{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34205690", "kind": "science-record", "revision": 8, "content_hash": "sha256:13dba7aec528ad1411613ecfc83b7ca02c30ce7955d038643d99817c4422668a", "created_at": "2026-11-01T15:41:41Z", "updated_at": "2026-11-01T22:46:59Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "A Comprehensive Bioinformatics Analysis of Notch Pathways in Bladder Cancer.", "doi": "10.3390/cancers13123089", "pmid": "34205690", "authors": ["Chuan Zhang", "Mandy Berndt-Paetz", "Jochen Neuhaus"], "journal": "Cancers", "year": 2021, "abstract": "BACKGROUND: A hallmark of Notch signaling is its variable role in tumor biology, ranging from tumor-suppressive to oncogenic effects. Until now, the mechanisms and functions of Notch pathways in bladder cancer (BCa) are still unclear.\nMETHODS: We used publicly available data from the GTEx and TCGA-BLCA databases to explore the role of the canonical Notch pathways in BCa on the basis of the RNA expression levels of Notch receptors, ligands, and downstream genes. For statistical analyses of cancer and non-cancerous samples, we used R software packages and public databases/webservers.\nRESULTS: We found differential expression between control and BCa samples for all Notch receptors (NOTCH1, 2, 3, 4), the delta-like Notch ligands (DLL1, 3, 4), and the typical downstream gene hairy and enhancer of split 1 (HES1). NOTCH2/3 and DLL4 can significantly differentiate non-cancerous samples from cancers and were broadly altered in subgroups. High expression levels of NOTCH2/3 receptors correlated with worse overall survival (OS) and shorter disease-free survival (DFS). However, at long-term (>8 years) follow-up, NOTCH2 expression was associated with a better OS and DFS. Furthermore, the cases with the high levels of DLL4 were associated with worse OS but improved DFS. Pathway network analysis revealed that NOTCH2/3 in particular correlated with cell cycle, epithelial-mesenchymal transition (EMT), numbers of lymphocyte subtypes, and modulation of the immune system.\nCONCLUSIONS: NOTCH2/3 and DLL4 are potential drivers of Notch signaling in BCa, indicating that Notch and associated pathways play an essential role in the progression and prognosis of BCa through directly modulating immune cells or through interaction with cell cycle and EMT.", "claims": [{"id": "claim-method", "statement": "Univariate analysis was performed using ANOVA, t-test, Wilcoxon test, Tukey’s HSD, and permutation tests.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34205690", "locator": "sections[9] \"2.7. Other Statistical Analyses\" paragraph 2", "quote": "Univariate analysis was performed using ANOVA, t-test, Wilcoxon test, Tukey’s HSD, and permutation tests."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The data presented in this study are openly available in the Cancer Genome Atlas Program (TCGA), the Genotype-Tissue Expression (GTEx), and the Human Protein Atlas (HPA). Furthermore, the other web servers provide easy access to publicly available cancer OMICS data (TCGA, GTEx, et al.) and allow users to identify biomarkers or to perform in silico validation of potential genes, including GEPIA, GeneMANIA, Oncomine, GSCALite, UALCAN, and TISIDB for analyzing RNA sequencing expression and other data projects via a standard processing pipeline, and following the guidelines in the Data Use Certification Agreement.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34205690", "locator": "sections[49] \"Data Availability Statement\" paragraph 2", "quote": "The data presented in this study are openly available in the Cancer Genome Atlas Program (TCGA), the Genotype-Tissue Expression (GTEx), and the Human Protein Atlas (HPA). Furthermore, the other web servers provide easy access to publicly available cancer OMICS data (TCGA, GTEx, et al.) and allow users to identify biomarkers or to perform in silico validation of potential genes, including GEPIA, GeneMANIA, Oncomine, GSCALite, UALCAN, and TISIDB for analyzing RNA sequencing expression and other data projects via a standard processing pipeline, and following the guidelines in the Data Use Certification Agreement."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:34205690"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "blocked", "blocked_on": "method:group_comparison_wilcoxon", "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:run_analysis blocked on method:group_comparison_wilcoxon", "step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34205690", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3390/cancers13123089", "sha256": "sha256:80b559e1a800a6abc00e778ad1b5b171223a86e8485a4b51c4190fe831b17a0e", "bytes": 91836, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3390/cancers13123089", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8235546", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "asset:table:pmid:34205690:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:efda238274a10c2ea1160bf8c74b905fc5c32df8317d58c84a7c3fccc0e26520", "bytes": 1699, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[10]/table-wrap[1]#cancers-13-03089-t001", "version": null, "note": "Demographics and tumor characteristics of patients with BCa in the present study in terms of TCGA-BLCA.", "structure": {"pmcid": "PMC8235546", "section_index": 10, "section_title": "3. Results", "row_count": 42, "column_count": 4}, "table": {"label": "Table 1", "caption": "Demographics and tumor characteristics of patients with BCa in the present study in terms of TCGA-BLCA.", "rows": [["Patient Characteristics", "Classification", "Number of Patients", "Percent (%)"], ["Age (years), median (IQR)", "69 (34–90)", "406", "100"], ["Gender", "Male", "299", "73.65"], ["", "Female", "107", "26.35"], ["Race", "Asian", "43", "10.59"], ["", "Caucasian (White)", "323", "79.56"], ["", "Black African American", "23", "5.67"], ["", "Unknown", "17", "4.19"], ["Family cancer history", "Yes", "143", "35.22"], ["", "No", "263", "64.78"], ["Histological subtype", "Papillary", "130", "32.02"], ["", "Non-papillary", "271", "66.75"], ["", "Unknown", "5", "1.23"], ["T stage", "T0-1", "4", "0.99"], ["", "T2-T2b", "118", "29.06"], ["", "T3-T3b", "193", "47.54"], ["", "T4-T4b", "58", "14.29"], ["", "Tx", "1", "0.25"], ["", "Unknown", "32", "7.88"], ["Recurrence", "Yes", "141", "34.73"], ["", "No", "177", "43.60"], ["", "Unknown", "88", "21.67"], ["Lymphnode (N) stage", "N0", "236", "58.13"], ["", "N1", "46", "11.33"], ["", "N2", "75", "18.47"], ["", "N3", "7", "1.72"], ["", "NX", "36", "8.87"], ["", "Unknown", "6", "1.48"], ["Metastatic (M) stage", "M0", "195", "48.03"], ["", "M1", "11", "2.71"], ["", "MX", "197", "48.52"], ["", "Unknown", "3", "0.74"], ["Tumor stage", "Stage I (T1, N0, M0)", "2", "0.49"], ["", "Stage II (T2a, T2b, N0, M0)", "129", "31.77"], ["", "Stage III (T1-4a, N0-3, M0)", "140", "34.48"], ["", "Stage IV (T1-4b, N1-3, M0-1)", "133", "32.76"], ["", "Unknown", "2", "0.49"], ["Tumor grade", "High grade", "383", "94.33"], ["", "Low grade", "20", "4.93"], ["", "Unknown", "3", "0.74"], ["Overall status", "Dead", "179", "44.09"], ["", "Alive", "227", "55.91"]], "row_count": 42, "column_count": 4, "numeric_cells": 86, "header_rows": 1, "locator": "section[10]/table-wrap[1]#cancers-13-03089-t001"}}, {"id": "asset:table:pmid:34205690:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:7c79f5b2ded969c408c37041a357a99ce3a599083edb5b18ad88aaaf40415bd9", "bytes": 3844, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#cancers-13-03089-t002", "version": null, "note": "Statistically significant difference of expression levels of target genes in subgroups (1).", "structure": {"pmcid": "PMC8235546", "section_index": 12, "section_title": "3.1.1. Gene Expression of Notch Pathway-Related Genes in BCa and Controls", "row_count": 29, "column_count": 13}, "table": {"label": "Table 2", "caption": "Statistically significant difference of expression levels of target genes in subgroups (1).", "rows": [["Target Genes", "BCa vs. Control", "p-Value", "Tumor Stage", "p-Value", "Lymph Nodal Metastasis", "p-Value", "HistologicalSubtypes", "p-Value", "Race", "p-Value", "Gender", "p-Value"], ["NOTCH1", "BCa (↓)", "p = 6.83 × 10−7", "", "", "C vs. N0 (↓)", "p = 7.35 × 10−3", "C vs. PT (↓)", "p = 1.52 × 10−3", "CAU vs. AFA (↑)", "p = 1.04 × 10−2", "", ""], ["", "", "", "", "C vs. N2 (↓)", "p = 3.67 × 10−4", "C vs. NPT (↓)", "p = 1.46 × 10−4", "", "", "", ""], ["NOTCH2", "BCa (↓)", "p = 9.46 × 10−9", "S2 vs. S3 (↑)", "p = 2.07 × 10−2", "C vs. N0 (↓)", "p = 1.00 × 10−7", "C vs. PT (↓)", "p = 6.00 × 10−5", "CAU vs. ASI (↓)", "p = 2.13 × 10−4", "", ""], ["", "", "S2 vs. S4 (↑)", "p = 2.81 × 10−2", "C vs. N1 (↓)", "p = 1.29 × 10−2", "C vs. NPT (↓)", "p < 0.000001", "AFA vs. ASI (↓)", "p = 1.00 × 10−7", "", ""], ["", "", "", "", "C vs. N2 (↓)", "p = 5.58 × 10−4", "PT vs. NPT (↑)", "p = 3.00 × 10−7", "", "", "", ""], ["NOTCH3", "BCa (↑)", "p = 1.98 × 10−4", "", "", "C vs. N0 (↑)", "p = 2.20 × 10−3", "C vs. PT (↑)", "p = 3.44 × 10−4", "", "", "", ""], ["", "", "", "", "C vs. N1 (↑)", "p = 6.35 × 10−4", "C vs. NPT (↑)", "p = 2.41 × 10−3", "", "", "", ""], ["", "", "", "", "C vs. N2 (↑)", "p = 1.45 × 10−2", "", "", "", "", "", ""], ["NOTCH4", "BCa (↓)", "p = 5.02 × 10−12", "", "", "C vs. N0 (↓)", "p < 0.000001", "C vs. PT (↓)", "p = 2.00 × 10−7", "AFA vs. ASI (↑)", "p = 2.59 × 10−3", "", ""], ["", "", "", "", "C vs. N1 (↓)", "p < 0.000001", "C vs. NPT (↓)", "p < 0.000001", "", "", "", ""], ["", "", "", "", "C vs. N2 (↓)", "p = 1.00 × 10−7", "PT vs. NPT (↓)", "p = 1.00 × 10−2", "", "", "", ""], ["", "", "", "", "C vs. N3 (↓)", "p = 7.17 × 10−4", "", "", "", "", "", ""], ["JAG1", "", "", "", "", "", "", "PT vs. NPT (↑)", "p = 6.77 × 10−4", "CAU vs. AFA (↑)", "p = 2.93 × 10−3", "", ""], ["", "", "", "", "", "", "", "", "AFA vs. ASI (↓)", "p = 1.47 × 10−2", "", ""], ["JAG2", "", "", "S2 vs. S4 (↓)", "p = 3.21 × 10−3", "C vs. N2 (↓)", "p = 1.06 × 10−2", "", "", "CAU vs. AFA (↑)", "p = 4.45 × 10−2", "Male vs. Female (↑)", "p = 3.20 × 10−4"], ["DLL1", "BCa (↓)", "p = 4.67 × 10−8", "", "", "C vs. N0 (↓)", "p = 1.84 × 10−4", "C vs. PT (↓)", "p = 1.00 × 10−7", "", "", "", ""], ["", "", "", "", "C vs. N1 (↓)", "p = 2.13 × 10−4", "C vs. NPT (↓)", "p = 1.85 × 10−5", "", "", "", ""], ["", "", "", "", "C vs. N2 (↓)", "p = 5.00 × 10−7", "PT vs. NPT (↑)", "p = 4.45 × 10−2", "", "", "", ""], ["", "", "", "", "C vs. N3 (↓)", "p = 1.08 × 10−2", "", "", "", "", "", ""], ["DLL3", "BCa (↑)", "p = 1.02 × 10−9", "", "", "C vs. N0 (↑)", "p = 3.00 × 10−7", "C vs. PT (↑)", "p = 9.51 × 10−5", "", "", "", ""], ["", "", "", "", "C vs. N1 (↑)", "p = 3.20 × 10−6", "C vs. NPT (↑)", "p < 0.000001", "", "", "", ""], ["", "", "", "", "C vs. N2 (↑)", "p = 3.80 × 10−6", "PT vs. NPT (↑)", "p = 2.26 × 10−2", "", "", "Male vs. Female (↑)", "p = 3.07 × 10−2"], ["", "", "", "", "C vs. N3 (↑)", "p = 2.36 × 10−3", "", "", "", "", "", ""], ["DLL4", "BCa (↓)", "p = 6.36 × 10−5", "", "", "C vs. N0 (↓)", "p = 7.29 × 10−3", "C vs. NPT (↓)", "p = 3.63 × 10−5", "CAU vs. ASI (↓)", "p = 1.55 × 10−02", "", ""], ["", "", "", "", "C vs. N1 (↓)", "p = 2.19 × 10−3", "PT vs. NPT (↓)", "p = 6.46 × 10−3", "AFA vs. ASI (↓)", "p = 2.22 × 10−02", "", ""], ["HES1", "BCa (↑)", "p = 2.61 × 10−5", "", "", "C vs. N0 (↑)", "p = 1.00 × 10−7", "C vs. PT (↑)", "p < 0.000001", "CAU vs. ASI (↓)", "p = 3.98 × 10−04", "", ""], ["", "", "", "", "C vs. N1 (↑)", "p = 3.63 × 10−3", "C vs. NPT (↑)", "p = 4.40 × 10−6", "", "", "", ""], ["", "", "", "", "C vs. N2 (↑)", "p = 2.25 × 10−5", "PT vs. NPT (↓)", "p = 5.05 × 10−3", "", "", "", ""]], "row_count": 29, "column_count": 13, "numeric_cells": 71, "header_rows": 1, "locator": "section[12]/table-wrap[1]#cancers-13-03089-t002"}}, {"id": "asset:table:pmid:34205690:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:ae4e2ed4d9a3066c1dbe7a91196ea65ff56065706c478a482a170af9fe104de7", "bytes": 3166, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[17]/table-wrap[1]#cancers-13-03089-t003", "version": null, "note": "Statistically significant differences of expression levels of target genes in subgroups (2).", "structure": {"pmcid": "PMC8235546", "section_index": 17, "section_title": "3.1.6. Gene Expression in Molecular Subtypes", "row_count": 33, "column_count": 9}, "table": {"label": "Table 3", "caption": "Statistically significant differences of expression levels of target genes in subgroups (2).", "rows": [["Target Genes", "Molecular Subtypes", "TP53 Mutation Status"], ["", "C-TCGA vs. Subtypes", "p-Value", "BST vs. LT/LIT", "p-Value", "C-TCGA vs. TP53M/TP53WT", "p-Value", "TP53M vs. TP53WT", "p-Value"], ["NOTCH1", "LT (↓)", "p = 8.20 × 10−3", "LT (↓)", "p = 3.31 × 10−2", "TP53M (↓)", "p = 6.20 × 10−3", "TP53WT (↑)", "p = 3.91 × 10−7"], ["", "", "", "LT (↓)", "p = 6.16 × 10−4", "", "", "", ""], ["NOTCH2", "LT (↓)", "p = 1.50 × 10−3", "LT (↓)", "p = 1.14 × 10−3", "TP53M (↓)", "p = 3.46 × 10−2", "TP53WT (↓)", "p = 4.34 × 10−2"], ["", "LIT (↓)", "p = 3.68 × 10−2", "", "", "TP53WT (↓)", "p = 1.17 × 10−2", "", ""], ["", "LPT (↓)", "p = 5.44 × 10−3", "", "", "", "", "", ""], ["NOTCH3", "BST (↑)", "p = 5.69 × 10−5", "LIT (↑)", "p = 4.05 × 10−2", "TP53M (↑)", "p = 5.83 × 10−4", "", ""], ["", "LT (↑)", "p = 1.26 × 10−3", "", "", "TP53WT (↑)", "p = 2.22 × 10−5", "", ""], ["", "LIT (↑)", "p = 1.06 × 10−2", "", "", "", "", "", ""], ["", "LPT (↑)", "p = 8.22 × 10−5", "", "", "", "", "", ""], ["NOTCH4", "BST (↓)", "p = 1.47 × 10−2", "LIT (↑)", "p = 9.78 × 10−3", "TP53M (↓)", "p = 3.02 × 10−2", "TP53WT (↑)", "p = 4.62 × 10−3"], ["JAG1", "BST (↑)", "p = 1.10 × 10−6", "LT (↓)", "p = 9.77 × 10−5", "TP53M (↑)", "p = 3.95 × 10−2", "", ""], ["", "", "", "LIT (↓)", "p = 1.13 × 10−7", "", "", "", ""], ["JAG2", "NET (↑)", "p = 2.09 × 10−2", "LT (↓)", "p = 5.25 × 10−12", "TP53M (↑)", "p = 1.32 × 10−3", "", ""], ["", "BST (↑)", "p = 4.76 × 10−8", "LIT (↓)", "p = 5.87 × 10−9", "TP53WT (↑)", "p = 3.98 × 10−4", "", ""], ["", "LPT (↑)", "p = 3.99 × 10−2", "", "", "", "", "", ""], ["DLL1", "LT (↓)", "p = 3.06 × 10−3", "LT (↓)", "p = 1.44 × 10−4", "", "", "TP53WT (↓)", "p = 2.86 × 10−2"], ["", "LIT (↓)", "p = 5.54 × 10−3", "LIT (↓)", "p = 7.74 × 10−5", "", "", "", ""], ["", "LPT (↓)", "p = 1.31 × 10−3", "", "", "", "", "", ""], ["DLL3", "BST (↑)", "p = 3.48 × 10−7", "LIT (↓)", "p = 1.96 × 10−3", "TP53M (↑)", "p = 1.00 × 10−2", "", ""], ["", "LT (↑)", "p = 4.68 × 10−2", "", "", "TP53WT (↑)", "p = 1.75 × 10−6", "", ""], ["", "LIT (↑)", "p = 9.80 × 10−3", "", "", "", "", "", ""], ["", "LPT (↑)", "p = 5.16 × 10−3", "", "", "", "", "", ""], ["DLL4", "", "", "LT (↑)", "p = 1.77 × 10−2", "", "", "TP53WT (↑)", "p = 4.02 × 10−3"], ["", "", "", "LIT (↑)", "p = 4.46 × 10−3", "", "", "", ""], ["HES1", "LT (↑)", "p = 3.51 × 10−3", "LT (↑)", "p = 3.97 × 10−5", "TP53WT (↑)", "p = 2.30 × 10−2", "TP53WT (↑)", "p = 2.11 × 10−2"], ["", "LIT (↑)", "p = 4.79 × 10−2", "LIT (↑)", "p = 2.18 × 10−3", "", "", "", ""], ["", "LPT (↑)", "p = 3.14 × 10−6", "", "", "", "", "", ""], ["HEY1", "NET (↑)", "p = 4.46 × 10−2", "LT (↑)", "p = 2.20 × 10−2", "TP53M (↑)", "p = 1.16 × 10−3", "", ""], ["", "BST (↑)", "p = 5.74 × 10−3", "", "", "TP53WT (↑)", "p = 1.63 × 10−6", "", ""], ["", "LT (↑)", "p = 1.68 × 10−3", "", "", "", "", "", ""], ["", "LIT (↑)", "p = 1.50 × 10−2", "", "", "", "", "", ""]], "row_count": 33, "column_count": 9, "numeric_cells": 87, "header_rows": 2, "locator": "section[17]/table-wrap[1]#cancers-13-03089-t003"}}, {"id": "asset:table:pmid:34205690:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:7167844ffc85754e135b8e3fdc860b07734456a444699116eb3bde94a28ba1c2", "bytes": 1038, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[24]/table-wrap[1]#cancers-13-03089-t004", "version": null, "note": "Risk assessment of Notch components on OS.", "structure": {"pmcid": "PMC8235546", "section_index": 24, "section_title": "3.3.1. Dependency of Overall Survival (OS) on the Expression Levels of Target Genes", "row_count": 13, "column_count": 8}, "table": {"label": "Table 4", "caption": "Risk assessment of Notch components on OS.", "rows": [["", "Univariate Test", "", "", "Multivariate Test", ""], ["Gene", "HR", "CI95", "p-Value", "Gene", "HR", "CI95", "p-Value"], ["NOTCH1", "1.21", "0.9–1.63", "0.208", "", "", "", ""], ["NOTCH2", "1.44", "1.06–1.96", "0.018 *", "NOTCH2", "1.27", "0.92–1.76", "0.151"], ["NOTCH3", "1.6", "1.2–2.15", "0.002 **", "NOTCH3", "1.65", "1.2–2.25", "0.002 **"], ["NOTCH4", "1.35", "0.85–2.15", "0.204", "", "", "", ""], ["JAG1", "4.26", "1.98–9.18", "0", "JAG1", "3.69", "1.67–8.15", "0.001 **"], ["JAG2", "1.25", "0.88–1.77", "0.221", "", "", "", ""], ["DLL1", "1.47", "0.87–2.5", "0.154", "", "", "", ""], ["DLL3", "0.89", "0.64–1.24", "0.483", "", "", "", ""], ["DLL4", "1.53", "1.11–2.1", "0.009 **", "DLL4", "1.54", "1.11–2.14", "0.009 **"], ["HES1", "0.57", "0.41–0.8", "0.001 **", "HES1", "0.56", "0.39–0.81", "0.002 **"], ["HEY1", "2.26", "1–5.11", "0.045 *", "HEY1", "1.63", "0.7–3.77", "0.255"]], "row_count": 13, "column_count": 8, "numeric_cells": 53, "header_rows": 2, "locator": "section[24]/table-wrap[1]#cancers-13-03089-t004"}}, {"id": "asset:table:pmid:34205690:5", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:58945db4b1ae3144c43fa25b29629ff7ce92d75478ba05fe02e5a63c40d38e25", "bytes": 1063, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[25]/table-wrap[1]#cancers-13-03089-t005", "version": null, "note": "Risk assessment of Notch components on DFS.", "structure": {"pmcid": "PMC8235546", "section_index": 25, "section_title": "3.3.2. Dependency of Disease-Free Survival (DFS) on the Expression Levels of Target Genes", "row_count": 13, "column_count": 8}, "table": {"label": "Table 5", "caption": "Risk assessment of Notch components on DFS.", "rows": [["", "Univariate Test", "", "", "Multivariate Test", ""], ["Gene", "HR", "CI95", "p-Value", "Gene", "HR", "CI95", "p-Value"], ["NOTCH1", "1.18", "0.85–1.65", "0.322", "", "", "", ""], ["NOTCH2", "1.53", "1.09–2.16", "0.014 *", "NOTCH2", "1.3", "0.91–1.85", "0.152"], ["NOTCH3", "1.46", "1.05–2.04", "0.026 *", "NOTCH3", "1.52", "1.08–2.15", "0.016 *"], ["NOTCH4", "0.88", "0.63–1.23", "0.447", "", "", "", ""], ["JAG1", "1.9", "1.02–3.52", "0.042 *", "JAG1", "1.42", "0.75–2.68", "0.28"], ["JAG2", "1.66", "1.07–2.58", "0.023 *", "JAG2", "1.63", "1.05–2.55", "0.03 *"], ["DLL1", "1.12", "0.81–1.56", "0.494", "", "", "", ""], ["DLL3", "1.19", "0.85–1.67", "0.3", "", "", "", ""], ["DLL4", "0.65", "0.44–0.95", "0.028 *", "DLL4", "0.68", "0.46–1.01", "0.056"], ["HES1", "0.56", "0.39–0.82", "0.003 **", "HES1", "0.59", "0.4–0.88", "0.01 *"], ["HEY1", "1.97", "1–3.87", "0.046 *", "HEY1", "1.67", "0.84–3.34", "0.146"]], "row_count": 13, "column_count": 8, "numeric_cells": 56, "header_rows": 2, "locator": "section[25]/table-wrap[1]#cancers-13-03089-t005"}}, {"id": "asset:table:pmid:34205690:6", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:c559fbbecd36873c68ce772b0b37527ecef87df6a0924e26ed5eb4a16b9f7842", "bytes": 2461, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[36]/table-wrap[1]#cancers-13-03089-t006", "version": null, "note": "The dual role of Notch receptors and ligands in BCa.", "structure": {"pmcid": "PMC8235546", "section_index": 36, "section_title": "4.1. NOTCH2/3 and DLL4 Are Potential Drivers of Notch Signaling in BCa", "row_count": 19, "column_count": 3}, "table": {"label": "Table 6", "caption": "The dual role of Notch receptors and ligands in BCa.", "rows": [["Name", "Role in BCa", "Description"], ["NOTCH1", "Suppression *(↓)", "Activated NOTCH1 suppressed BCa in vitro and in vivo by reducing ERK1 and ERK2(ERK1/2) [8]. Suppression of NOTCH1 may be advantageous for tumor progression [6]."], ["Oncogene (↑)", "NOTCH1 knockdown led to cancer cell growth and significantly inhibited growth and proliferation [72]."], ["NOTCH2", "Suppression *(↓)", "NOTCH2 was significantly downregulated in BCa [6,8]. Inactivation of NOTCH2 favors the process of EMT and promotes BCa progression [7]."], ["Oncogene (↑)", "High rate of NOTCH2 copy number gain and over-expression in BCa, and the activation of NOTCH2 promotes metastasis, resulting in poor survival [5]."], ["NOTCH3", "Suppression (↓)", "Deletion of the intracellular domain of NOTCH3 leads to negative function in BCa, i.e., turning it into potential tumor-suppressive gene [8]."], ["Oncogene*(↑)", "Significantly upregulated NOTCH3 enhanced the BCa growth and chemoresistance in urothelial carcinoma with worse survival [9]."], ["NOTCH4", "Suppression * (↓)", "NOTCH4 was significantly downregulated in BCa, especially in the T1 stage of bladder tumor. However, in patients diagnosed with muscle-invasive bladder tumor (MIBC), high NOTCH4 expression correlated with poor survival and more vascular invasion [73]."], ["Oncogene", "NA"], ["JAG1", "Suppression (↓)", "JAG1 significantly decreased in BCa and was associated with poor prognosis [74]."], ["Oncogene (↑)", "miR-489 directly suppressed JAG1 expression, inhibiting the proliferation and invasion of human bladder cancer cells [75]."], ["JAG2", "Suppression", "NA"], ["Oncogene (↑)", "JAG2 was overexpressed in BCa and was significantly associated with the metastasis and recurrence [76]."], ["DLL1", "Suppression *(↓)", "DLL1 was significantly decreased in BCa. Supposed to be a suppressive gene [6]."], ["Oncogene", "NA"], ["DLL3", "Suppression", "NA"], ["Oncogene * (↑)", "DLL3 was significantly upregulated in small cell components correlated with worse clinical outcomes in small cell bladder cancer (SCBC) [77]."], ["DLL4", "Suppression", "NA"], ["Oncogene (↑)", "DLL4 was significantly upregulated in BCa, and the expression of DLL4 was found to be associated with vascular differentiation in BCa [78]."]], "row_count": 19, "column_count": 3, "numeric_cells": 13, "header_rows": 1, "locator": "section[36]/table-wrap[1]#cancers-13-03089-t006"}}, {"id": "asset:table:pmid:34205690:7", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:c111a0a22795f380172ebf4ada6439c441aa0e9f3fc38cb11fcff65602905e42", "bytes": 1940, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[43]/table-wrap[1]#array1", "version": null, "note": null, "structure": {"pmcid": "PMC8235546", "section_index": 43, "section_title": "Abbreviations", "row_count": 47, "column_count": 2}, "table": {"label": null, "caption": null, "rows": [["AFA", "Black or African American"], ["ASI", "Asian"], ["AUC", "Accuracy"], ["BCa", "Bladder cancer"], ["BP", "Biological process"], ["BST", "Basal squamous tumors"], ["CAU", "Caucasian"], ["DC", "Dendritic cell"], ["DFS", "Disease-free survival"], ["DLL", "Delta-like canonical Notch ligand"], ["EMT", "Epithelial to mesenchymal transition"], ["ER", "Hormone estrogen receptor"], ["FC", "Fold change"], ["FDR", "False discovery rate"], ["FWER", "Familywise error rate"], ["GEPIA", "Gene expression profiling interactive analysis"], ["GGI", "Gene‒gene interaction"], ["GO", "Gene ontology"], ["GSEA", "Gene set enrichment analysis"], ["GTEx", "Gene expression omnibus"], ["HPA", "Human protein atlas"], ["HR", "Hormone androgen receptor"], ["IHC", "Immunochemistry"], ["JAG", "Serrate-like jagged canonical Notch ligand"], ["KEGG", "Kyoto Encyclopedia of Genes and Genomes"], ["LIT", "Luminal-infiltrated tumors"], ["LPT", "Luminal-papillary tumors"], ["LT", "Luminal tumors"], ["MIBC", "Muscle-invasive bladder cancer"], ["NCBI", "National Center for Biotechnology Information"], ["NES", "Normalized enrichment score"], ["NET", "Neuronal tumors"], ["NMIBC", "Non-muscle-invasive bladder cancer"], ["NOTCH", "Neurogenic locus Notch homologue"], ["NPT", "Non-papillary tumor"], ["OS", "Overall survival"], ["OPLA-DA", "Orthogonal partial least squares discriminant analysis"], ["PT", "Papillary tumor"], ["RTK", "Receptor tyrosine kinase signaling"], ["RAS/MAPK", "Ras/mitogen-activated protein kinase pathway"], ["PCA", "Principal component analysis"], ["ROC", "Receiver operating characteristic"], ["SCBC", "Small cell bladder cancer"], ["TCGA-BLCA", "Cancer genome atlas bladder cancer"], ["TSC-mTOR", "Tuberous sclerosis complex–mammalian target of rapamycin (TSC-mTOR) pathway"], ["TISIDB", "Tumor and immune system interaction database"], ["TPM", "Transcripts per million"]], "row_count": 47, "column_count": 2, "numeric_cells": 0, "header_rows": 0, "locator": "section[43]/table-wrap[1]#array1"}}], "gaps": []}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "group_comparison", "specific": "wilcoxon", "label": "Group comparison", "dsl_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "expressible": false, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "Univariate analysis was performed using ANOVA, t-test, Wilcoxon test, Tukey’s HSD, and permutation tests."}}, {"id": "method-2", "family": "group_comparison", "specific": "anova", "label": "Group comparison", "dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], 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The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R4", "reachable": false, "accessions": [], "resolved_accessions": [], "statements": ["The data presented in this study are openly available in the Cancer Genome Atlas Program (TCGA), the Genotype-Tissue Expression (GTEx), and the Human Protein Atlas (HPA). Furthermore, the other web servers provide easy access to publicly available cancer OMICS data (TCGA, GTEx, et al.) and allow users to identify biomarkers or to perform in silico validation of potential genes, including GEPIA, GeneMANIA, Oncomine, GSCALite, UALCAN, and TISIDB for analyzing RNA sequencing expression and other data projects via a standard processing pipeline, and following the guidelines in the Data Use Certification Agreement."], "basis": "The paper names no accession to its source data, so the data has to come from the authors."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:34205690", "asset:table:pmid:34205690:1", "asset:table:pmid:34205690:2", "asset:table:pmid:34205690:3", "asset:table:pmid:34205690:4", "asset:table:pmid:34205690:5", "asset:table:pmid:34205690:6", "asset:table:pmid:34205690:7"], "steps": []}, "must_build": {"dsl_operations": [{"operation": "group_comparison_wilcoxon", "unlocks_papers": null, "priority": null}], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T19:39:32Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 79565, "completion_tokens": 3530, "cached_tokens": 784}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:34205690", "type": "paper", "label": "pmid:34205690"}, {"id": "source:pmid:34205690", "type": "manuscript", "label": "PMID 34205690 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:34205690", "type": "paper", "label": "pmid:34205690"}, {"id": "source:pmid:34205690", "type": "manuscript", "label": "PMID 34205690 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-34205690", "type": "extraction", "used": ["source:pmid:34205690"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:34205690", "parent_hash": "sha256:db48337cb0afade33ceaa59488182ab85816990f6e989de569a191898b41ff92", "fork_of": null, "generation": 7}, "gaps": ["execution.not_run", "method.group_comparison_wilcoxon", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent", "step:run_analysis blocked on method:group_comparison_wilcoxon"], "assays": [{"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ins in Normal Bladder Tissue and BCa Samples Immunohistochemistry (IHC) protein expression data from the Human", ") [58], transcripts per million (TPM). (iii) IHC image credit: Human Protein Atlas (https://w", "as.org/, accessed on 13 December 2020) [62]; IHC staining of NOTCH3 (A3) and DLL4 (B3) in nor", "get genes is summarized in Figure S9. 3.5.3. IHC of Notch-Related Proteins in Normal Bladder"], "order_basis": "paper_text_order:7902", "id": "assay:1"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Univariate analysis was performed using ANOVA, t-test, Wilcoxon test, Tukey’s HSD, and permutation tests."], "order_basis": "consumes_earlier_output", "id": "assay:2"}]},"meta":{"api_version":"v1","automation_ladder_snapshot":"ba34b49490d9bfaf","automation_ladder_caveats":["Method extraction is rule-based and has no hand-judged accuracy sample. 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Resolving one blocker can leave another at the same tier."],"engine":"corpus_engine","engine_provider":"rule_based_v1+lex99e1195c7d6f","run_id":"run-20261023T122449232913","source":"esearch","source_detail":"PubMed mirror biomed_pubmed (read-only)","run_status":"complete","imported_at":"2026-11-03T20:16:52+00:00","generated_at":"2026-11-04T02:13:41+00:00","total_papers":5529,"total_assays_tracked":29,"automatable_assay_families":6,"validated":true,"caveat_count":9,"blocking_caveats":5,"caveats":[{"code":"low_evidence_dominates","basis":["4,152 of 5,529 classifications (75.1%) matched no cue evidence and sit at the 0.05 floor.","34 of 230 data_only calls (14.8%) are in that group."],"claim":"Work type and confidence bands","gloss":"Most records were classified from their title and framing alone, with assay-cue coverage at zero.","detail":"Most classifications in this run rest on no matched evidence at all. At the evidence floor the work type comes from title framing and a fixed prior, not from anything in the paper, so the published work-type split should be read as a rough triage signal rather than a measured distribution. The impact is bounded but not removed: since 2026-10-23 the engine excludes floor-confidence records from the shortlist entirely and publishes them separately as held out, so the recommendation is unaffected even though the census is.","status":"unverified","severity":"high"},{"code":"runtime_is_modelled","basis":["Runtime is summed from published per-assay hour figures. Timing awaits the first executed replication.","4,407 of 5,529 records (79.7%) model to 0.00 hours because no assay was matched, which the ranking then reads as \"cheapest\".","0 of 10 shortlisted records carry a 0.00-hour estimate."],"claim":"Estimated replication runtime","gloss":"The hour figures are estimates built from assay mentions; timing awaits the first executed replication.","detail":"The hour figures are a cost model derived from the bench steps implied by each matched assay family. The first executed replication will supply measured timing. Records without an assay match currently receive a zero-hour model value.","status":"unverified","severity":"high"},{"code":"signal_score_without_citations","basis":["5,529 of 5,529 records (100.0%) have no citation count from the source metadata."],"claim":"Signal score","gloss":"The signal score uses publication-type weight because the mirror supplied zero citation counts.","detail":"The source supplied no citation counts for any record in this run, so the signal score is publication-type weight only. The citation term of the ranking is inert here, and the shortlist is ordered by publication type alone.","status":"unverified","severity":"high"},{"code":"abstract_absent","basis":["1,667 of 5,529 records (30.2%) carry no abstract at all."],"claim":"Evidence base for classification","gloss":"Some records contain a title and publication type only, defining the available classification evidence.","detail":"Where the mirror contains a title and publication types only, those fields define the classifier evidence. A methods section is required for fuller automated and human review.","status":"unverified","severity":"medium"},{"code":"classifier_agreement_measured","basis":["Published two-way decision agreement 77.7% (310 of 399 decidable records) from a stratified hand-check of 438 real records.","Three-way diagnostic agreement 73.9% (288 of 390 decidable records).","data_only agreement 75.2% (100 of 133 decidable).","48 record(s) could not be decided from title and abstract and were excluded from the denominator.","56 analysis-only records were published under another work type, so the data_only share is not an upper bound."],"claim":"Published automatable decision","gloss":"This figure has been checked against a human reading the same papers, so we know how often it is right.","detail":"The published automatable / not-automatable distribution comes from a rule-based classifier that was hand-checked against a fixed ground-truth definition. The agreement rates below are measured, not estimated. The three-way work type remains a diagnostic and is reported separately.","status":"measured","severity":"high"},{"code":"llm_comparison_not_measured","basis":["rule_based_v1+lex99e1195c7d6f produced 5,529 of 5,529 classifications.","Measured on 438 labelled records; these are RULE-BASED figures, not model results."],"claim":"Rule-based versus LLM agreement","gloss":"Every number here is the rule engine’s own. Model comparison begins when a working API credential is connected and measured.","detail":"The published two-way decision agreed with a human reading on 310 of 399 decidable records (77.7%). The diagnostic three-way label agreed on 288 of 390 decidable records (73.9%). Every percentage in this run belongs to the rule engine. Model comparison begins when a working API credential is connected and measured.","status":"not_measured","severity":"high"},{"code":"confidence_is_a_band","basis":["low band: 135 of 210 hand-judged records were correct, 64.3% [57.6, 70.5] (95% CI).","medium band: 80 of 104 hand-judged records were correct, 76.9% [68.0, 84.0] (95% CI).","high band: 73 of 76 hand-judged records were correct, 96.0% [89.0, 98.7] (95% CI).","A fitted calibrated probability was built, measured and withdrawn: it overstated held-out accuracy and reorders nothing."],"claim":"Confidence band and evidence score","gloss":"The confidence band carries a measured accuracy interval; 0.85 represents relative rank strength.","detail":"Confidence on this run is a BAND plus its measured accuracy interval. The number stored alongside each record is a monotone evidence score that orders records; 0.85 represents relative rank strength. A fitted probability was withdrawn after it overstated held-out accuracy. Threshold on the band.","status":"measured","severity":"medium"},{"code":"three_way_split_is_diagnostic","basis":["The corpus is published at the two-way decision: automatable or not-automatable. The three-way split (data_only / physical / mixed) is published as a diagnostic with its measured reliability attached, not as a claim, because the rule engine's `mixed` call cannot be defended.","The engine called 22 record(s) mixed; 10 matched the human judgement (45.5%, 95% CI 26.9-65.3).","The engine's `mixed` call is right on 10/22 hand-judged records (45.5%, 95% CI 26.9%-65.3%); a constant `physical` guess scores 36.4%.","The engine's `mixed` call does not reliably beat a constant `physical` guess on the hand-judged records it labels mixed.","The sign of that difference flips between two independent samples, so the three-way refinement is not demonstrably informative.","The mixed stratum contributes a disproportionate share of errors relative to its size.","At title-only depth the physical/mixed split collapses: a title says that work was done, not whether it was also analysed."],"claim":"The published decision is two-way","gloss":"The three-way split is shown for diagnosis only. The published split is two ways.","detail":"Count and filter the corpus on automatable versus not-automatable. The data_only / physical / mixed split remains an internal engine diagnostic because the mixed call has lower measured reliability.","status":"measured","severity":"medium"},{"code":"automatable_flag_unproven","basis":["6 of 29 assay families are marked automatable now: meta_analysis, machine_learning, survival_analysis, pca, molecular_docking, differential_expression.","The flag is a rule over assay family and work type; validation begins with the first executed replication.","It inherits the 75.2% data_only agreement rate, because the flag requires the record to be analysis-only."],"claim":"Automatable now","gloss":"This flag marks assay families the rules classify as data-only. The first executed replication will validate it.","detail":"This flag marks families the rules consider replicable from data alone. Its validity depends on the analysis-only classification and will be measured through an executed replication.","status":"unverified","severity":"medium"}],"confidence_policy":"band_with_measured_interval","confidence_contract":{"policy":"band_with_measured_interval","summary":"Confidence is reported as a BAND with a measured accuracy interval. The raw evidence score supplies monotone ordering. A fitted point estimate was withdrawn after it overstated held-out accuracy.","evidence_score":"A monotone evidence score in [0,1] built from cue mass, axis separation and text coverage. Use it to order records. Interpret 0.85 as relative rank strength.","confidence_band":"low | medium | high. Consumers threshold on this value.","band_accuracy":"Wilson 95% interval on the measured agreement of the hand-judged records in this band.","calibrated_confidence":"WITHDRAWN. Reintroduction requires held-out evidence demonstrating reliable estimates across every bin."},"band_accuracy":{"low":{"n":210,"low":0.576,"band":"low","high":0.7046,"agree":135,"accuracy":0.6429},"high":{"n":76,"low":0.8903,"band":"high","high":0.9865,"agree":73,"accuracy":0.9605},"medium":{"n":104,"low":0.6795,"band":"medium","high":0.8397,"agree":80,"accuracy":0.7692}},"provider":"rule_based_v1+lex99e1195c7d6f","lexicon_id":"99e1195c7d6f","contract_published_at":"2026-10-23T12:25:29.022232+00:00","confidence_is_band":true,"confidence_is_probability":false,"decision_taxonomy":"two_way","decidable_fraction_two_way":0.8854,"decidable_fraction_two_way_low":0.8565,"decidable_fraction_two_way_high":0.9143,"decidable_fraction_three_way":0.8586,"decidable_fraction_three_way_low":0.8287,"decidable_fraction_three_way_high":0.8884,"decidable_population":5529,"validation_sample_size":438,"three_way_cost_fraction":0.0268,"three_way_cost_records":148,"decision_counts":{"automatable":230,"not_automatable":5299},"decision_split":{"automatable":{"count":230,"share":0.04159884246699222},"not_automatable":{"count":5299,"share":0.9584011575330078}},"diagnostic_work_type_counts":{"mixed":24,"physical":5275,"data_only":230}}}