Journal of Molecular Diagnostics最新文献

{"title":"Improving Specificity for Ovarian Cancer Screening Using a Novel Extracellular Vesicle-Based Blood Test: Performance in a Training and Verification Cohort.","authors":"Emily S Winn-Deen, Laura T Bortolin, Daniel Gusenleitner, Kelly M Biette, Karen Copeland, Aleksandra Gentry-Maharaj, Sophia Apostolidou, Anthony D Couvillon, Daniel P Salem, Sanchari Banerjee, Jonian Grosha, Ibukunoluwapo O Zabroski, Christopher R Sedlak, Delaney M Byrne, Bilal F Hamzeh, MacKenzie S King, Lauren T Cuoco, Peter A Duff, Brendan J Manning, Troy B Hawkins, Dawn Mattoon, Toumy Guettouche, Steven J Skates, Amy Jamieson, Jessica N McAlpine, David Huntsman, Usha Menon","doi":"10.1016/j.jmoldx.2024.09.001","DOIUrl":"10.1016/j.jmoldx.2024.09.001","url":null,"abstract":"<p><p>The low incidence of ovarian cancer (OC) dictates that any screening strategy needs to be both highly sensitive and highly specific. This study explored the utility of detecting multiple colocalized proteins or glycosylation epitopes on single tumor-associated extracellular vesicles from blood. The novel Mercy Halo Ovarian Cancer Test (OC Test) uses immunoaffinity capture of tumor-associated extracellular vesicles, followed by proximity-ligation real-time quantitative PCR to detect combinations of up to three biomarkers to maximize specificity and measures multiple combinations to maximize sensitivity. A high-grade serous carcinoma (HGSC) case-control training set of EDTA plasma samples from 397 women was used to lock down the test design, the data interpretation algorithm, and the cutoff between cancer and noncancer. Performance was verified and compared with cancer antigen 125 in an independent blinded case-control set of serum samples from 390 women (132 controls, 66 HGSC, 83 non-HGSC OC, and 109 benign). In the verification study, the OC Test showed a specificity of 97.0% (128/132; 95% CI, 92.4%-99.6%), a HGSC sensitivity of 97.0% (64/66; 95% CI, 87.8%-99.2%), and an area under the curve of 0.97 (95% CI, 0.93-0.99) and detected 73.5% (61/83; 95% CI, 62.7%-82.6%) of the non-HGSC OC cases. This test exhibited fewer false positives in subjects with benign ovarian tumors, nonovarian cancers, and inflammatory conditions when compared with cancer antigen 125. The combined sensitivity and specificity of this new test suggests it may have potential in OC screening.</p>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colocalization of Cancer-Associated Biomarkers on Single Extracellular Vesicles for Early Detection of Cancer.","authors":"Daniel P Salem, Laura T Bortolin, Dan Gusenleitner, Jonian Grosha, Ibukunoluwapo O Zabroski, Kelly M Biette, Sanchari Banerjee, Christopher R Sedlak, Delaney M Byrne, Bilal F Hamzeh, MacKenzie S King, Lauren T Cuoco, Timothy Santos-Heiman, Gabrielle N Barcaskey, Katherine S Yang, Peter A Duff, Emily S Winn-Deen, Toumy Guettouche, Dawn R Mattoon, Eric K Huang, Randy W Schekman, Anthony D Couvillon, Joseph C Sedlak","doi":"10.1016/j.jmoldx.2024.08.006","DOIUrl":"10.1016/j.jmoldx.2024.08.006","url":null,"abstract":"<p><p>Detection of cancer early, when it is most treatable, remains a significant challenge because of the lack of diagnostic methods sufficiently sensitive to detect nascent tumors. Early-stage tumors are small relative to their tissue of origin, heterogeneous, and infrequently manifest in clinical symptoms. Detection of their presence is made more difficult by a lack of abundant tumor-specific indicators (ie, protein biomarkers, circulating tumor DNA) that would enable detection using a noninvasive diagnostic assay. To overcome these obstacles, we have developed a liquid biopsy assay that interrogates circulating extracellular vesicles (EVs) to detect tumor-specific biomarkers colocalized on the surface of individual EVs. We demonstrate the technical feasibility of this approach in human cancer cell line-derived EVs, where we show strong correlations between assay signal and cell line gene/protein expression for the ovarian cancer-associated biomarkers bone marrow stromal antigen-2, folate receptor-α, and mucin-1. Furthermore, we demonstrate that detecting distinct colocalized biomarkers on the surface of EVs significantly improves discrimination performance relative to single biomarker measurements. Using this approach, we observe promising discrimination of high-grade serous ovarian cancer versus benign ovarian masses and healthy women in a proof-of-concept clinical study.</p>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Versatile and Upgraded Version of the LundTax Classification Algorithm Applied to Independent Cohorts.","authors":"Elena Aramendía Cotillas, Carina Bernardo, Srinivas Veerla, Fredrik Liedberg, Gottfrid Sjödahl, Pontus Eriksson","doi":"10.1016/j.jmoldx.2024.08.005","DOIUrl":"10.1016/j.jmoldx.2024.08.005","url":null,"abstract":"<p><p>Stratification of cancer into biologically and molecularly similar subgroups is a cornerstone of precision medicine. The Lund Taxonomy classification system for urothelial carcinoma aims to be applicable across the whole disease spectrum including both non-muscle-invasive and invasive bladder cancer. A successful classification system is one that can be robustly and reproducibly applied to new samples. However, transcriptomic methods used for subtype classification are affected by analytic platform, data preprocessing, cohort composition, and tumor purity. Furthermore, only limited data have been published evaluating the transferability of existing classification algorithms to external data sets. In this study, a single sample classifier was developed based on in-house microarray and RNA-sequencing data, intended to be broadly applicable across studies and platforms. The new classification algorithm was applied to 10 published external bladder cancer cohorts (n = 2560 cases) to evaluate its ability to capture characteristic subtype-associated gene expression signatures and complementary data such as mutations, clinical outcomes, treatment response, or histologic subtypes. The effect of sample purity on the classification results was evaluated by generating low-purity versions of samples in silico. The classifier was robustly applicable across different gene expression profiling platforms and preprocessing methods and was less sensitive to variations in sample purity.</p>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Haplotype-Aware Detection of SERPINA1 Variants by Nanopore Sequencing","authors":"","doi":"10.1016/j.jmoldx.2024.08.002","DOIUrl":"10.1016/j.jmoldx.2024.08.002","url":null,"abstract":"<div><div>α-1 Antitrypsin (AAT) is an acute-phase reactant with immunomodulatory properties that mainly inhibits neutrophil elastase. Low serum levels cause AAT deficiency (AATD), an underdiagnosed condition that predisposes to pulmonary and hepatic diseases. The <em>SERPINA1</em> gene, which encodes AAT, contains &gt;500 variants. <em>PI∗Z</em> and <em>PI∗S</em> alleles are the most diagnosed causes of AATD, but the role of the <em>SERPINA1</em> haplotypes in AAT function remains unknown. <em>SERPINA1</em> gene was PCR amplified from 94 patients with asthma, using primers with tails for indexing. Sequencing libraries were loaded into a MinION-Mk1C, and MinKNOW was used for basecalling and demultiplexing. Nanofilt and Minimap2 were used for filtering and mapping/alignment. Variant calling/phasing were performed with PEPPER-Margin-DeepVariant. <em>SERPINA1</em> gene was 100% covered for all samples, with a minimum sequencing depth of 500×. A total of 75 single-nucleotide variants (SNVs) and 4 insertions/deletions were detected, with 45 and 2 of them highly polymorphic (minor allele frequency &gt;0.1), respectively. Nine of the SNVs showed differences in allele frequencies when compared with the overall Spanish population. More than 90% of heterozygous SNVs were phased, yielding 91 and 58 different haplotypes for each <em>SERPINA1</em> amplified region. Haplotype-based linkage disequilibrium analysis suggests that a recombination hotspot could generate variation in the <em>SERPINA1</em> gene. The proposed workflow enables haplotype-aware genotyping of the <em>SERPINA1</em> gene by nanopore sequencing, which will allow the development of novel AATD diagnostic strategies.</div></div>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Results from Two Commercially Available In-House Tissue-Based Comprehensive Genomic Profiling Solutions","authors":"","doi":"10.1016/j.jmoldx.2024.08.001","DOIUrl":"10.1016/j.jmoldx.2024.08.001","url":null,"abstract":"<div><div>Increased adoption of personalized medicine has brought comprehensive genomic profiling (CGP) to the forefront. However, differences in assay, bioinformatics, and reporting systems and lack of understanding of their complex interplay are a challenge for implementation and achieving uniformity in CGP testing. Two commercially available, tissue-based, in-house CGP assays were compared, in combination with a tertiary analysis solution in a research use only (RUO) context: the AVENIO Tumor Tissue CGP RUO Kit paired with navify Mutation Profiler (RUO) software and the TruSight Oncology 500 RUO assay paired with PierianDx Clinical Genomics Workspace software. Agreements and differences between the assays were assessed for short variants, copy number alterations, rearrangements, tumor mutational burden, and microsatellite instability, including variant categorization and clinical trial-matching (CTM) recommendations. Results showed good overall agreement for short variant, known gene fusion, and microsatellite instability detection. Important differences were obtained in tumor mutational burden scoring, copy number alteration detection, and CTM. Differences in variant and biomarker detection could be explained by bioinformatic approaches to variant calling, filtering, tiering, and normalization; differences in CTM, by underlying reported variants and conceptual differences in system parameters. Thus, distinctions between different approaches may lead to inconsistent results. Complexities in calling, filtering, and interpreting variants illustrate key considerations for implementation of any high-quality CGP in the laboratory and bringing uniformity to genomic insight results.</div></div>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical Validation of an Early Detection Pancreatic Cancer Test Using 5-Hydroxymethylation Signatures","authors":"","doi":"10.1016/j.jmoldx.2024.06.007","DOIUrl":"10.1016/j.jmoldx.2024.06.007","url":null,"abstract":"<div><p>Early detection of pancreatic cancer has been shown to improve patient survival rates. However, effective early detection tools to detect pancreatic cancer do not currently exist. The Avantect Pancreatic Cancer Test, leveraging the 5-hydroxymethylation [5-hydroxymethylcytosine (5hmC)] signatures in cell-free DNA, was developed and analytically validated to address this unmet need. We report a comprehensive analytical validation study encompassing precision, sample stability, limit of detection, interfering substance studies, and a comparison with an alternative method. The assay performance on an independent case-control patient cohort was previously reported with a sensitivity for early-stage (stage I/II) pancreatic cancer of 68.3% (95% CI, 51.9%–81.9%) and an overall specificity of 96.9% (95% CI, 96.1%–97.7%). Precision studies showed a cancer classification of 100% concordance in biological replicates. The sample stability studies revealed stable assay performance for up to 7 days after blood collection. The limit of detection studies revealed equal results between early- and late-stage cancer samples, emphasizing strong early-stage performance characteristics. Comparisons of concordance of the Avantect assay with the enzymatic methyl sequencing (EM-Seq) method, which measures both methylation (5-methylcytosine) and 5hmC, were &gt;95% for all samples tested. The Avantect Pancreatic Cancer Test showed strong analytical validation in multiple validation studies required for laboratory-developed test accreditation. The comparison of 5hmC versus EM-Seq further validated the 5hmC approach as a robust and reproducible assay.</p></div>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1525157824001582/pdfft?md5=adc6e94f71f3c1506c11dec2c7acce89&pid=1-s2.0-S1525157824001582-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tailored Digital PCR Follow-Up of Rare Fusion Transcripts after Initial Detection through RNA Sequencing in Hematological Malignancies","authors":"","doi":"10.1016/j.jmoldx.2024.07.004","DOIUrl":"10.1016/j.jmoldx.2024.07.004","url":null,"abstract":"<div><div>Minimal residual disease (MRD) monitoring plays a pivotal role in the management of hematologic malignancies. Well-established molecular targets, such as <em>PML</em>::<em>RARA, CBFB::MYH11</em>, or <em>RUNX1</em>::<em>RUNX1T1</em>, are conventionally tracked by quantitative RT-PCR. Recently, a broader landscape of fusion transcripts has been unveiled through transcriptomic analysis. These newly discovered fusion transcripts may emerge as novel molecular markers for MRD quantification. In this study, we compared a targeted RNA-sequencing (RNA-seq) approach (FusionPlex) with a whole-transcriptomic strategy (Advanta RNA-Seq XT) for fusion detection in a training set of 21 samples. We evidenced a concordance of 100% for the detection of known fusions, and showed a good correlation for gene expression quantification between the two techniques (Spearman <em>r</em> = 0.77). Additionally, we prospectively evaluated the identification of fusions by targeted RNA-seq in a real-life series of 126 patients with hematological malignancy. At least one fusion transcript was detected for 60 patients (48%). We designed tailored digital PCR assays for 11 rare fusions, and validated this technique for MRD quantification with a limit of detection of &lt;0.01%. The combination of RNA-seq and tailored digital PCR may become a new standard for MRD evaluation in patients lacking conventional molecular targets.</div></div>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype and Phenotype Correlation of the TPMT∗8 Allele in Thiopurine Metabolism","authors":"","doi":"10.1016/j.jmoldx.2024.07.005","DOIUrl":"10.1016/j.jmoldx.2024.07.005","url":null,"abstract":"<div><div>Thiopurine 6-mercaptopurine (6-MP) is metabolized by thiopurine methyl transferase (TPMT). <em>TPMT</em> genetic variation results in some individuals having reduced or absent TPMT enzyme activity. If these individuals take a full thiopurine dose, life-threatening adverse events can occur. Testing identifies patients with reduced or absent TPMT activity and is recommended before initiation of therapy. The <em>TPMT∗8</em> allele, defined by c.644G&gt;A (p.Arg215His), is common among individuals of African ancestry (approximately 2.3% minor allele frequency) but is not included in genotyping recommendations due to its uncertain function. Here, a clinical TPMT enzyme activity assay was used to assess <em>TPMT</em> activity in red blood cells from 982 patients, including those with <em>∗1/∗8</em> (<em>n</em> = 22), <em>∗3A/∗8</em> (<em>n</em> = 1), and <em>∗3C/∗8</em> (<em>n</em> = 1) <em>TPMT</em> diplotypes. The average production of 6-methylmercaptopurine (primary TPMT product measured clinically) was 3.08 ± 0.16 nmol/mL per hour for <em>∗1/∗8</em> individuals, compared with 3.77 ± 0.03 nmol/mL per hour for normal metabolizers (<em>P</em> = 0.0001) and 2.39 ± 0.06 nmol 6-methylmercaptopurine/mL per hour for intermediate metabolizers (<em>P</em> &lt; 0.0001). Individuals with a <em>TPMT∗1/∗8</em> diplotype displayed reduced 6-MP metabolism between that of normal metabolizers and intermediate metabolizers, suggesting that <em>TPMT∗8</em> is a reduced function allele.</div></div>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purity Independent Subtyping of Tumors (PurIST) Pancreatic Cancer Classifier","authors":"","doi":"10.1016/j.jmoldx.2024.07.002","DOIUrl":"10.1016/j.jmoldx.2024.07.002","url":null,"abstract":"<div><div>The two major molecular subtypes of pancreatic adenocarcinoma reportedly have differential response to FOLFIRINOX-based therapy. To promote rapid assignment of basal versus classical subtypes, an array-based single-sample classifier assay was developed and applied to 74 formalin-fixed, paraffin-embedded biopsy or resection specimens of known subtype based on transcriptomics. The Purity Independent Subtyping of Tumors (PurIST) algorithm assigns subtype based on relative expression of 16 RNAs counted by RNA sequencing (RNAseq) versus more practical array-based NanoString nCounter Elements XT technology. Subtype calls were largely concordant between RNAseq and array methods (72/74, 97% agreement). Compared with the lengthy RNAseq protocol, the array-based assay takes just 3 working days to analyze, permitting rapid reporting of tumor subtype. In conclusion, the PurIST pancreatic cancer classifier has robust performance to classify pancreatic adenocarcinoma into basal versus classical subtypes. Clinical validation studies are underway to evaluate outcome in patients whose standard-of-care chemotherapy regimen is selected on the basis of rapid subtype assignment (<span><span>NCT04683315</span><svg><path></path></svg></span>).</div></div>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance Characteristics of Next-Generation Sequencing–Based Engraftment Monitoring and Microchimerism Detection in Allogeneic Hematopoietic Cell Transplantation","authors":"","doi":"10.1016/j.jmoldx.2024.07.003","DOIUrl":"10.1016/j.jmoldx.2024.07.003","url":null,"abstract":"<div><div>Chimerism analysis by next-generation sequencing (NGS) is an emerging method for engraftment monitoring after allogeneic hematopoietic cell transplantation. A high-sensitivity method is required for the detection of microchimerism (&lt;1% chimerism), which may have clinical utility in early relapse detection, allograft monitoring in organ transplantation, and other allogeneic cellular therapies (such as microtransplantations). As more clinical laboratories adopt this method, a thorough assessment of performance is needed. This study evaluated one such NGS-based assay that uses both single-nucleotide polymorphisms and insertions/deletions as genetic markers. An assessment of accuracy, linearity, sensitivity, and reproducibility was performed. Analytical sensitivity was 0.2% donor for single donor and 0.5% donors for double donors. The assay showed a high degree of reproducibility over a full range of chimerism. Comparison to short-tandem-repeat (STR) PCR showed high concordance; yet &lt;5% chimerism was consistently detected by NGS, but not by STR-PCR. Comparison to real-time quantitative PCR showed high concordance, but with lower correlation in the midrange (40% to 60% chimerism). Overall, the assay showed consistent performance with high sensitivity and accuracy compared with STR-PCR and real-time quantitative PCR across a full range of chimerism in the setting of single-donor and multidonor transplantations. In addition, criteria for quality metrics were established for sequencing performance and data analysis and considerations made for clinical laboratory validation of NGS-based chimerism assay and analysis software.</div></div>","PeriodicalId":50128,"journal":{"name":"Journal of Molecular Diagnostics","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}