{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:29541007", "kind": "science-record", "revision": 6, "content_hash": "sha256:ece5c3d7fffbb3b62961508a7f18b14b7400f2dad09712db2483762c35885b2a", "created_at": "2026-11-01T15:40:32Z", "updated_at": "2026-11-01T21:21:20Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Proteomics-based insights into mitogen-activated protein kinase inhibitor resistance of cerebral melanoma metastases.", "doi": "10.1186/s12014-018-9189-x", "pmid": "29541007", "authors": ["Nina Zila", "Andrea Bileck", "Besnik Muqaku", "Lukas Janker", "Ossia M Eichhoff", "Phil F Cheng", "Reinhard Dummer", "Mitchell P Levesque", "Christopher Gerner", "Verena Paulitschke"], "journal": "Clinical proteomics", "year": 2018, "abstract": "BACKGROUND: MAP kinase inhibitor (MAPKi) therapy for BRAF mutated melanoma is characterized by high response rates but development of drug resistance within a median progression-free survival (PFS) of 9-12 months. Understanding mechanisms of resistance and identifying effective therapeutic alternatives is one of the most important scientific challenges in melanoma. Using proteomics, we want to specifically gain insight into the pathophysiological process of cerebral metastases.\nMETHODS: Cerebral metastases from melanoma patients were initially analyzed by a LC-MS shotgun approach performed on a QExactive HF hybrid quadrupole-orbitrap mass spectrometer. For further validation steps after bioinformatics analysis, a targeted LC-QQQ-MS approach, as well as Western blot, immunohistochemistry and immunocytochemistry was performed.\nRESULTS: In this pilot study, we were able to identify 5977 proteins by LC-MS analysis (data are available via ProteomeXchange with identifier PXD007592). Based on PFS, samples were classified into good responders (PFS ≥ 6 months) and poor responders (PFS [Formula: see text] 3 months). By evaluating these proteomic profiles according to gene ontology (GO) terms, KEGG pathways and gene set enrichment analysis (GSEA), we could characterize differences between the two distinct groups. We detected an EMT feature (up-regulation of N-cadherin) as classifier between the two groups, V-type proton ATPases, cell adhesion proteins and several transporter and exchanger proteins to be significantly up-regulated in poor responding patients, whereas good responders showed an immune activation, among other features. We identified class-discriminating proteins based on nearest shrunken centroids, validated and quantified this signature by a targeted approach and could correlate parts of this signature with resistance using the CPL/MUW proteome database and survival of patients by TCGA analysis. We further validated an EMT-like signature as a major discriminator between good and poor responders on primary melanoma cells derived from cerebral metastases. Higher immune activity is demonstrated in patients with good response to MAPKi by immunohistochemical staining of biopsy samples of cerebral melanoma metastases.\nCONCLUSIONS: Employing proteomic analysis, we confirmed known extra-cerebral resistance mechanisms in the cerebral metastases and further discovered possible brain specific mechanisms of drug efflux, which might serve as treatment targets or as predictive markers for these kinds of metastasis.", "claims": [{"id": "claim-method", "statement": "To identify a potential biomarker profile, a classifier based on nearest shrunken centroids was constructed using ClaNC and R [43]. Priors were chosen according to the number of samples. The performance of the classifier was tested by leaving-one-out cross validation.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29541007", "locator": "sections[5] \"LC–MS shotgun data analysis\" paragraph 2", "quote": "To identify a potential biomarker profile, a classifier based on nearest shrunken centroids was constructed using ClaNC and R [43]. Priors were chosen according to the number of samples. The performance of the classifier was tested by leaving-one-out cross validation."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD007592 and https://doi.org/10.6019/pxd007592.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29541007", "locator": "sections[31] \"Availability of data and material\" paragraph 2", "quote": "The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD007592 and https://doi.org/10.6019/pxd007592."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The paper used a nearest-shrunken-centroids classifier to identify discriminative proteins, and the underlying LC–MS proteomics source data were made available through ProteomeXchange under identifier PXD007592.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:29541007", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "We identified class-discriminating proteins based on nearest shrunken centroids, validated and quantified this signature by a targeted approach and could correlate parts of this signature with resistance using the CPL/MUW proteome database and survival of patients by TCGA analysis."}, {"asset": "source:pmid:29541007", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "In this pilot study, we were able to identify 5977 proteins by LC–MS analysis (data are available via ProteomeXchange with identifier PXD007592)."}, {"asset": "source:pmid:29541007", "locator": "sections[17] \"Identification of discriminative proteins\" paragraph 2", "quote": "To generalize our proteomic findings and enable the translation of the results towards clinical application, we constructed a classifier based on nearest shrunken centroids to identify a potential biomarker profile."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The paper used a nearest-shrunken-centroids classifier to identify discriminative proteins, and the underlying LC–MS proteomics source data were made available through ProteomeXchange under identifier PXD007592.", "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:29541007"], "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:PXD007592"], "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:PXD007592"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:29541007", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s12014-018-9189-x", "sha256": "sha256:f62a81b8303c459ffbebda6170703a4fa3852551d3ff8d10dee783357a6ff5e2", "bytes": 79206, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s12014-018-9189-x", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC5844114", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:PXD007592", "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=PXD007592", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "PXD007592", "version": null, "note": "The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD007592 and https://doi.org/10.6019/pxd007592.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD007592 and https://doi.org/10.6019/pxd007592.", "access_statement_kind": "data_availability_statement", "sample_accessions": [], "sample_count": null, "group_sizes": null, "group_sizes_basis": null, "platform": null, "taxon": null, "title": "Proteomics-based insights into mitogen-activated protein kinase inhibitor resistance of cerebral melanoma metastases", "resolution_checked_at": "2026-10-31T18:35:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:29541007:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:98cdeee604786d1a96eed6c0485f2a3576c0c8d53ee8171cb5ca44b0dff046b7", "bytes": 7155, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#Tab1", "version": null, "note": "Proteins significantly up-regulated in poor responder patients as indicated in the volcano plot", "structure": {"pmcid": "PMC5844114", "section_index": 16, "section_title": "Functional discrimination of the subgroups", "row_count": 86, "column_count": 6}, "table": {"label": "Table 1", "caption": "Proteins significantly up-regulated in poor responder patients as indicated in the volcano plot", "rows": [["Acc. Nr.", "Protein name", "Gene name", "log2 fold change (t-test difference)", "p value", "t-test significant"], ["Eukaryotic translation initiation factors (EIFs)"], ["Q14232", "Translation initiation factor eIF-2B subunit alpha", "EIF2B1", "1.04", "2.48E − 03", ""], ["Q14152", "Eukaryotic translation initiation factor 3 subunit A", "EIF3A", "1.13", "5.71E − 03", ""], ["P55884", "Eukaryotic translation initiation factor 3 subunit B", "EIF3B", "1.57", "3.62E − 03", ""], ["O00303", "Eukaryotic translation initiation factor 3 subunit F", "EIF3F", "1.23", "9.41E − 03", ""], ["O75821", "Eukaryotic translation initiation factor 3 subunit G", "EIF3G", "1.59", "4.81E − 02", ""], ["Q13347", "Eukaryotic translation initiation factor 3 subunit I", "EIF3I", "2.88", "4.29E − 05", "*"], ["Q9UBQ5", "Eukaryotic translation initiation factor 3 subunit K", "EIF3 K", "1.85", "3.50E − 05", ""], ["Q9Y262", "Eukaryotic translation initiation factor 3 subunit L", "EIF3L", "1.57", "7.30E − 03", ""], ["P23588", "Eukaryotic translation initiation factor 4B", "EIF4B", "1.69", "1.44E − 03", ""], ["Q15056", "Eukaryotic translation initiation factor 4H", "EIF4H", "1.68", "3.92E − 04", ""], ["O60841", "Eukaryotic translation initiation factor 5B", "EIF5B", "1.26", "2.53E − 02", ""], ["Neuronal proteins"], ["Q8N111", "Cell cycle exit and neuronal differentiation protein 1", "CEND1", "2.86", "1.98E − 03", ""], ["P51674", "Neuronal membrane glycoprotein M6-a", "GPM6A", "5.30", "5.24E − 05", "*"], ["P62166", "Neuronal calcium sensor 1", "NCS1", "3.55", "6.65E − 05", "*"], ["Q7Z3B1", "Neuronal growth regulator 1", "NEGR1", "3.71", "1.93E − 03", ""], ["Q15818", "Neuronal pentraxin-1", "NPTX1", "3.07", "4.79E − 03", ""], ["Q92823", "Neuronal cell adhesion molecule", "NRCAM", "2.44", "3.48E − 03", ""], ["Q9UH03", "Neuronal-specific septin-3", "SEPT3", "3.40", "3.68E − 04", ""], ["P17600", "Synapsin-1", "SYN1", "4.68", "2.47E − 04", "*"], ["Q92777", "Synapsin-2", "SYN2", "5.49", "3.17E − 04", "*"], ["O14994", "Synapsin-3", "SYN3", "2.46", "5.70E − 03", ""], ["Transporter proteins"], ["P30531", "Sodium- and chloride-dependent GABA transporter 1", "SLC6A1", "3.44", "8.85E − 06", "*"], ["P43003", "Excitatory amino acid transporter 1", "SLC1A3", "3.17", "2.51E − 03", ""], ["P43004", "Excitatory amino acid transporter 2", "SLC1A2", "4.98", "5.16E − 03", ""], ["P43007", "Neutral amino acid transporter A", "SLC1A4", "1.81", "4.10E − 02", ""], ["P48066", "Sodium- and chloride-dependent GABA transporter 3", "SLC6A11", "2.12", "4.95E − 04", ""], ["Q15043", "Zinc transporter ZIP14", "SLC39A14", "1.28", "3.30E − 03", ""], ["Q6PML9", "Zinc transporter 9", "SLC30A9", "1.57", "1.36E − 02", ""], ["Q8N4V1", "Membrane magnesium transporter 1", "MMGT1", "1.19", "3.22E − 02", ""], ["Q8TBB6", "Probable cationic amino acid transporter", "SLC7A14", "1.78", "6.86E − 03", ""], ["Q96QE2", "Proton myo-inositol cotransporter", "SLC2A13", "2.68", "1.94E − 06", "*"], ["Q99726", "Zinc transporter 3", "SLC30A3", "2.03", "2.95E − 02", ""], ["Q9H1V8", "Sodium-dependent neutral amino acid transporter SLC6A17", "SLC6A17", "2.51", "1.39E − 02", ""], ["Q9NS82", "Asc-type amino acid transporter 1", "SLC7A10", "1.44", "6.39E − 03", ""], ["Exchanger proteins"], ["P32418", "Sodium/calcium exchanger 1", "SLC8A1", "1.66", "4.06E − 02", ""], ["Q8TCU6", "Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein", "PREX1", "1.03", "1.03E − 03", ""], ["Q92581", "Sodium/hydrogen exchanger 6", "SLC9A6", "1.76", "9.73E − 03", ""], ["Q9UPR5", "Sodium/calcium exchanger 2", "SLC8A2", "4.39", "1.18E − 03", ""], ["V-type proton ATPases"], ["Q15904", "V-type proton ATPase subunit S1", "ATP6AP1", "1.41", "3.12E − 02", ""], ["Q93050", "V-type proton ATPase 116 kDa subunit a isoform 1", "ATP6V0A1", "2.57", "2.75E − 04", ""], ["P27449", "V-type proton ATPase 16 kDa proteolipid subunit", "ATP6V0C", "2.36", "5.37E − 03", ""], ["P61421", "V-type proton ATPase subunit d 1", "ATP6V0D1", "3.96", "8.92E − 07", "*"], ["P38606", "V-type proton ATPase catalytic subunit A", "ATP6V1A", "1.82", "6.37E − 05", ""], ["P21281", "V-type proton ATPase subunit B, brain isoform", "ATP6V1B2", "1.62", "2.37E − 04", ""], ["P21283", "V-type proton ATPase subunit C 1", "ATP6V1C1", "1.51", "5.27E − 05", ""], ["Q9Y5K8", "V-type proton ATPase subunit D", "ATP6V1D", "2.19", "5.15E − 04", ""], ["P36543", "V-type proton ATPase subunit E 1", "ATP6V1E1", "1.27", "6.60E − 04", ""], ["Q16864", "V-type proton ATPase subunit F", "ATP6V1F", "3.12", "5.47E − 07", "*"], ["O75348", "V-type proton ATPase subunit G 1", "ATP6V1G1", "2.39", "5.16E − 04", ""], ["O95670", "V-type proton ATPase subunit G 2", "ATP6V1G2", "1.40", "4.11E − 04", ""], ["Q9UI12", "V-type proton ATPase subunit H", "ATP6V1H", "2.75", "4.83E − 04", ""], ["MAP-kinases"], ["P28482", "Mitogen-activated protein kinase 1", "MAPK1", "1.78", "6.70E − 04", ""], ["P53779", "Mitogen-activated protein kinase 10", "MAPK10", "2.27", "1.27E − 03", ""], ["P27361", "Mitogen-activated protein kinase 3", "MAPK3", "1.79", "1.39E − 03", ""], ["Q9UPT6", "C-Jun-amino-terminal kinase-interacting protein 3", "MAPK8IP3", "2.21", "1.83E − 03", ""], ["Cell adhesion proteins"], ["O00533", "Neural cell adhesion molecule L1-like protein", "CHL1", "1.59", "3.85E − 02", ""], ["O15394", "Neural cell adhesion molecule 2", "NCAM2", "2.56", "1.84E − 02", ""], ["P13591", "Neural cell adhesion molecule 1", "NCAM1", "3.72", "1.12E − 04", "*"], ["P32004", "Neural cell adhesion molecule L1", "L1CAM", "4.27", "1.91E − 06", "*"], ["Q14982", "Opioid-binding protein/cell adhesion molecule", "OPCML", "4.53", "7.99E − 04", "*"], ["Q14CZ8", "Hepatocyte cell adhesion molecule", "HEPACAM", "2.49", "1.23E − 02", ""], ["Q8N3J6", "Cell adhesion molecule 2", "CADM2", "4.32", "1.24E − 03", ""], ["Q8NFZ8", "Cell adhesion molecule 4", "CADM4", "1.74", "2.53E − 02", ""], ["Q92823", "Neuronal cell adhesion molecule", "NRCAM", "2.44", "3.48E − 03", ""], ["Calcium-ion binding proteins"], ["P62158", "Calmodulin", "CALM1", "1.36", "9.22E − 06", ""], ["Q14012", "Calcium/calmodulin-dependent protein kinase type 1", "CAMK1", "2.17", "4.56E − 04", ""], ["Q9UQM7", "Calcium/calmodulin-dependent protein kinase type II subunit alpha", "CAMK2A", "3.00", "5.85E − 04", ""], ["Q13554", "Calcium/calmodulin-dependent protein kinase type II subunit beta", "CAMK2B", "3.98", "2.08E − 03", ""], ["Q13555", "Calcium/calmodulin-dependent protein kinase type II subunit gamma", "CAMK2G", "2.77", "5.24E − 03", ""], ["Q16566", "Calcium/calmodulin-dependent protein kinase type IV", "CAMK4", "1.98", "1.25E − 02", ""], ["Q8N5S9", "Calcium/calmodulin-dependent protein kinase kinase 1", "CAMKK1", "2.13", "8.09E − 03", ""], ["Q96RR4", "Calcium/calmodulin-dependent protein kinase kinase 2", "CAMKK2", "2.03", "8.67E − 03", ""], ["Q9P1Y5", "Calmodulin-regulated spectrin-associated protein 3", "CAMSAP3", "2.35", "8.13E − 03", ""], ["P54750", "Calcium/calmodulin-dependent 3,5-cyclic nucleotide phosphodiesterase 1A", "PDE1A", "1.97", "5.00E − 03", ""], ["Q01064", "Calcium/calmodulin-dependent 3,5-cyclic nucleotide phosphodiesterase 1B", "PDE1B", "2.54", "1.25E − 02", ""], ["EMT"], ["P19022", "Cadherin-2", "CDH2", "2.53", "1.02E − 03", ""]], "row_count": 86, "column_count": 6, "numeric_cells": 277, "header_rows": 1, "locator": "section[16]/table-wrap[1]#Tab1"}}, {"id": "asset:table:pmid:29541007:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:3364b96bb8beb44a8da39939d6af356a3e8e6b383a1f3a6306d46906a9fc2b9c", "bytes": 3146, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[2]#Tab2", "version": null, "note": "Proteins significantly up-regulated in good responder patients as indicated in the volcano plot", "structure": {"pmcid": "PMC5844114", "section_index": 16, "section_title": "Functional discrimination of the subgroups", "row_count": 39, "column_count": 6}, "table": {"label": "Table 2", "caption": "Proteins significantly up-regulated in good responder patients as indicated in the volcano plot", "rows": [["Acc. Nr.", "Protein name", "Gene name", "log2 fold change (t-test difference)", "p value", "t-test significant"], ["Immune response related proteins"], ["P05164", "Myeloperoxidase", "MPO", "4.53", "1.69E − 05", "*"], ["P01909", "HLA class II histocompatibility antigen, DQ alpha 1 chain", "HLA-DQA1", "1.43", "1.01E − 03", ""], ["P04233", "HLA class II histocompatibility antigen gamma chain", "CD74", "1.74", "7.47E − 03", ""], ["P20039", "HLA class II histocompatibility antigen, DRB1-11 beta chain", "HLA-DRB1", "2.99", "2.46E − 03", ""], ["Q95365", "HLA class I histocompatibility antigen, B-38 alpha chain", "HLA-B", "1.84", "3.64E − 03", ""], ["Q5Y7A7", "HLA class II histocompatibility antigen, DRB1-13 beta chain", "HLA-DRB1", "1.38", "1.70E − 03", ""], ["P01594", "Ig kappa chain V-I region AU", "", "1.07", "7.46E − 03", ""], ["P01609", "Ig kappa chain V-I region Scw", "", "1.58", "2.02E − 03", ""], ["P01613", "Ig kappa chain V-I region Ni", "", "1.86", "1.68E − 02", ""], ["P01617", "Ig kappa chain V-II region TEW", "", "1.61", "4.60E − 03", ""], ["P01623", "Ig kappa chain V-III region WOL", "", "1.89", "1.87E − 03", ""], ["P01777", "Ig heavy chain V-III region TEI", "", "1.78", "1.97E − 03", ""], ["P01767", "Ig heavy chain V-III region BUT", "", "1.46", "3.39E − 02", ""], ["P01779", "Ig heavy chain V-III region TUR", "", "2.24", "9.82E − 04", ""], ["P01834", "Ig kappa chain C region", "IGKC", "1.56", "4.17E − 03", ""], ["P01857", "Ig gamma-1 chain C region", "IGHG1", "1.40", "9.49E − 03", ""], ["P01860", "Ig gamma-3 chain C region", "IGHG3", "1.42", "1.01E − 02", ""], ["P01871", "Ig mu chain C region", "IGHM", "2.24", "7.25E − 03", ""], ["P01876", "Ig alpha-1 chain C region", "IGHA1", "1.12", "5.26E − 02", ""], ["P01880", "Ig delta chain C region", "IGHD", "1.36", "4.04E − 02", ""], ["Apolipoproteins"], ["O14791", "Apolipoprotein L1", "APOL1", "1.82", "1.43E − 03", ""], ["P02647", "Apolipoprotein A-I", "APOA1", "1.94", "2.86E − 04", ""], ["P04114", "Apolipoprotein B-100", "APOB", "3.55", "1.17E − 03", ""], ["P06727", "Apolipoprotein A-IV", "APOA4", "5.06", "2.61E − 06", "*"], ["Cell adhesion (in immune response)"], ["P16284", "Platelet endothelial cell adhesion molecule", "PECAM1", "1.48", "5.04E − 02", ""], ["P31997", "Carcinoembryonic antigen-related cell adhesion molecule 8", "CEACAM8", "1.86", "3.08E − 03", ""], ["P40199", "Carcinoembryonic antigen-related cell adhesion molecule 6", "CEACAM6", "1.16", "3.99E − 02", ""], ["Extracellular matrix (ECM) components"], ["P02452", "Collagen alpha-1(I) chain", "COL1A1", "3.67", "2.18E − 02", ""], ["P02751", "Fibronectin", "FN1", "2.61", "4.26E − 03", ""], ["P08123", "Collagen alpha-2(I) chain", "COL1A2", "3.24", "1.25E − 02", ""], ["P25067", "Collagen alpha-2(VIII) chain", "COL8A2", "1.29", "9.84E − 03", ""], ["P39059", "Collagen alpha-1(XV) chain", "COL15A1", "1.48", "4.46E − 02", ""], ["Q05707", "Collagen alpha-1(XIV) chain", "COL14A1", "2.53", "5.55E − 02", ""], ["Q96P44", "Collagen alpha-1(XXI) chain", "COL21A1", "1.78", "3.42E − 02", ""]], "row_count": 39, "column_count": 6, "numeric_cells": 121, "header_rows": 1, "locator": "section[16]/table-wrap[2]#Tab2"}}, {"id": "asset:table:pmid:29541007:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:7ef1ee85a3f72714a45e0c2812388f54d449eb4d7c9ee650fda8af7cc14f9dc1", "bytes": 3521, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[17]/table-wrap[1]#Tab3", "version": null, "note": "Classification to nearest shrunken centroids for identification of the most class-discriminating proteins", "structure": {"pmcid": "PMC5844114", "section_index": 17, "section_title": "Identification of discriminative proteins", "row_count": 10, "column_count": 7}, "table": {"label": "Table 3", "caption": "Classification to nearest shrunken centroids for identification of the most class-discriminating proteins", "rows": [["Acc. Nr.", "Protein name", "Gene name", "log2 fold change (t-test difference)upregulated in poor responder", "p value", "t-test significant", "Functional role"], ["P21266", "Glutathione S-transferase Mu 3", "GSTM3", "2.68", "7.13E − 07", "*", "Uptake and detoxification of endogenous compounds and xenobiotics at the blood brain barrier [80]; many anticancer drugs are substrates for GST and, therefore, overexpression of GST is responsible for resistance to anti-cancer drugs in tumor cell lines [81]"], ["P61962", "DDB1- and CUL4-associated factor 7", "DCAF7", "2.06", "1.11E − 07", "*", "Substrate receptor for a ubiquitin-protein ligase complex; involved in the pathway protein ubiquitination; involved in normal and disease skin development [82]; has been shown to function as a scaffold protein for protein complexes involved in kinase signalling [83]"], ["P62937", "Peptidyl-prolyl cis–trans isomerase A", "PPIA", "0.75", "4.98E − 07", "", "Upregulated in resistant human breast cancer cell line (vs. sensitive cell line) [84]; PPIases accelerate the folding of proteins; catalyzes the cis–trans isomerization of proline imidic peptide bonds in oligopeptides [85]"], ["Q16864", "V-type proton ATPase subunit F", "ATP6V1F", "3.12", "5.47E − 07", "*", "V-ATPases are responsible for acidifying intracellular compartments [86]; an acidic environment leads to inactivation of T cells [56, 57]; supports the hypothesis that resistance is caused by the tumor inactivating immune cells"], ["Q6FI81", "Anamorsin", "CIAPIN1", "2.46", "2.38E − 05", "", "Anti-apoptotic effects in the cell; involved in negative control of cell death upon cytokine withdrawal [87]; may participate in breast cancer multi drug resistance (MDR) by regulating MDR1 and P53 expression, changing cell cycle and enhancing the anti-apoptotic capability of cells [88]"], ["Q6UWP2", "Dehydrogenase/reductase SDR family member 11", "DHRS11", "2.10", "1.64E − 07", "*", "Involved in estrogen biosynthesis, which is part of steroid biosynthesis [89]; proposed role in sex hormone, neurosteroid, androgen, estrogen and bile acid metabolism; mRNA highly expressed in testis, small intestine, colon, kidney and cancer cell lines [90]"], ["Q7Z7E8", "Ubiquitin-conjugating enzyme E2 Q1", "UBE2Q1", "1.80", "3.14E − 05", "", "Catalyzes the covalent attachment of ubiquitin to other proteins [91]; may function as an oncogene that induces proliferation of cancer cells, and could be a novel diagnostic tool and a potential therapeutic target for colorectal cancer (CRC) [92]"], ["Q8IVD9", "NudC domain-containing protein 3", "NUDCD3", "2.42", "2.78E − 05", "", "Interacts selectively and non-covalently with an unfolded protein; functions to maintain the stability of dynein intermediate chain [93]; depletion of this gene product results in aggregation and degradation of dynein intermediate chain, mislocalization of the dynein complex from kinetochores, spindle microtubules, and spindle poles, and loss of gamma-tubulin from spindle poles [94]"], ["Q8N4Q0", "Prostaglandin reductase 3", "ZADH2", "2.48", "2.44E − 06", "*", "Negatively modulates adipogenesis through regulation of PPARγ activity [95]; knockdown of prostaglandin reductase 1 (PTGR1) suppresses prostate cancer cell proliferation by inducing cell cycle arrest and apoptosis [96]"]], "row_count": 10, "column_count": 7, "numeric_cells": 38, "header_rows": 1, "locator": "section[17]/table-wrap[1]#Tab3"}}], "gaps": ["asset:data:geo:PXD007592 not downloaded", "asset:data:geo:PXD007592 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "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-2", "family": null, "specific": null, "label": "Nearest shrunken centroids classifier, tested by leaving-one-out cross-validation", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "verbatim", "quote": "To identify a potential biomarker profile, a classifier based on nearest shrunken centroids was constructed using ClaNC and R [43]. Priors were chosen according to the number of samples. The performance of the classifier was tested by leaving-one-out cross validation."}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "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": ["survival_km"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: kaplan_meier."}, "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": ["PXD007592"], "resolved_accessions": ["PXD007592"], "statements": ["The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD007592 and https://doi.org/10.6019/pxd007592."], "basis": "The paper names PXD007592 in ProteomeXchange Consortium via the PRIDE partner repository and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["survival_km"], "assets": ["source:pmid:29541007", "data:geo:PXD007592", "asset:table:pmid:29541007:1", "asset:table:pmid:29541007:2", "asset:table:pmid:29541007:3"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:PXD007592"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:33:53Z", "independence": "same_provider"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 8, "usage": {"prompt_tokens": 161412, "completion_tokens": 4258, "cached_tokens": 2088}}, "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:29541007", "type": "paper", "label": "pmid:29541007"}, {"id": "source:pmid:29541007", "type": "manuscript", "label": "PMID 29541007 full text"}, {"id": "data:geo:PXD007592", "type": "dataset", "label": "GEO PXD007592"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:29541007", "type": "paper", "label": "pmid:29541007"}, {"id": "source:pmid:29541007", "type": "manuscript", "label": "PMID 29541007 full text"}, {"id": "data:geo:PXD007592", "type": "dataset", "label": "GEO PXD007592"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-29541007", "type": "extraction", "used": ["source:pmid:29541007"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-PXD007592", "type": "accession_resolution", "used": ["data:geo:PXD007592"], "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:29541007", "parent_hash": "sha256:4459388df60e502c236bb49cbf06e16c4afa984b1faf42864991c8f8e31205bc", "fork_of": null, "generation": 5}, "gaps": ["asset:data:geo:PXD007592 licence not read", "asset:data:geo:PXD007592 not downloaded", "execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["s, a targeted LC-QQQ-MS approach, as well as Western blot, immunohistochemistry and immunocytochemistr", "erived from cerebral melanoma metastases and Western blot on the lysates of these cells with E- and N-", "in negativity in immunocytochemistry (b) and Western blot (c), whereas resistant cells show E-cadherin"], "order_basis": "paper_text_order:836", "id": "assay:1"}, {"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": ["LC-QQQ-MS approach, as well as Western blot, immunohistochemistry and immunocytochemistry was performed. RESUL", "d in patients with good response to MAPKi by immunohistochemical staining of biopsy samples of cerebral melan"], "order_basis": "paper_text_order:850", "id": "assay:2"}, {"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": ["r the BRAF/MEK inhibitors as determined by a viability assay. By these experiments we could show that the", "fication of the samples by proliferation and viability assay and calculation of the IC50 for BRAF/MEK inh"], "order_basis": "paper_text_order:8000", "id": "assay:3"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Kaplan-meier"], "order_basis": "consumes_earlier_output", "id": "assay:4"}]},"meta":{"api_version":"v1","automation_ladder_snapshot":"ba34b49490d9bfaf","automation_ladder_caveats":["Method extraction is rule-based and has no hand-judged accuracy sample. Evidence bands order textual support; method agreement intervals are null (n=0), never probabilities. Work-type validation does not validate methods.","Operation coverage describes only explicitly named methods. It does not prove a complete protocol, compatible parameters, successful compilation or re-execution. Unrecognised or ambiguous methods require review.","Data reachability is a textual accession or public-data statement. No dataset was downloaded or checked for access, completeness or licence.","Capabilities are planning states seeded from the dated equipment register. No bench ownership, completed quote or partner booking is inferred. Procurement counts are dependencies, not guaranteed replications or financial returns.","Tier and blocker counts are deterministic assessments of this corpus, not measured agreement. R3 is reserved for procurement; unresolved methods and data require human work (R4). The most restrictive axis wins, with capability, method, data as tie-breaks. 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":"2026-11-04T02:57:58+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}}}