies. In this report, we present the results of integrative genomic and transcriptomic profiling of 230 patients with malignant solid tumors (the “primary cohort”) and 18 patients with recurrent or otherwise difficult-to-treat nonmalignant conditions (the “secondary cohort”). The integrative workflow for the primary cohort enabled the identification of clinically significant single nucleotide variants, small insertions/deletions, and fusion genes, which were found in 55% and 28% of patients, respectively. For 38% of patients, molecularly informed treatment recommendations were made. In the secondary cohort, known or potentially driving alteration was detected in 89% of cases, including a suspected novel causal gene for patients with inclusion body infantile digital fibromatosis. Furthermore, 47% of findings also brought therapeutic implications for subsequent management. Across both cohorts, changes or refinements to the original histopathological diagnoses were achieved in 4% of cases. Our study demonstrates the efficacy of integrating advanced genomic and transcriptomic analyses to identify therapeutic targets, refine diagnoses, and optimize treatment strategies for challenging pediatric and young adult malignancies and underscores the need for broad implementation of precision oncology in clinical settings.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 12","pages":"Article 102161"},"PeriodicalIF":5.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of DNA Methylation in Gliomas: Assessment of Preanalytical Variables","authors":"Karol Bomsztyk ,&nbsp;Daniel Mar ,&nbsp;Oleg Denisenko ,&nbsp;Suzanne Powell ,&nbsp;Monika Vishnoi ,&nbsp;Zheng Yin ,&nbsp;Jennifer Delegard ,&nbsp;Caroline Hadley ,&nbsp;Nitin Tandon ,&nbsp;Akash J. Patel ,&nbsp;Anoop P. Patel ,&nbsp;Richard G. Ellenbogen ,&nbsp;Rohan Ramakrishna ,&nbsp;Robert C. Rostomily","doi":"10.1016/j.labinv.2024.102160","DOIUrl":"10.1016/j.labinv.2024.102160","url":null,"abstract":"<div><div>Precision oncology is driven by biomarkers. For glioblastoma multiforme (GBM), the most common malignant adult primary brain tumor, O⁶-methylguanine-DNA methyltransferase (<em>MGMT</em>) gene promoter methylation is an important prognostic and treatment clinical biomarker. Time-consuming preanalytical steps such as biospecimen storage, fixation, sampling, and processing are sources of data irreproducibility, and all these preanalytical variables are confounded by intratumor heterogeneity of <em>MGMT</em> promoter methylation. To assess the effect of preanalytical variables on GBM DNA methylation, tissue storage/sampling (CryoGrid), sample preparation multisonicator (PIXUL), and 5-methylcytosine DNA immunoprecipitation (Matrix-MeDIP-qPCR/seq) platforms were used. <em>MGMT</em> promoter methylation status assayed by MeDIP-qPCR was validated with methylation-specific polymerase chain reaction. <em>MGMT</em> promoter methylation levels in frozen and formalin-fixed paraffin-embedded sample pairs were not statistically different, confirming the reliability of formalin-fixed paraffin-embedded for <em>MGMT</em> promoter methylation analysis. Warm ex vivo ischemia (up to 4 hours at 37 °C) and 3 cycles of repeated sample thawing and freezing did not statistically impact 5-methylcytosine at <em>MGMT</em> promoter, exon, and enhancer regions, indicating the resistance of DNA methylation to common variations in sample processing conditions that might be encountered in research and clinical settings. Twenty-six percent to 34% of specimens exhibited intratumor heterogeneity in the <em>MGMT</em> DNA promoter methylation. These data demonstrate that variations in sample fixation, ischemia duration and temperature, and DNA methylation assay technique do not have a statistically significant impact on <em>MGMT</em> promoter methylation assessment. However, intratumor methylation heterogeneity underscores the value of multiple biopsies at different GBM geographic tumor sites in the evaluation of <em>MGMT</em> promoter methylation status. Matrix-MeDIP-seq analysis revealed that <em>MGMT</em> promoter methylation status clustered with other differentially methylated genomic loci (eg, <em>HOXA</em> and <em>lncRNAs</em>) that are resilient to variation in the above preanalytical conditions. These observations offer new opportunities to develop more granular data-based epigenetic GBM biomarkers. In this regard, the high-throughput CryoGrid-PIXUL-Matrix toolbox could be useful.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 12","pages":"Article 102160"},"PeriodicalIF":5.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunoproteomics Reveal Different Characteristics for the Prognostic Markers of Intratumoral-Infiltrating CD3+ T Lymphocytes and Immunoscore in Colorectal Cancer","authors":"Saiyan Ji ,&nbsp;Huanying Fang ,&nbsp;Jingjie Guan ,&nbsp;Kun He ,&nbsp;Qingyuan Yang","doi":"10.1016/j.labinv.2024.102159","DOIUrl":"10.1016/j.labinv.2024.102159","url":null,"abstract":"<div><div>Tumor-infiltrating lymphocytes (TILs) and immunoscoring based on densities of CD3+ and CD8+ TILs are both favorable prognostic markers in colorectal cancer (CRC). However, determination of the molecular features of TILs, particularly their immunoproteomic signatures would require the development of large scale in situ spatiotemporal technologies. Recently, a multiplex in situ digital spatial proteomic profiling (DSP) tool GeoMx DSP has been applied to identify biomarkers predictive of therapeutic responses and to understand disease mechanisms and progression. Taking advantage of this tool, we simultaneously characterized the spatial distribution and interactions of 42 immune proteins in tumor cells (TCs), CD3+ T stromal TILs (sTILs), and CD20+ B sTILs using tissue microarrays, and further studied their associations with CD3+ T TILs and immunoscores in CRC. First, our data showed that well-known immune checkpoints, such as PD-L1, PD-L2, and LAG3, were expressed at low levels, whereas some other immune proteins, such as CD11c, CD68, STING, and CD44, were highly expressed. Second, 8 spatial interactions were identified, including 5 interactions between TC and CD20+ B sTILs, 2 interactions between CD3+ T sTILs and CD20+ B sTILs, and 1 interaction among TC, CD3+ T sTILs, and CD20+ B sTILs. Third, the differential immune microlandscape in the spatial compartments was identified in tissues with positive CD3+ T intratumoral TILs and high immunoscores. Collectively, to our knowledge, our study is the first to provide in situ spatial immune characteristics at the proteomic level. Moreover, our findings provide direct evidence supporting the infiltration of CD3+ T sTILs from stoma to TC and shed important insights into better understanding and treating CRC patients related to different immune prognostic markers.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 12","pages":"Article 102159"},"PeriodicalIF":5.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid Biopsy in Lung Cancer: Nano–Flow Cytometry Detection of Non–Small Cell Lung Cancer in Blood","authors":"Andong Zhang ,&nbsp;Qiqi Gao ,&nbsp;Chen Tian ,&nbsp;Wentao Chen ,&nbsp;Catherine Pan ,&nbsp;Ling Wang ,&nbsp;Jie Huang ,&nbsp;Jing Zhang","doi":"10.1016/j.labinv.2024.102151","DOIUrl":"10.1016/j.labinv.2024.102151","url":null,"abstract":"<div><div>Non–small cell lung cancer (NSCLC) remains a leading cause of global mortality, with current screening and diagnostic methods often lacking in sensitivity and specificity. In our endeavor to develop precise, objective, and easily accessible diagnostic biomarkers for NSCLC, this study aimed to leverage rapidly evolving liquid biopsy techniques in the field of pathology to differentiate NSCLC patients from healthy controls by isolating peripheral blood samples and enriching extracellular vesicles (EVs) containing lung-derived proteins (thyroid transcription factor-1 [TTF-1] and surfactant protein B [SFTPB]), along with the cancer-associated protein CD151⁺ EVs. Additionally, for practical applications, we established a nano–flow cytometry assay to detect plasma EVs readily. NSCLC patients demonstrated significantly reduced counts of TTF-1⁺ EVs and CD151⁺ EVs in plasma compared with healthy controls (<em>P</em> &lt; .0001), whereas SFTPB⁺ EVs showed no significant difference (<em>P</em> &gt; .05). Integrated analysis of TTF-1⁺, CD151⁺, and SFTPB⁺ EVs yielded an area under the curve values of 0.913 and 0.854 in the discovery and validation cohorts, respectively. Thus, although further validation is essential, the newly developed technologies are of great significance for the robust detection of NSCLC biomarkers.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 12","pages":"Article 102151"},"PeriodicalIF":5.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptidomics and Machine Learning–based Evaluation of Noncoding RNA–Derived Micropeptides in Breast Cancer: Expression Patterns and Functional/Therapeutic Insights","authors":"Alexandre Luiz Korte de Azevedo ,&nbsp;Talita Helen Bombardelli Gomig ,&nbsp;Michel Batista ,&nbsp;Jaqueline Carvalho de Oliveira ,&nbsp;Iglenir João Cavalli ,&nbsp;Daniela Fiori Gradia ,&nbsp;Enilze Maria de Souza Fonseca Ribeiro","doi":"10.1016/j.labinv.2024.102150","DOIUrl":"10.1016/j.labinv.2024.102150","url":null,"abstract":"<div><div>Breast cancer is a highly heterogeneous disease characterized by different subtypes arising from molecular alterations that give the disease different phenotypes, clinical behaviors, and prognostic. The noncoding RNA (ncRNA)–derived micropeptides (MPs) represent a novel layer of complexity in cancer study once they can be biologically active and can present potential as biomarkers and also in therapeutics. However, few large-scale studies address the expression of these peptides at the peptidomics level or evaluate their functions and potential in peptide-based therapeutics for breast cancer. In this study, we propose deepening the landscape of ncRNA-derived MPs in breast cancer subtypes and advance the comprehension of the relevance of these molecules to the disease. First, we constructed a 16,349 unique putative MP sequence data set by integrating 2 previously published lists of predicted ncRNA-derived MPs. We evaluated its expression on high-throughput mass spectrometry data of breast tumor samples from different subtypes. Next, we applied several machine and deep learning tools, such as AntiCP 2.0, MULocDeep, PEPstrMOD, Peptipedia, and PreAIP, to predict its functions, cellular localization, tertiary structure, physicochemical features, and other properties related to therapeutics. We identified 58 peptides expressed on breast tissue, including 27 differentially expressed MPs in tumor compared with nontumor samples and MPs exhibiting tumor or subtype specificity. These peptides presented physicochemical features compatible with the canonical proteome and were predicted to influence the tumor immune environment and participate in cell communication, metabolism, and signaling processes. In addition, some MPs presented potential as anticancer, antiinflammatory, and antiangiogenic molecules. Our data demonstrate that MPs derived from ncRNAs have expression patterns associated with specific breast cancer subtypes and tumor specificity, thus highlighting their potential as biomarkers for molecular classification. We also reinforce the relevance of MPs as biologically active molecules that play a role in breast tumorigenesis, besides their potential in peptide-based therapeutics.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 12","pages":"Article 102150"},"PeriodicalIF":5.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the Tumor Immune Landscape Across Multiple Spatial Scales to Differentiate Immunotherapy Response in Metastatic Non-Small Cell Lung Cancer","authors":"Ashley P. Tsang ,&nbsp;Santhoshi N. Krishnan ,&nbsp;Joel N. Eliason ,&nbsp;Jake J. McGue ,&nbsp;Angel Qin ,&nbsp;Timothy L. Frankel ,&nbsp;Arvind Rao","doi":"10.1016/j.labinv.2024.102148","DOIUrl":"10.1016/j.labinv.2024.102148","url":null,"abstract":"<div><div>Although immune checkpoint inhibitor-based therapy has shown promising results in non-small cell lung cancer patients with high programmed death-ligand 1 expression, not all patients respond to therapy. The tumor microenvironment (TME) is complex and heterogeneous, making it challenging to understand the key agents and features that influence response to therapies. In this study, we leverage multiplex fluorescent immunohistochemistry to quantitatively assess interactions between tumor and immune cells in an effort to identify patterns occurring at multiple spatial levels of the TME. To do so, we introduce several computational methods novel to a data set of 1,269 multiplex fluorescent immunohistochemistry images from a cohort of 52 patients with metastatic non-small cell lung cancer. With the spatial G-cross function, we quantify the degree of cell interaction at an entire image level, where we see significantly increased activity of cytotoxic T cells and helper T cells with epithelial tumor cells in responders to immune checkpoint inhibitor-based (<em>P</em> = .022 and <em>P &lt; .</em>001, respectively) and decreased activity of T-regulatory cells with epithelial tumor cells compared with nonresponders (<em>P</em> = .010). By leveraging spatial overlap methods, we define tumor subregions (which we call the tumor “periphery,” “edge.” and “center”) and discover more localized immune-immune interactions influencing positive response, including those between cytotoxic T cells and helper T cells with antigen presenting cells in these subregions specifically. Finally, we trained an interpretable deep learning model that identified key cellular regions of interest that most influenced response classification (area under the curve = 0.71 ± 0.02). Assessing spatial interactions within these subregions further revealed new insights that were not significant at the whole image level, particularly the elevated association of antigen presenting cells and T-regulatory cells with one another in responder groups (<em>P</em> = .024). Altogether, we demonstrate that elucidating patterns of cell composition and interplay across multiple levels of spatial analyses can improve our understanding of the TME and better differentiate patient responses to immunotherapy.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 11","pages":"Article 102148"},"PeriodicalIF":5.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the Crosstalk B:Neoplastic T Follicular Helper Cells in the Pathobiology of Nodal T Follicular Helper Cell Lymphomas","authors":"Tania P. Sainz ,&nbsp;Vishal Sahu ,&nbsp;Javier A. Gomez ,&nbsp;Nicholas J. Dcunha ,&nbsp;Akshay V. Basi ,&nbsp;Claudia Kettlun ,&nbsp;Iman Sarami ,&nbsp;Jared K. Burks ,&nbsp;Deepa Sampath ,&nbsp;Francisco Vega","doi":"10.1016/j.labinv.2024.102147","DOIUrl":"10.1016/j.labinv.2024.102147","url":null,"abstract":"<div><div>Angioimmunoblastic T-cell lymphoma (AITL), the most common form of peripheral T-cell lymphoma, originates from follicular helper T (Tfh) cells and is notably resistant to current treatments. The disease progression and maintenance, at least in early stages, are driven by a complex interplay between neoplastic Tfh and clusters of B-cells within the tumor microenvironment, mirroring the functional crosstalk observed inside germinal centers. This interaction is further complicated by recurrent mutations, such as <em>TET2</em> and <em>DNMT3A</em>, which are present in both Tfh cells and B-cells. These findings suggest that the symbiotic relationship between these 2 cell types could represent a therapeutic vulnerability. This review examines the key components and signaling mechanisms involved in the synapses between B-cells and Tfh cells, emphasizing their significant role in the pathobiology of AITL and potential as therapeutic targets.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 11","pages":"Article 102147"},"PeriodicalIF":5.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Biomarker Detection in Cancer: A Comparative Analysis of Preanalytical Reverse Transcription Enzymes for Liquid Biopsy Application","authors":"Neele Wüstmann ,&nbsp;Verena Humberg ,&nbsp;Julia Vieler ,&nbsp;Konstantin Seitzer ,&nbsp;Sabine von Rüden ,&nbsp;Mazen A. Juratli ,&nbsp;Andreas Pascher ,&nbsp;Marcel Kemper ,&nbsp;Annalen Bleckmann ,&nbsp;André Franken ,&nbsp;Hans Neubauer ,&nbsp;Tanja N. Fehm ,&nbsp;Martin Bögemann ,&nbsp;Katrin Schlack ,&nbsp;Andres Jan Schrader ,&nbsp;Christof Bernemann","doi":"10.1016/j.labinv.2024.102142","DOIUrl":"10.1016/j.labinv.2024.102142","url":null,"abstract":"<div><div>Circulating tumor cells and liquid biopsy-based biomarkers might one day play a crucial role in the treatment decision process for patients of several cancer entities. However, clinical studies on liquid biopsy approaches revealed distinct detection rates and thus, different risk scoring for patients. This study delves into the comparison of 2 utilized reverse transcription enzymes, namely, SuperScript IV VILO (VILO) and Sensiscript (SS), aiming to understand their impact on biomarker detection rates. Prostate cancer cell lines were used to assess detection limits, followed by an investigation of biomarker status in clinical liquid biopsy samples of distinct tumor entities. Our findings highlight the superior reverse transcription efficacy of VILO over SS, commonly used in studies employing the AdnaTest platform. The enhanced efficacy of VILO results in a significantly higher number of patients positive for biomarkers. Clinically, the use of a less-sensitive enzyme system may lead to the misclassification of genuinely biomarker-positive patients, potentially altering their prognosis due to inadequate clinical monitoring or inappropriate treatment strategies.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 10","pages":"Article 102142"},"PeriodicalIF":5.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Keratins 8 and 18 Genetic Variants on the Severity of Alcoholic Liver Disease","authors":"Matthieu Tihy ,&nbsp;Nathalie Lin-Marq ,&nbsp;Thierry Berney ,&nbsp;Laurent Spahr ,&nbsp;Laura Rubbia-Brandt ,&nbsp;Laure Elkrief","doi":"10.1016/j.labinv.2024.102133","DOIUrl":"10.1016/j.labinv.2024.102133","url":null,"abstract":"<div><div>Alcohol-related liver disease (ALD) affects ∼30% of heavy drinkers and is characterized by liver steatosis, fibrosis, and steatohepatitis. The aggregation of keratins 8 (KRT8) and 18 (KRT18) plays a key role in the formation of Mallory–Denk bodies, a hallmark of ALD. Circulating levels of KRT18 fragments are elevated during ALD, and several <em>KRT8/18</em> genetic variants have been linked to an increased risk of liver disease. In this study, we explored the relationship between the histologic features of ALD and genetic variants of <em>KRT8/18</em> in 106 severe patients with ALD from the Hôpitaux Universitaires de Genève. We found a significant over-representation of several <em>KRT8</em> (rs2070910, rs137898974, rs1065306) and <em>KRT18</em> (rs17120866, rs1492241) variants located in the noncoding regions of these genes. Increased circulating level of keratins 18 fragments were associated with rs17120866 and alcoholic hepatitis. The combination of several <em>KRT18</em> variants appeared associated with a poorer prognosis. These results highlight the possible role of <em>KRT18</em> variants in ALD.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 10","pages":"Article 102133"},"PeriodicalIF":5.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Tree Shrew Model of Parkinson Disease: A Cost-Effective Alternative to Nonhuman Primate Models","authors":"Hao Li ,&nbsp;Leyi Mei ,&nbsp;Xiupeng Nie ,&nbsp;Liping Wu ,&nbsp;Longbao Lv ,&nbsp;Xiaofeng Ren ,&nbsp;Jitong Yang ,&nbsp;Haonan Cao ,&nbsp;Jing Wu ,&nbsp;Yuhua Zhang ,&nbsp;Yingzhou Hu ,&nbsp;Wenchao Wang ,&nbsp;Christoph W. Turck ,&nbsp;Bingyin Shi ,&nbsp;Jiali Li ,&nbsp;Lin Xu ,&nbsp;Xintian Hu","doi":"10.1016/j.labinv.2024.102145","DOIUrl":"10.1016/j.labinv.2024.102145","url":null,"abstract":"<div><div>The surge in demand for experimental monkeys has led to a rapid increase in their costs. Consequently, there is a growing need for a cost-effective model of Parkinson disease (PD) that exhibits all core clinical and pathologic phenotypes. Evolutionarily, tree shrews (<em>Tupaia belangeri</em>) are closer to primates in comparison with rodents and could be an ideal species for modeling PD. To develop a tree shrew PD model, we used the 1-methyl-4-phenylpyridinium (MPP⁺), a metabolite derived from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, to induce lesions in dopaminergic neurons of the unilateral substantia nigra. The induced tree shrew model consistently exhibited and maintained all classic clinical manifestations of PD for a 5-month period. The symptoms included bradykinesia, rest tremor, and postural instability, and ∼50% individuals showed apomorphine-induced rotations, a classic phenotype of unilateral PD models. All these are closely resembled the ones observed in PD monkeys. Meanwhile, this model was also sensitive to L-dopa treatment in a dose-dependent manner, which suggested that the motor deficits are dopamine dependent. Immunostaining showed a significant loss of dopaminergic neurons (∼95%) in the lesioned substantia nigra, which is a crucial PD pathological marker. Moreover, a control group of nigral saline injection did not show any motor deficits and pathological changes. Cytomorphologic analysis revealed that the size of nigral dopaminergic neurons in tree shrews is much bigger than that of rodents and is close to that of macaques. The morphologic similarity may be an important structural basis for the manifestation of the highly similar phenotypes between monkey and tree shrew PD models. Collectively, in this study, we have successfully developed a PD model in a small animal species that faithfully recapitulated the classic clinical symptoms and key pathological indicators of PD monkeys, providing a novel and low-cost avenue for evaluation of PD treatments and underlying mechanisms.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"104 11","pages":"Article 102145"},"PeriodicalIF":5.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}