Identifying Apoptosis-Related Transcriptomic Aberrations and Revealing Clinical Relevance as Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33680905", "kind": "science-record", "revision": 7, "content_hash": "sha256:c7bfba05c3dd6a4ad9abbeed169ecc187c9002773a62c90e8f11432561adb6d7", "created_at": "2026-11-01T15:41:27Z", "updated_at": "2026-11-01T22:03:15Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identifying Apoptosis-Related Transcriptomic Aberrations and Revealing Clinical Relevance as Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma.", "doi": "10.3389/fonc.2020.519180", "pmid": "33680905", "authors": ["Jinyu Zhu", "Bufu Tang", "Xiuling Lv", "Miaomiao Meng", "Qiaoyou Weng", "Nannan Zhang", "Jie Li", "Kai Fan", "Liyun Zheng", "Shiji Fang", "Min Xu", "Jiansong Ji"], "journal": "Frontiers in oncology", "year": 2020, "abstract": "In view of the unsatisfactory treatment outcome of liver cancer under current treatment, where the mortality rate is high and the survival rate is poor, in this study we aimed to use RNA sequencing data to explore potential molecular markers that can be more effective in predicting diagnosis and prognosis of hepatocellular carcinoma. RNA sequencing data and corresponding clinical information were obtained from multiple databases. After matching with the apoptotic genes from the Deathbase database, 14 differentially expressed human apoptosis genes were obtained. Using univariate and multivariate Cox regression analyses, two apoptosis genes (BAK1 and CSE1L) were determined to be closely associated with overall survival (OS) in HCC patients. And subsequently experiments also validated that knockdown of BAK1 and CSE1L significantly inhibited cell proliferation and promoted apoptosis in the HCC. Then the two genes were used to construct a prognostic signature and diagnostic models. The high-risk group showed lower OS time compared to low-risk group in the TCGA cohort (P < 0.001, HR = 2.11), GSE14520 cohort (P = 0.003, HR = 1.85), and ICGC cohort (P < 0.001, HR = 4). And the advanced HCC patients showed higher risk score and worse prognosis compared to early-stage HCC patients. Moreover, the prognostic signature was validated to be an independent prognostic factor. The diagnostic models accurately predicted HCC from normal tissues and dysplastic nodules in the training and validation cohort. These results indicated that the two apoptosis-related signature effectively predicted diagnosis and prognosis of HCC and may serve as a potential biomarker and therapeutic target for HCC.", "claims": [{"id": "claim-data-access", "statement": "Publicly available datasets were analyzed in this study; these can be found in The Cancer Genome Atlas (https://www.tcga.org/) and Deathbase (http://www.deathbase.org/).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33680905", "locator": "sections[28] \"Data Availability Statement\" paragraph 2", "quote": "Publicly available datasets were analyzed in this study; these can be found in The Cancer Genome Atlas (https://www.tcga.org/) and Deathbase (http://www.deathbase.org/)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "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:33680905"], "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:GSE14520"], "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:GSE14520"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33680905", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fonc.2020.519180", "sha256": "sha256:de5f9c814505fb9a56751a6a28e5059ceecccd9239d226e453b63ef4a47ac482", "bytes": 56918, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fonc.2020.519180", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7931692", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE14520", "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=GSE14520", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE14520", "version": null, "note": "Publicly available datasets were analyzed in this study; these can be found in The Cancer Genome Atlas (https://www.tcga.org/) and Deathbase (http://www.deathbase.org/).", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Publicly available datasets were analyzed in this study; these can be found in The Cancer Genome Atlas (https://www.tcga.org/) and Deathbase (http://www.deathbase.org/).", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM362947", "GSM362948", "GSM362949", "GSM362950", "GSM362951", "GSM362952", "GSM362953", "GSM362954", "GSM362955", "GSM362956", "GSM362957", "GSM362958", "GSM362959", "GSM362960", "GSM362961", "GSM362962", "GSM362963", "GSM362964", "GSM362965", "GSM362966", "GSM362967", "GSM362968", "GSM362969", "GSM362970", "GSM362971", "GSM362972", "GSM362973", "GSM362974", "GSM362975", "GSM362976", "GSM362977", "GSM362978", "GSM362979", "GSM362980", "GSM362981", "GSM362982", "GSM362983", "GSM362984", "GSM362985", "GSM362986", "GSM362987", "GSM362988", "GSM362989", "GSM362990", "GSM362991", "GSM362992", "GSM362993", "GSM362994", "GSM362995", "GSM362996", "GSM362997", "GSM362998", "GSM362999", "GSM363000", "GSM363001", "GSM363002", "GSM363003", "GSM363004", "GSM363005", "GSM363006", "GSM363007", "GSM363008", "GSM363009", "GSM363010", "GSM363011", "GSM363012", "GSM363013", "GSM363014", "GSM363015", "GSM363016", "GSM363017", "GSM363018", "GSM363019", "GSM363020", "GSM363021", "GSM363022", "GSM363023", "GSM363024", "GSM363025", "GSM363026", "GSM363027", "GSM363028", "GSM363029", "GSM363030", "GSM363031", "GSM363032", "GSM363033", "GSM363034", "GSM363035", "GSM363036", "GSM363037", "GSM363038", "GSM363039", "GSM363040", "GSM363041", "GSM363042", "GSM363043", "GSM363044", "GSM363045", "GSM363046", "GSM363047", "GSM363048", "GSM363049", "GSM363050", "GSM363051", "GSM363052", "GSM363053", "GSM363054", "GSM363055", "GSM363056", "GSM363057", "GSM363058", "GSM363059", "GSM363060", "GSM363061", "GSM363062", "GSM363063", "GSM363064", "GSM363065", "GSM363066", "GSM363067", "GSM363068", "GSM363069", "GSM363070", "GSM363071", "GSM363072", "GSM363073", "GSM363074", "GSM363075", "GSM363076", "GSM363077", "GSM363078", "GSM363079", "GSM363080", "GSM363081", "GSM363082", "GSM363083", "GSM363084", "GSM363085", "GSM363086", "GSM363087", "GSM363088", "GSM363089", "GSM363090", "GSM363091", "GSM363092", "GSM363093", "GSM363094", "GSM363095", "GSM363096", "GSM363097", "GSM363098", "GSM363099", "GSM363100", "GSM363101", "GSM363102", "GSM363103", "GSM363104", "GSM363105", "GSM363106", "GSM363107", "GSM363108", "GSM363109", "GSM363110", "GSM363111", "GSM363112", "GSM363113", "GSM363114", "GSM363115", "GSM363116", "GSM363117", "GSM363118", "GSM363119", "GSM363120", "GSM363121", "GSM363122", "GSM363123", "GSM363124", "GSM363125", "GSM363126", "GSM363127", "GSM363128", "GSM363129", "GSM363130", "GSM363131", "GSM363132", "GSM363133", "GSM363134", "GSM363135", "GSM363136", "GSM363137", "GSM363138", "GSM363139", "GSM363140", "GSM363141", "GSM363142", "GSM363143", "GSM363144", "GSM363145", "GSM363146", "GSM363147", "GSM363148", "GSM363149", "GSM363150", "GSM363151", "GSM363152", "GSM363153", "GSM363154", "GSM363155", "GSM363156", "GSM363157", "GSM363158", "GSM363159", "GSM363160", "GSM363161", "GSM363162", "GSM363163", "GSM363164", "GSM363165", "GSM363166", "GSM363167", "GSM363168", "GSM363169", "GSM363170", "GSM363171", "GSM363172", "GSM363173", "GSM363174", "GSM363175", "GSM363176", "GSM363177", "GSM363178", "GSM363179", "GSM363180", "GSM363181", "GSM363182", "GSM363183", "GSM363184", "GSM363185", "GSM363186", "GSM363187", "GSM363188", "GSM363189", "GSM363190", "GSM363191", "GSM363192", "GSM363193", "GSM363194", "GSM363195", "GSM363196", "GSM363197", "GSM363198", "GSM363199", "GSM363200", "GSM363201", "GSM363202", "GSM363203", "GSM363204", "GSM363205", "GSM363206", "GSM363207", "GSM363208", "GSM363209", "GSM363210", "GSM363211", "GSM363212", "GSM363213", "GSM363214", "GSM363215", "GSM363216", "GSM363217", "GSM363218", "GSM363219", "GSM363220", "GSM363221", "GSM363222", "GSM363223", "GSM363224", "GSM363225", "GSM363226", "GSM363227", "GSM363228", "GSM363229", "GSM363230", "GSM363231", "GSM363232", "GSM363233", "GSM363234", "GSM363235", "GSM363236", "GSM363237", "GSM363238", "GSM363239", "GSM363240", "GSM363241", "GSM363242", "GSM363243", "GSM363244", "GSM363245", "GSM363246", "GSM363247", "GSM363248", "GSM363249", "GSM363250", "GSM363251", "GSM363252", "GSM363253", "GSM363254", "GSM363255", "GSM363256", "GSM363257", "GSM363258", "GSM363259", "GSM363260", "GSM363261", "GSM363262", "GSM363263", "GSM363264", "GSM363265", "GSM363266", "GSM363267", "GSM363268", "GSM363269", "GSM363270", "GSM363271", "GSM363272", "GSM363273", "GSM363274", "GSM363275", "GSM363276", "GSM363277", "GSM363278", "GSM363279", "GSM363280", "GSM363281", "GSM363282", "GSM363283", "GSM363284", "GSM363285", "GSM363286", "GSM363287", "GSM363288", "GSM363289", "GSM363290", "GSM363291", "GSM363292", "GSM363293", "GSM363294", "GSM363295", "GSM363296", "GSM363297", "GSM363298", "GSM363299", "GSM363300", "GSM363301", "GSM363302", "GSM363303", "GSM363304", "GSM363305", "GSM363306", "GSM363307", "GSM363308", "GSM363309", "GSM363310", "GSM363311", "GSM363312", "GSM363313", "GSM363314", "GSM363315", "GSM363316", "GSM363317", "GSM363318", "GSM363319", "GSM363320", "GSM363321", "GSM363322", "GSM363323", "GSM363324", "GSM363325", "GSM363326", "GSM363327", "GSM363328", "GSM363329", "GSM363330", "GSM363331", "GSM363332", "GSM363333", "GSM363334", "GSM363335", "GSM363336", "GSM363337", "GSM363338", "GSM363339", "GSM363340", "GSM363341", "GSM363342", "GSM363343", "GSM363344", "GSM363345", "GSM363346", "GSM363347", "GSM363348", "GSM363349", "GSM363350", "GSM363351", "GSM363352", "GSM363353", "GSM363354", "GSM363355", "GSM363356", "GSM363357", "GSM363358", "GSM363359", "GSM363360", "GSM363361", "GSM363362", "GSM363363", "GSM363364", "GSM363365", "GSM363366", "GSM363367", "GSM363368", "GSM363369", "GSM363370", "GSM363371", "GSM363372", "GSM363373", "GSM363374", "GSM363375", "GSM363376", "GSM363378", "GSM363380", "GSM363381", "GSM363382", "GSM363384", "GSM363386", "GSM363388", "GSM363391", "GSM363393", "GSM363397", "GSM363400", "GSM363402", "GSM363404", "GSM363407", "GSM363417", "GSM363420", "GSM363421", "GSM363422", "GSM363423", "GSM363424", "GSM363425", "GSM363426", "GSM363427", "GSM363428", "GSM363429", "GSM363430", "GSM363431", "GSM363432", "GSM363433", "GSM363434", "GSM363435", "GSM363436", "GSM363437", "GSM363438", "GSM363439", "GSM363440", "GSM363441", "GSM363442", "GSM363443", "GSM363444", "GSM363445", "GSM363446", "GSM363447", "GSM363448", "GSM363449", "GSM363450", "GSM363451", "GSM712532", "GSM712533", "GSM712534", "GSM712535", "GSM712536", "GSM712537", "GSM712538", "GSM712539", "GSM712540", "GSM712541", "GSM712542"], "sample_count": 488, "group_sizes": null, "group_sizes_basis": null, "platform": "3921;571", "taxon": "Homo sapiens", "title": "Gene expression data of human hepatocellular carcinoma (HCC)", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE14520 not downloaded", "asset:data:geo:GSE14520 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "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"], "evidence": {"score": 0.8, "band": "high", "quote": "analysis of variance"}}, {"id": "method-2", "family": "survival_analysis", "specific": "kaplan_meier", "label": "Survival analysis", "dsl_operations": ["survival_km"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "Kaplan-Meier"}}, {"id": "method-3", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.7, "band": "medium", "quote": "Cox regression"}}, {"id": "method-4", "family": "diagnostic_evaluation", "specific": "roc", "label": "Diagnostic test evaluation", "dsl_operations": ["confusion_counts", "roc_curve", "sensitivity_specificity", "solve_confusion_matrix", "classification_metrics", "published_precision_envelope"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["reference_standard_and_test"], "evidence": {"score": 0.8, "band": "high", "quote": "ROC curve"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: anova."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE14520"], "resolved_accessions": ["GSE14520"], "statements": ["Publicly available datasets were analyzed in this study; these can be found in The Cancer Genome Atlas (https://www.tcga.org/) and Deathbase (http://www.deathbase.org/)."], "basis": "The paper names GSE14520 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "assets": ["source:pmid:33680905", "data:geo:GSE14520"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE14520"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T19:26:57Z", "independence": "single_reader"}, "evidence_check": {"method": "absent", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 42009, "completion_tokens": 2492, "cached_tokens": 776}}, "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:33680905", "type": "paper", "label": "pmid:33680905"}, {"id": "source:pmid:33680905", "type": "manuscript", "label": "PMID 33680905 full text"}, {"id": "data:geo:GSE14520", "type": "dataset", "label": "GEO GSE14520"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:33680905", "type": "paper", "label": "pmid:33680905"}, {"id": "source:pmid:33680905", "type": "manuscript", "label": "PMID 33680905 full text"}, {"id": "data:geo:GSE14520", "type": "dataset", "label": "GEO GSE14520"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-33680905", "type": "extraction", "used": ["source:pmid:33680905"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE14520", "type": "accession_resolution", "used": ["data:geo:GSE14520"], "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:33680905", "parent_hash": "sha256:a43bcf10ad6e9ea5a57122e99578882efa5bb51c6d2f92f004ea518848a6d0e9", "fork_of": null, "generation": 6}, "gaps": ["asset:data:geo:GSE14520 licence not read", "asset:data:geo:GSE14520 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["Identifying Apoptosis-Related Transcriptomic Aberrations and Revea", "database, 14 differentially expressed human apoptosis genes were obtained. Using univariate and mu", "nd multivariate Cox regression analyses, two apoptosis genes (BAK1 and CSE1L) were determined to be", "ly inhibited cell proliferation and promoted apoptosis in the HCC. Then the two genes were used to"], "order_basis": "paper_text_order:0", "id": "assay:1"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["Identifying Apoptosis-Related Transcriptomic Aberrations and Revealing Clinical Relevance", "rate is poor, in this study we aimed to use RNA sequencing data to explore potential molecular markers", "s and prognosis of hepatocellular carcinoma. RNA sequencing data and corresponding clinical information"], "order_basis": "paper_text_order:0", "id": "assay:2"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["subsequently experiments also validated that knockdown of BAK1 and CSE1L significantly inhibited ce", "erature incubator. SK-HEP1 and SMMC-7721 was transfected 50 nM BAK1 and CSE1L siRNA in basic DMEM med", "Materials and Methods Cell Culture and siRNA Treatment The human hepatocellular carcinoma", "MC-7721 was transfected 50 nM BAK1 and CSE1L siRNA in basic DMEM media for 6–8 h before change"], "order_basis": "paper_text_order:911", "id": "assay:3"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["Collection (ATCC) (Manassas, VA, USA). Cells cultured in DMEM media supplemented with 2 mM L-glutamin"], "order_basis": "paper_text_order:2029", "id": "assay:4"}, {"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["lore the role of two apoptotic genes in HCC, qPCR assay was used to measure the mRNA of BAK1 a"], "order_basis": "paper_text_order:5828", "id": "assay:5"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["analysis of variance"], "order_basis": "consumes_earlier_output", "id": "assay:6"}]}