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Clinical Application of Optical Genome Mapping for Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-05-10 Yeeun Shim, Jieun Seo, Seung-Tae Lee, Jong Rak Choi, Young-Chul Choi, Saeam Shin, Hyung Jun Park
Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy that mainly affects skeletal muscle. FSHD1 accounts for 95% of all FSHD cases and can be diagnosed based on the pathogenic contraction of the D4Z4-repeat array on chromosome 4q35. Genetic diagnosis of FSHD1 is challenging because of the large size and repetitive nature of the D4Z4 region. We evaluated the clinical
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Determination of Clinically Acceptable Analytical Variation of Cardiac Troponin at Decision Thresholds Clin. Chem. (IF 9.3) Pub Date : 2024-05-07 John W Pickering, Peter Kavsak, Robert H Christenson, Richard W Troughton, Christopher J Pemberton, A Mark Richards, Laura Joyce, Martin P Than
Background Clinical decision-making for risk stratification for possible myocardial infarction (MI) uses high-sensitivity cardiac troponin (hs-cTn) thresholds that range from the limit of detection to several-fold higher than the upper reference limit (URL). To establish a minimum analytical variation standard, we can quantify the effect of variation on the population clinical measures of safety (sensitivity)
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Vitamin D: Analytical Advances, Clinical Impact, and Ongoing Debates on Health Perspectives Clin. Chem. (IF 9.3) Pub Date : 2024-05-07 Etienne Cavalier, Konstantinos Makris, Annemieke C Heijboer, Markus Herrmann, Jean-Claude Souberbielle
Background Vitamin D, acknowledged since the 1930s for its role in preventing rickets, gained additional prominence in relation to fragility fracture prevention in the late 1980s. From the early 2000s, connections between vitamin D deficiency and extra-skeletal pathologies emerged, alongside increased awareness of widespread deficits. This prompted crucial debates on optimal serum concentrations, expected
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Exploring Appropriate Reference Intervals and Clinical Decision Limits for Glucose-6-Phosphate Dehydrogenase Activity in Individuals From Guangzhou, China. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-05-03 Zhenyi Huang, Ziyan Li, Yating Li, Yunshan Cao, Suping Zhong, Jinlu Liu, Zhiqian Lin, Lijuan Lin, Yanping Fang, Jing Zeng, Zhaoying Su, Huibin Li, Jianfen Liang, Biqing Zhu, Zipei Lin, Yongxin Huang, Xuexi Yang, Lingxiao Jiang
Quantitative detection of glucose-6-phosphate dehydrogenase (G6PD) is commonly done to screen for G6PD deficiency. However, current reference intervals (RIs) of G6PD are unsuitable for evaluating G6PD-activity levels with local populations or associating G6PD variants with hemolysis risk to aid clinical decision-making. We explored appropriate RIs and clinical decision limits (CDLs) for G6PD activity
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Worldwide Increasing Use of Nonfasting Rather Than Fasting Lipid Profiles Clin. Chem. (IF 9.3) Pub Date : 2024-04-22 Anne Langsted, Børge G Nordestgaard
Background Historically, lipids and lipoproteins were measured in the fasting state for cardiovascular risk prediction; however, since 2009 use of nonfasting lipid profiles has increased substantially worldwide. For patients, nonfasting lipid profiles are convenient and avoid any risk of hypoglycemia. For laboratories, blood sampling in the morning and extra visits for patients who have not fasted
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Reliability of the DI-60 Digital Image Analyzer for Detecting Platelet Clumping and Obtaining Accurate Platelet Counts. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-04-19 Suhyeon Woo, Bohyun Kim, Nam Hun Heo, Min-Sun Kim, Young Ahn Yoon, Young-Jin Choi
Pseudothrombocytopenia caused by platelet clumping (PC) can lead to unnecessary platelet transfusions or underdiagnosis of hematologic neoplasms. To overcome these limitations, we assessed the capacity of the Sysmex DI-60 digital morphology analyzer (Sysmex, Kobe, Japan) for detecting PC and determining an accurate platelet count in the presence of PC. For this purpose, 135 samples with or without
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Microsatellite Instability Detection in Cancer: A Multiplex qPCR Approach that Obviates the Need for Matching Normal Samples Clin. Chem. (IF 9.3) Pub Date : 2024-04-06 Wei Chen, Yan Helen Yan, Blake Young, Alessandro Pinto, Qi Jiang, Nanjia Song, Adam Yaseen, Weijie Yao, David Yu Zhang, Jinny Xuemeng Zhang
Background Microsatellite instability (MSI) indicates DNA mismatch repair deficiency in certain types of cancer, such as colorectal cancer. The current gold standard technique, PCR–capillary electrophoresis (CE), requires matching normal samples and specialized instrumentation. We developed VarTrace, a rapid and low-cost quantitative PCR (qPCR) assay, to evaluate MSI using solely the tumor sample DNA
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Integration of an MC-80 Digital Image Analyzer With an Automated BC-6800Plus Hematology Analyzer Enables Accurate Platelet Counting in Samples With EDTA-Induced Pseudothrombocytopenia. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-04-04 Min-Kyung So, Jungwon Huh, Seunghwan Kim, Sholhui Park
EDTA-induced pseudothrombocytopenia (PTCP) during whole blood collection requires significant laboratory resources to obtain accurate results. We evaluated platelet-deaggregation function in EDTA-induced PTCP and platelet-clump flagging by the BC-6800Plus hematology analyzer using integrated digital image analysis.
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Biological Testing and Interpretation of Laboratory Results Associated with Detecting Newborns with Substance Exposure Clin. Chem. (IF 9.3) Pub Date : 2024-03-29 Gwendolyn A McMillin, Anna W Morad, Jessica M Boyd, Kamisha L Johnson-Davis, Torri D Metz, Marcela C Smid, Matthew D Krasowski
Background Substance use during pregnancy is common, as is biological testing that is intended to help identify prenatal exposures. However, there is no standardized requirement for biological testing with either maternal or newborn specimens, nor is there standardization related to when testing occurs, how frequently testing occurs, what specimen(s) to test, what substances to test for, or how to
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Interlaboratory Comparison of Antibody-Free LC-MS/MS Measurements of C-peptide and Insulin Clin. Chem. (IF 9.3) Pub Date : 2024-03-29 Annie Moradian, Elisha Goonatilleke, Tai-Tu Lin, Maya Hatten-Beck, Michelle Emrick, Athena A Schepmoes, Thomas L Fillmore, Michael J MacCoss, Salvatore Sechi, Kimia Sobhani, Randie Little, Kuanysh Kabytaev, Jennifer E van Eyk, Wei-Jun Qian, Andrew N Hoofnagle
Background The enhanced precision and selectivity of liquid chromatography–tandem mass spectrometry (LC-MS/MS) makes it an attractive alternative to certain clinical immunoassays. Easily transferrable work flows could help facilitate harmonization and ensure high-quality patient care. We aimed to evaluate the interlaboratory comparability of antibody-free multiplexed insulin and C-peptide LC-MS/MS
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A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency Clin. Chem. (IF 9.3) Pub Date : 2024-03-26 Fátima Marín, Júlia Canet-Hermida, Vanessa Bianchi, Jiil Chung, Katharina Wimmer, William Foulkes, Vanesa Pérez-Alonso, Nerea Domínguez-Pinilla, Constantino Sábado, Felisa Vázquez-Gómez, Antonio Molinés, Victoria Fioravantti, Estela Carrasco, Lucie Stengs, Melissa Edwards, Logine Negm, Anirban Das, Melyssa Aronson, Ángela Pastor, Daniel Rueda, Luis Ignacio González-Granado, Uri Tabori, Gabriel Capellá
Background Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for
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Metformin Suppresses Both PD-L1 Expression in Cancer Cells and Cancer-Induced PD-1 Expression in Immune Cells to Promote Antitumor Immunity. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-03-26 Su Hwan Park, Juheon Lee, Hye Jin Yun, Seok-Ho Kim, Jong-Ho Lee
Metformin, a drug prescribed for patients with type 2 diabetes, has potential efficacy in enhancing antitumor immunity; however, the detailed underlying mechanisms remain to be elucidated. Therefore, we aimed to identify the inhibitory molecular mechanisms of metformin on programmed death ligand 1 (PD-L1) expression in cancer cells and programmed death 1 (PD-1) expression in immune cells.
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Comprehensive Analysis of PKD1 and PKD2 by Long-Read Sequencing in Autosomal Dominant Polycystic Kidney Disease Clin. Chem. (IF 9.3) Pub Date : 2024-03-25 Dechao Xu, Aiping Mao, Libao Chen, Le Wu, Yiyi Ma, Changlin Mei
Background Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by heterogeneous variants in the PKD1 and PKD2 genes. Genetic analysis of PKD1 has been challenging due to homology with 6 PKD1 pseudogenes and high GC content. Methods A single-tube multiplex long-range-PCR and long-read sequencing-based assay termed “comprehensive analysis of ADPKD” (CAPKD) was developed and evaluated
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Prospective Investigation of Optical Genome Mapping for Prenatal Genetic Diagnosis Clin. Chem. (IF 9.3) Pub Date : 2024-03-22 Min Xie, Zhao-Jing Zheng, Ying Zhou, Yu-Xin Zhang, Qiong Li, Li-Yun Tian, Juan Cao, Yan-Ting Xu, Jie Ren, Qi Yu, Shan-Shan Wu, Shu Fang, Dan-Yan Zhuang, Juan Geng, Chang-Shui Chen, Hai-Bo Li
Background Optical genome mapping (OGM) is a novel assay for detecting structural variants (SVs) and has been retrospectively evaluated for its performance. However, its prospective evaluation in prenatal diagnosis remains unreported. This study aimed to prospectively assess the technical concordance of OGM with standard of care (SOC) testing in prenatal diagnosis. Methods A prospective cohort of 204
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External Quality Assessment on Molecular Tumor Profiling with Circulating Tumor DNA-Based Methodologies Routinely Used in Clinical Pathology within the COIN Consortium Clin. Chem. (IF 9.3) Pub Date : 2024-03-14 Paul van der Leest, Pim Rozendal, John Hinrichs, Carel J M van Noesel, Karen Zwaenepoel, Birgit Deiman, Cornelis J J Huijsmans, Ronald van Eijk, Ernst Jan M Speel, Rick J van Haastert, Marjolijn J L Ligtenberg, Ron H N van Schaik, Maurice P H M Jansen, Hendrikus J Dubbink, Wendy W de Leng, Mathie P G Leers, Menno Tamminga, Daan van den Broek, Léon C van Kempen, Ed Schuuring
Background Identification of tumor-derived variants in circulating tumor DNA (ctDNA) has potential as a sensitive and reliable surrogate for tumor tissue-based routine diagnostic testing. However, variations in pre(analytical) procedures affect the efficiency of ctDNA recovery. Here, an external quality assessment (EQA) was performed to determine the performance of ctDNA mutation detection work flows
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Plasma Biomarker Profiles for Premature and Nonpremature Coronary Heart Disease in Women Clin. Chem. (IF 9.3) Pub Date : 2024-03-13 Sagar B Dugani, M Vinayaga Moorthy, Olga V Demler, Chunying Li, Paul M Ridker, Robert J Glynn, Samia Mora
Background Premature coronary heart disease (CHD) is a major cause of death in women. We aimed to characterize biomarker profiles of women who developed CHD before and after age 65 years. Methods In the Women’s Health Study (median follow-up 21.5 years), women were grouped by age and timing of incident CHD: baseline age <65 years with premature CHD by age 65 years (25 042 women; 447 events) and baseline
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TSHR Variant Screening and Phenotype Analysis in 367 Chinese Patients With Congenital Hypothyroidism. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-03-04 Hai-Yang Zhang, Feng-Yao Wu, Xue-Song Li, Ping-Hui Tu, Cao-Xu Zhang, Rui-Meng Yang, Ren-Jie Cui, Chen-Yang Wu, Ya Fang, Liu Yang, Huai-Dong Song, Shuang-Xia Zhao
Genetic defects in the human thyroid-stimulating hormone (TSH) receptor (TSHR) gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype-phenotype relationships for most TSHR variants associated with CH remain unexplored. We aimed to identify TSHR variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships
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Comparison of Optical Genome Mapping With Conventional Diagnostic Methods for Structural Variant Detection in Hematologic Malignancies. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-03-04 Yeeun Shim, Yu-Kyung Koo, Saeam Shin, Seung-Tae Lee, Kyung-A Lee, Jong Rak Choi
Structural variants (SVs) are currently analyzed using a combination of conventional methods; however, this approach has limitations. Optical genome mapping (OGM), an emerging technology for detecting SVs using a single-molecule strategy, has the potential to replace conventional methods. We compared OGM with conventional diagnostic methods for detecting SVs in various hematologic malignancies.
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Clonal Distribution and Its Association With the Carbapenem Resistance Mechanisms of Carbapenem-Non-Susceptible Pseudomonas aeruginosa Isolates From Korean Hospitals. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-03-04 Nayeong Kim, Seo Yeon Ko, Seong Yong Park, Seong Yeob Kim, Da Eun Lee, Ki Tae Kwon, Yu Kyung Kim, Je Chul Lee
Carbapenem resistance in Pseudomonas aeruginosa is a serious global health problem. We investigated the clonal distribution and its association with the carbapenem resistance mechanisms of carbapenem-non-susceptible P. aeruginosa isolates from three Korean hospitals.
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Effects of AFQ056 on language learning in fragile X syndrome J. Clin. Invest. (IF 15.9) Pub Date : 2023 Elizabeth Berry-Kravis, Leonard Abbeduto, Randi Hagerman, Christopher S. Coffey, Merit Cudkowicz, Craig A. Erickson, Andrea McDuffie, David Hessl, Lauren Ethridge, Flora Tassone, Walter E. Kaufmann, Katherine Friedmann, Lauren Bullard, Anne Hoffmann, Jeremy Veenstra-VanderWeele, Kevin Staley, David Klements, Michael Moshinsky, Brittney Harkey, Jeff Long, Janel Fedler, Elizabeth Klingner, Dixie Ecklund
BACKGROUND. FXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old
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Inaccurately Reported Statin Use Affects the Assessing of Lipid Profile Measures and Their Association with Coronary Artery Disease Risk Clin. Chem. (IF 9.3) Pub Date : 2024-03-02 Anna A Ivanova, Michael S Gardner, Jennifer D Kusovschi, Bryan A Parks, David M Schieltz, Akshay Bareja, Robert W McGarrah, William E Kraus, Zsuzsanna Kuklenyik, James L Pirkle, John R Barr
Background Lipid profiling is central for coronary artery disease (CAD) risk assessment. Nonadherence or unreported use of lipid-lowering drugs, particularly statins, can significantly complicate the association between lipid profile measures and CAD clinical outcomes. By combining medication history evaluation with statin analysis in plasma, we determined the effects of inaccurately reported statin
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Applying Machine Learning to Blood Count Data Predicts Sepsis with ICU Admission Clin. Chem. (IF 9.3) Pub Date : 2024-03-02 Daniel Steinbach, Paul C Ahrens, Maria Schmidt, Martin Federbusch, Lara Heuft, Christoph Lübbert, Matthias Nauck, Matthias Gründling, Berend Isermann, Sebastian Gibb, Thorsten Kaiser
Background Timely diagnosis is crucial for sepsis treatment. Current machine learning (ML) models suffer from high complexity and limited applicability. We therefore created an ML model using only complete blood count (CBC) diagnostics. Methods We collected non-intensive care unit (non-ICU) data from a German tertiary care centre (January 2014 to December 2021). Using patient age, sex, and CBC parameters
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Exposure to Synthetic Psychoactive Substances: A Potential Cause for Increased Human Hepatotoxicity Markers Clin. Chem. (IF 9.3) Pub Date : 2024-03-01 Aurora Balloni, Anastasio Tini, Emilia Prospero, Francesco Paolo Busardò, Marilyn Ann Huestis, Alfredo Fabrizio Lo Faro
Background Approximately 30 million people worldwide consume new psychoactive substances (NPS), creating a serious public health issue due to their toxicity and potency. Drug-induced liver injury is the leading cause of liver disease, responsible for 4% of global deaths each year. Content A systematic literature search revealed 64 case reports, in vitro and in vivo studies on NPS hepatotoxicity. Maximum
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Analytical Performance Specifications for Input Variables: Investigation of the Model of End-Stage Liver Disease Clin. Chem. (IF 9.3) Pub Date : 2024-02-28 Eline S Andersen, Richard Röttger, Claus L Brasen, Ivan Brandslund
Background Artificial intelligence models constitute specific uses of analysis results and, therefore, necessitate evaluation of analytical performance specifications (APS) for this context specifically. The Model of End-stage Liver Disease (MELD) is a clinical prediction model based on measurements of bilirubin, creatinine, and the international normalized ratio (INR). This study evaluates the propagation
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Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer Clin. Chem. (IF 9.3) Pub Date : 2024-02-28 Xinmin Zhao, Xin Zhang, Hanlin Chen, Hairong Bao, Xianghua Wu, Huijie Wang, Hua Bao, Jiaohui Pang, Sha Wang, Jialei Wang
Background ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits. Methods 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma
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Adjustment for Renal Function Improves the Prognostic Performance of Urinary Thromboxane Metabolites Clin. Chem. (IF 9.3) Pub Date : 2024-02-28 Bruce A Barton, Shari S Kronsberg, Essa Hariri, Ramachandran S Vasan, Grace A Rade, Vanessa Xanthakis, Thomas S Kickler, Jeffrey J Rade
Background Systemic thromboxane A2 generation, assessed by quantifying the concentration of stable thromboxane B2 metabolites (TXB2-M) in the urine adjusted for urinary creatinine, is strongly associated with mortality risk. We sought to define optimal TXB2-M cutpoints for aspirin users and nonusers and determine if adjusting TXB2-M for estimated glomerular filtration rate (eGFR) in addition to urinary
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Investigating the Current Harmonization Status of Tumor Markers Using Global External Quality Assessment Programs: A Feasibility Study Clin. Chem. (IF 9.3) Pub Date : 2024-02-22 Huub H van Rossum, Stefan Holdenrieder, Bart E P B Ballieux, Tony C Badrick, Yeo-Min Yun, Chuanbao Zhang, Dina Patel, Marc Thelen, Junghan Song, Nathalie Wojtalewicz, Nick Unsworth, Hubert W Vesper, Wei Cui, Lakshmi V Ramanathan, Catharine Sturgeon, Qing H Meng
Background The harmonization status of most tumor markers (TMs) is unknown. We report a feasibility study performed to determine whether external quality assessment (EQA) programs can be used to obtain insights into the current harmonization status of the tumor markers α-fetoprotein (AFP), prostate specific antigen (PSA), carcinoembryonic antigen (CEA), cancer antigen (CA)125, CA15-3 and CA19-9. Methods
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Guide to Rho(D) Immune Globulin in Women With Molecularly Defined Asian-type DEL (c.1227G>A). Ann. Lab. Med. (IF 4.9) Pub Date : 2024-02-22 In Hwa Jeong, SooHo Yu, Tae Yeul Kim, Soo-Young Oh, Duck Cho
Rh hemolytic disease of the fetus and newborn is a potential risk for D-negative mothers who produce anti-D during pregnancy, which can lead to morbidity and mortality in subsequent pregnancies. To prevent this hemolytic disease, Rho(D) immune globulin (RhIG) is generally administered to D-negative mothers without anti-D at 28 weeks of gestation and shortly after delivery. However, current guidelines
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Evaluating the TaqMan Jra-Genotyping Method for Rapidly Predicting the Presence of Anti-Jra Antibodies. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-02-20 Yu-Kyung Koo, Soon Sung Kwon, Eun Jung Suh, Na Hyeong Kim, Hyun Kyung Kim, Youn Keong Cho, Seung Jun Choi, Sinyoung Kim, Kyung-A Lee
The Jra antigen is a high-prevalence red blood cell (RBC) antigen. Reports on cases of fatal hemolytic disease of the fetus and newborn and acute hemolytic transfusion reactions suggest that antibodies against Jra (anti-Jra) have potential clinical significance. Identifying anti-Jra is challenging owing to a lack of commercially available antisera. We developed an alternative approach to rapidly predict
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Educational Outcomes and Perception Changes in Medical Students After Visiting a Blood Donation Center. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-02-20 Junseo Lee, Seryeong Kim, Sun Young Jeong, Seug Yun Yoon, Namsu Lee, Jong-Ho Won, Jeong Won Shin, Soon Hyo Kwon, Min-Young Lee, Kyoung Ha Kim
Educating primary care physicians about blood donation and transfusion is critical. The Division of Hematology and Oncology at Soonchunhyang University Seoul Hospital in Korea introduced an on-site educational program termed the Blood Donation Center Visiting Program in the clerkship education for final-year medical students. We evaluated the educational outcomes and changes in perception among medical
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CTRP4/interleukin-6 receptor signaling ameliorates autoimmune encephalomyelitis by suppressing Th17 cell differentiation J. Clin. Invest. (IF 15.9) Pub Date : 2023 Lulu Cao, Jinhai Deng, Wei Chen, Minwei He, Ning Zhao, He Huang, Lu Ling, Qi Li, Xiaoxin Zhu, Lu Wang
C1q/TNF-related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrate that Th17 cell–associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4–/– mice compared
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AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments J. Clin. Invest. (IF 15.9) Pub Date : 2023 Wenrui Zhang, Lu Cao, Jian Yang, Shuai Zhang, Jianyi Zhao, Zhonggang Shi, Keman Liao, Haiwei Wang, Binghong Chen, Zhongrun Qian, Haoping Xu, Linshi Wu, Hua Liu, Hongxiang Wang, Chunhui Ma, Yongming Qiu, Jianwei Ge, Jiayi Chen, Yingying Lin
Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation–induced asparagine endopeptidase
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Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations J. Clin. Invest. (IF 15.9) Pub Date : 2023 Joseph H. Garcia, Erin A. Akins, Saket Jain, Kayla J. Wolf, Jason Zhang, Nikita Choudhary, Meeki Lad, Poojan Shukla, Jennifer Rios, Kyounghee Seo, Sabraj A. Gill, William H. Carson, Luis R. Carette, Allison C. Zheng, David R. Raleigh, Sanjay Kumar, Manish K. Aghi
While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site–directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations
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Biomarkers vs Machines: The Race to Predict Acute Kidney Injury Clin. Chem. (IF 9.3) Pub Date : 2024-02-01 Lama Ghazi, Kassem Farhat, Melanie P Hoenig, Thomas J S Durant, Joe M El-Khoury
Background Acute kidney injury (AKI) is a serious complication affecting up to 15% of hospitalized patients. Early diagnosis is critical to prevent irreversible kidney damage that could otherwise lead to significant morbidity and mortality. However, AKI is a clinically silent syndrome, and current detection primarily relies on measuring a rise in serum creatinine, an imperfect marker that can be slow
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Circulating Cell-Free SHOX2 DNA Methylation Is a Predictive, Prognostic, and Monitoring Biomarker in Adjuvant and Palliative Anti-PD-1-Treated Melanoma Clin. Chem. (IF 9.3) Pub Date : 2024-02-01 Simon Fietz, Eric Diekmann, Luka de Vos, Romina Zarbl, Alina Hunecke, Ann-Kathrin Glosch, Moritz Färber, Judith Sirokay, Friederike Hoffmann, Anne Fröhlich, Alina Franzen, Sebastian Strieth, Jennifer Landsberg, Dimo Dietrich
Background The majority of metastatic melanoma patients initially do not respond or acquire resistance to anti-programmed cell death 1 (PD-1) immunotherapy. Liquid biopsy biomarkers might provide useful early response information and allow for personalized treatment decisions. Methods We prospectively assessed circulating cell-free SHOX2 DNA methylation (SHOX2 ccfDNAm) levels and their dynamic changes
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A Retrospective Study of Factors Contributing to the Performance of an Interferon-Gamma Release Assay Blood Test for Tuberculosis Infection Clin. Chem. (IF 9.3) Pub Date : 2024-02-01 Junhyup Song, Sinyoung Kim, Younhee Park
Background Tuberculosis (TB) remains a significant global health concern. Accurate detection of latent TB infection is crucial for effective control and prevention. We aimed to assess the performance of an interferon-gamma release assay blood test (QuantiFERON-TB Gold Plus [QFT-Plus]) in various clinical contexts and identify conditions that affect its results. Methods We conducted a retrospective
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Comparative Analysis of AB vs. ABO-specific Plasma for Desensitization in Blood Group O Recipients: An In Vitro Study. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-01-19 Young Ae Lim
Neutralizing capacity measurement (NCM) of soluble ABH substances (SAS) in plasma was assessed to guide the selection of the appropriate ABO group of fresh-frozen plasma (FFP) for plasma exchange (PE) in blood group O recipients with ABO-incompatible transplantations. Neutralizing capacity was assessed by measuring anti-A and/or anti-B titers in samples comprising one unit of O FFP and 10 O EDTA plasma
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Comparison of Measurable Residual Disease in Pediatric B-Lymphoblastic Leukemia Using Multiparametric Flow Cytometry and Next-Generation Sequencing. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-01-19 Sang Mee Hwang, Inseong Oh, Seok Ryun Kwon, Jee-Soo Lee, Moon-Woo Seong
Measurable residual disease (MRD) testing, a standard procedure in B-lymphoblastic leukemia (B-ALL) diagnostics, is assessed using multiparametric flow cytometry (MFC) and next-generation sequencing (NGS) analysis of immunoglobulin gene rearrangements. We evaluated the concordance between eight-color, two-tube MFC-MRD the LymphoTrack NGS-MRD assays using 139 follow-up samples from 54 pediatric patients
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Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice J. Clin. Invest. (IF 15.9) Pub Date : 2023 Milagros C. Romay, Russell H. Knutsen, Feiyang Ma, Ana Mompeón, Gloria E. Hernandez, Jocelynda Salvador, Snezana Mirkov, Ayush Batra, David P. Sullivan, Daniele Procissi, Samuel Buchanan, Elise Kronquist, Elisa A. Ferrante, William A. Muller, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Craig Horbinski, Elisabeth Tournier‑Lasserve, Adam M. Sonabend, Farzaneh A. Sorond, Michael M. Wang, Manfred
Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences
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Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells J. Clin. Invest. (IF 15.9) Pub Date : 2023 Livia de Souza Goncalves, Tifany Chu, Riya Master, Parth D. Chhetri, Qi Gao, Onur Cil
Cholera is a global health problem with no targeted therapies. The Ca2+-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca2+ is considered its main agonist. We found that increasing extracellular Ca2+ had a minimal effect on forskolin-induced Cl– secretion in human intestinal epithelial T84 cells. However, extracellular Mg2+, an often-neglected
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A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III J. Clin. Invest. (IF 15.9) Pub Date : 2023 Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, Romain Launay, Mallaury Vie, Youssef Krimi Benchekroun, Jérémie Cosette, Bérangère Bertin, Tiziana La Bella, Guillaume Dubreuil, Justine Nozi, Louisa Jauze, Romain Fragnoud, Nathalie Daniele, Laetitia Van Wittenberghe, Jérémy Esque, Isabelle André, Xavier Nissan, Lucile Hoch, Giuseppe Ronzitti
Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus–derived (rAAV-derived)
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Impaired glycine neurotransmission causes adolescent idiopathic scoliosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Xiaolu Wang, Ming Yue, Jason Pui Yin Cheung, Prudence Wing Hang Cheung, Yanhui Fan, Meicheng Wu, Xiaojun Wang, Sen Zhao, Anas M. Khanshour, Jonathan J. Rios, Zheyi Chen, Xiwei Wang, Wenwei Tu, Danny Chan, Qiuju Yuan, Dajiang Qin, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Shiro Ikegawa, Nan Wu, Carol A. Wise, Yong Hu, Keith Dip Kei Luk, You-Qiang Song, Bo Gao
Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. Because of this, treatment of AIS is limited to bracing and/or invasive surgery after onset. Preonset diagnosis or preventive treatment remains unavailable. Here, we performed a genetic analysis of a large multicenter AIS
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Chronic graft-versus-host disease detected by tissue-specific cell-free DNA methylation biomarkers J. Clin. Invest. (IF 15.9) Pub Date : 2023 Batia Avni, Daniel Neiman, Elior Shaked, Ofer Gal-Rosenberg, Sigal Grisariu, Mona Kuzli, Ilai Avni, Andrea Fracchia, Polina Stepensky, Tsila Zuckerman, Ahinoam Lev-Sagie, Ilana Fox-Fisher, Sheina Piyanzin, Joshua Moss, Seth J. Salpeter, Benjamin Glaser, Ruth Shemer, Yuval Dor
BACKGROUND. Accurate detection of graft-versus-host disease (GVHD) is a major challenge in the management of patients undergoing hematopoietic stem cell transplantation (HCT). Here, we demonstrated the use of circulating cell-free DNA (cfDNA) for detection of tissue turnover and chronic GVHD (cGVHD) in specific organs.
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Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders J. Clin. Invest. (IF 15.9) Pub Date : 2023 Huilun H. Wang, Liangguang L. Lin, Zexin J. Li, Xiaoqiong Wei, Omar Askander, Gerarda Cappuccio, Mais O. Hashem, Laurence Hubert, Arnold Munnich, Mashael Alqahtani, Qi Pang, Margit Burmeister, You Lu, Karine Poirier, Claude Besmond, Shengyi Sun, Nicola Brunetti-Pierri, Fowzan S. Alkuraya, Ling Qi
Recent studies using cell type–specific knockout mouse models have improved our understanding of the pathophysiological relevance of suppressor of lin-12-like–HMG-CoA reductase degradation 1 (SEL1L-HRD1) endoplasmic reticulum–associated (ER-associated) degradation (ERAD); however, its importance in humans remains unclear, as no disease variant has been identified. Here, we report the identification
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Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death J. Clin. Invest. (IF 15.9) Pub Date : 2023 Denisa Weis, Liangguang L. Lin, Huilun H. Wang, Zexin Jason Li, Katarina Kusikova, Peter Ciznar, Hermann M. Wolf, Alexander Leiss-Piller, Zhihong Wang, Xiaoqiong Wei, Serge Weis, Katarina Skalicka, Gabriela Hrckova, Lubos Danisovic, Andrea Soltysova, Tingxuan T. Yang, René Günther Feichtinger, Johannes A. Mayr, Ling Qi
Suppressor of lin-12-like–HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients
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Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation J. Clin. Invest. (IF 15.9) Pub Date : 2023 Magnus T. Dillon, Jeane Guevara, Kabir Mohammed, Emmanuel C. Patin, Simon A. Smith, Emma Dean, Gemma N. Jones, Sophie E. Willis, Marcella Petrone, Carlos Silva, Khin Thway, Catey Bunce, Ioannis Roxanis, Pablo Nenclares, Anna Wilkins, Martin McLaughlin, Adoracion Jayme-Laiche, Sarah Benafif, Georgios Nintos, Vineet Kwatra, Lorna Grove, David Mansfield, Paula Proszek, Philip Martin, Luiza Moore, Karen
BACKGROUND. Phase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.
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Galectin-3 aggravates microglial activation and tau transmission in tauopathy J. Clin. Invest. (IF 15.9) Pub Date : 2023 Jian Jing Siew, Hui-Mei Chen, Feng-Lan Chiu, Chia-Wei Lee, Yao-Ming Chang, Hung-Lin Chen, Thi Ngoc Anh Nguyen, Hung-Ting Liao, Mengyu Liu, Hsiao-Tien Hagar, Yung-Chen Sun, Hsing-Lin Lai, Min-Hao Kuo, David Blum, Luc Buée, Lee-Way Jin, Shih-Yu Chen, Tai-Ming Ko, Jie-Rong Huang, Hung-Chih Kuo, Fu-Tong Liu, Yijuang Chern
Alzheimer’s disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside–binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered
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Interactions among insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts J. Clin. Invest. (IF 15.9) Pub Date : 2023 Nida Haider, C. Ronald Kahn
About 25% of people in the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of induced pluripotent stem cells differentiated into myoblasts (iMyos) from insulin-resistant (I-Res) versus insulin-sensitive (I-Sen) nondiabetic individuals revealed that 306 genes increased and 271 genes decreased in expression in iMyos
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The pan-microbiome profiling system Taxa4Meta identifies clinical dysbiotic features and classifies diarrheal disease J. Clin. Invest. (IF 15.9) Pub Date : 2023 Qinglong Wu, Shyam Badu, Sik Yu So, Todd J. Treangen, Tor C. Savidge
Targeted metagenomic sequencing is an emerging strategy to survey disease-specific microbiome biomarkers for clinical diagnosis and prognosis. However, this approach often yields inconsistent or conflicting results owing to inadequate study power and sequencing bias. We introduce Taxa4Meta, a bioinformatics pipeline explicitly designed to compensate for technical and demographic bias. We designed and
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Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring J. Clin. Invest. (IF 15.9) Pub Date : 2023 Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H. Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud
Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can
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Truncated titin protein in dilated cardiomyopathy incorporates into the sarcomere and transmits force J. Clin. Invest. (IF 15.9) Pub Date : 2023 Quentin McAfee, Matthew A. Caporizzo, Keita Uchida, Kenneth C. Bedi Jr., Kenneth B. Margulies, Zolt Arany, Benjamin L. Prosser
TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance J. Travis Hinson, Stuart G. Campbell J. Travis Hinson, Stuart G. Campbell Commentary
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Clinical Practice Guideline for Blood-Based Circulating Tumor DNA Assays. Ann. Lab. Med. (IF 4.9) Pub Date : 2024-01-15 Jee-Soo Lee, Eun Hye Cho, Boram Kim, Jinyoung Hong, Young-Gon Kim, Yoonjung Kim, Ja-Hyun Jang, Seung-Tae Lee, Sun-Young Kong, Woochang Lee, Saeam Shin, Eun Young Song
Circulating tumor DNA (ctDNA) has emerged as a promising tool for various clinical applications, including early diagnosis, therapeutic target identification, treatment response monitoring, prognosis evaluation, and minimal residual disease detection. Consequently, ctDNA assays have been incorporated into clinical practice. In this review, we offer an in-depth exploration of the clinical implementation
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High-Sensitivity Cardiac Troponin and the Management of Congenital Heart Disease in Newborns and Infants Clin. Chem. (IF 9.3) Pub Date : 2024-01-05 Simona Ferraro, Elia Biganzoli, Savina Mannarino, Monica Lanzoni, Gianvincenzo Zuccotti, Mario Plebani, Peter Kavsak
Background Early cardiac interventions in newborns and infants suspected for congenital heart disease (CHD) decrease morbidity and mortality. After updating current evidence on the use of cardiac troponins (cTn) in the context of CHD for risk stratification at early ages, we discuss relevant issues, starting from the evidence that only the measurement of the cTnT form is useful in this population.
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Detection of Multiple HPV Types in Liquid Biopsies of Cervical Neoplasia Clin. Chem. (IF 9.3) Pub Date : 2024-01-04 Johanna Herbst, Vanessa Vohl, Maroje Krajina, Markus Leffers, Jolanthe Kropidlowski, Katharina Prieske, Anna Jaeger, Leticia Oliveira Ferrer, Barbara Schmalfeldt, Yvonne Goy, Eike Burandt, Klaus Pantel, Caren Vollmert, Alexander Sartori, Linn Woelber, Katharina Effenberger, Harriet Wikman
Background More than 95% of cervical cancers and their precancerous lesions are caused by human papillomavirus (HPV). Cell-free (cf) HPV DNA detection in blood samples may serve as a monitoring tool for cervical cancer. Methods In our methodological study, an HPV panel for simultaneous detection of 24 types using mass spectrometry-based analysis was developed for liquid biopsy approaches and tested
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Critical Factors in the Analytical Work Flow of Circulating Tumor DNA-Based Molecular Profiling Clin. Chem. (IF 9.3) Pub Date : 2024-01-04 Paul van der Leest, Ed Schuuring
Background Liquid biopsy testing, especially molecular tumor profiling of circulating tumor DNA (ctDNA) in cell-free plasma, has received increasing interest in recent years as it serves as a reliable alternative for the detection of tumor-specific aberrations to guide treatment decision-making in oncology. Many (commercially available) applications have been developed, however, broad divergences in
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Circulating Tumor Cells: From Basic to Translational Research Clin. Chem. (IF 9.3) Pub Date : 2024-01-04 Luis Enrique Cortés-Hernández, Zahra Eslami-S, Klaus Pantel, Catherine Alix-Panabières
Background Metastasis is the leading cause of cancer-related deaths. Most studies have focused on the primary tumor or on overt metastatic lesions, leaving a significant knowledge gap concerning blood-borne cancer cell dissemination, a major step in the metastatic cascade. Circulating tumor cells (CTCs) in the blood of patients with solid cancer can now be enumerated and investigated at the molecular
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Meta-Analysis of Circulating Tumor Cell PD-L1 Expression and the Association with Clinical Outcomes in Non-Small Cell Lung Cancer Clin. Chem. (IF 9.3) Pub Date : 2024-01-04 Emmanuel Acheampong, Rebecca C Allsopp, Karen Page, Marc K Wadsley, Aaron B Beasley, R Charles Coombes, Jacqui A Shaw, Elin S Gray
Background Programmed death ligand-1 (PD-L1) expression on circulating tumor cells (CTCs) has been suggested to provide prognostic information in non-small cell lung cancer (NSCLC), but consensus relative to treatment outcomes is lacking. We conducted the first comprehensive meta-analysis exploring its potential as a prognostic and predictive marker, and assessed the concordance between PD-L1 + CTCs
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Deciphering the Exact Sequence of Endogenous Soluble B Cell Maturation Antigen and Unbiased Quantitation in Multiple Myeloma Patient Samples by LC-MS Clin. Chem. (IF 9.3) Pub Date : 2024-01-04 Xiaomeng Shen, Xue Dong, Jianxia Shi, Hao Chen, Yun Lan, Ai Ching Lim, Fang Xie, Agnes Ang, Andrea Kratzer, Dan A Rock, Brooke M Rock
Background B-cell maturation antigen is a pivotal therapeutic target for multiple myeloma (MM). Membrane-bound BCMA can be cleaved by γ-secretase and shed as soluble BCMA (sBCMA). sBCMA can act as a neutralizing sink to compete with drug, as well as serve as a diagnostic/prognostic biomarker for MM. Antibody-capture based methods, such as enzyme-linked immunosorbent assay (ELISA) and immunoaffinity-liquid
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A Practical Approach to Interpreting Circulating Tumor DNA in the Management of Gastrointestinal Cancers Clin. Chem. (IF 9.3) Pub Date : 2024-01-04 Zexi Allan, David S Liu, Margaret M Lee, Jeanne Tie, Nicholas J Clemons
Background There is accumulating evidence supporting the clinical use of circulating tumor DNA (ctDNA) in solid tumors, especially in different types of gastrointestinal cancer. As such, appraisal of the current and potential clinical utility of ctDNA is needed to guide clinicians in decision-making to facilitate its general applicability. Content In this review, we firstly discuss considerations surrounding
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Contributions of the Microbiome-Derived Metabolome for Risk Assessment and Prognostication of Pancreatic Cancer Clin. Chem. (IF 9.3) Pub Date : 2024-01-04 Ricardo A León-Letelier, Rongzhang Dou, Jody Vykoukal, Michele T Yip-Schneider, Anirban Maitra, Ehsan Irajizad, Ranran Wu, Jennifer B Dennison, Kim-An Do, Jianjun Zhang, C Max Schmidt, Samir Hanash, Johannes F Fahrmann
Background Increasing evidence implicates microbiome involvement in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Studies suggest that reflux of gut or oral microbiota can lead to colonization in the pancreas, resulting in dysbiosis that culminates in release of microbial toxins and metabolites that potentiate an inflammatory response and increase susceptibility to PDAC