{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41613113", "kind": "science-record", "revision": 3, "content_hash": "sha256:372477b90f3848a6e5fe10bb059d350d30e1780653c9e061ac83162d094b22c9", "created_at": "2026-11-01T20:31:42Z", "updated_at": "2026-11-01T22:15:32Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Neoadjuvant therapy-associated malignant phenotype score predicts prognosis and highlights the roles of MIF signaling and DUXAP8 in ESCC.", "doi": "10.3389/fimmu.2025.1683349", "pmid": "41613113", "authors": ["Wenchao Xia", "Tan Lin", "Mengnan Shi", "Qiuqiao Mu", "Han Zhang", "Yijun Xu"], "journal": "Frontiers in immunology", "year": 2025, "abstract": "Background: Esophageal squamous cell carcinoma (ESCC) remains a major malignancy globally, and long-term survival outcomes remain poor despite advances in multimodal treatment strategies. Neoadjuvant therapy (NAT) has become the standard of care for resectable ESCC; however, substantial interpatient heterogeneity in treatment response persists. Defining malignant cell-intrinsic molecular determinants linked to NAT response is essential for improving prognostic stratification and informing individualized therapeutic decision-making.\nMethods: To investigate transcriptional alterations in malignant epithelial cells, we analyzed scRNA-seq datasets obtained from ESCC patients both before and after NAT. Overlapping molecular features were identified by integrating differentially expressed genes from pre- and post-treatment malignant cells with bulk RNA-seq data from TCGA and GEO cohorts. Functional enrichment analyses, pseudotime trajectory reconstruction, and transcription factor regulatory network assessments were subsequently performed. Candidate prognostic genes were initially screened through univariate Cox analysis, followed by the development of the NTAMPS model using LASSO-Cox regression. Its prognostic performance was validated in the TCGA-ESCA and GSE53624 cohorts, and clinical applicability was further examined using a nomogram, calibration curves, and decision curve analysis. Immune-related associations, immunotherapy response prediction (IMvigor210 and GSE78220), and drug sensitivity profiling were also conducted. DUXAP8, which carried the largest coefficient in the NTAMPS, was selected for further validation through both in vivo and in vitro assays, including qRT-PCR and evaluations of cell proliferation, migration, invasion, and colony formation.\nResults: Malignant epithelial cells exhibited pronounced transcriptional remodeling after NAT, characterized by enrichment of pathways related to the cell cycle, DNA replication, and epithelial-mesenchymal transition. Cell-cell communication analysis revealed substantial reorganization of the MIF signaling pathway, including increased interactions of MIF-ACKR3 and MIF-(CD74+CXCR4/CD44), with fibroblasts acting as major signal senders and macrophages serving as primary receivers. Twenty-one prognosis-related genes were identified, and a ten-gene NTAMPS demonstrated strong prognostic performance. Both NTAMPS and clinical stage emerged as independent prognostic factors and were integrated into a nomogram with favorable calibration and decision curve characteristics. A high NTAMPS was associated with an immunosuppressive microenvironment, reduced predicted response to immunotherapy, and distinct drug sensitivity patterns. DUXAP8, the top positive risk gene within NTAMPS, was highly expressed in ESCC tissues and cell lines, and its silencing suppressed cell proliferation, migration, invasion, and clonogenic potential.\nConclusion: This study establishes NTAMPS as a novel malignant cell-derived prognostic signature for ESCC by integrating single-cell and bulk transcriptomic data. NTAMPS enables effective prognostic stratification, predicts potential immunotherapy benefit, and highlights therapeutic vulnerabilities. DUXAP8 was further identified as a candidate molecular driver that may improve ESCC management in the context of neoadjuvant therapy.", "claims": [{"id": "claim-method", "statement": "Candidate prognostic genes were initially screened through univariate Cox analysis, followed by the development of the NTAMPS model using LASSO-Cox regression.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41613113", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Candidate prognostic genes were initially screened through univariate Cox analysis, followed by the development of the NTAMPS model using LASSO-Cox regression."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The original contributions presented in the study are included in the article/Supplementary Material. 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Further inquiries can be directed to the corresponding author."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Twenty-one prognosis-related genes were identified, and a ten-gene NTAMPS demonstrated strong prognostic performance.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41613113", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Twenty-one prognosis-related genes were identified, and a ten-gene NTAMPS demonstrated strong prognostic performance."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Twenty-one prognosis-related genes were identified, and a ten-gene NTAMPS demonstrated strong prognostic performance.", "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:41613113"], "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": "complete", "blocked_on": null, "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": ["data:geo:GSE53624"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE53624"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:41613113", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fimmu.2025.1683349", "sha256": "sha256:75a6c48b765ea17aa5f9484f1d564f6d3dd3c07be4bbaccf97502e9e3ffc5d43", "bytes": 81700, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fimmu.2025.1683349", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12847432", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE53624", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE53624", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE53624", "version": null, "note": "The original contributions presented in the study are included in the article/Supplementary Material. 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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}}}