{"version":"6.9","hitCount":10,"resultList":{"result":[{"id":"PPR1221412","source":"PPR","doi":"10.64898/2026.03.02.709044","title":"Proteomics-Enhanced AI-Digital Pathology in Metastatic Mucinous Colorectal Carcinoma: A Case Report","authorString":"Fülöp L, Szigeti B, Guedes J, Woldmar N, Oskolás H, Marko-Varga M, Appelqvist R, Wieslander E, Pawlowski K, Szadai L, Christersson L, Malm J, Németh IB, Szasz MA, Gil J, Marko-Varga G.","authorList":{"author":[{"fullName":"Fülöp L","firstName":"Livia","lastName":"Fülöp","initials":"L"},{"fullName":"Szigeti B","firstName":"Balázs","lastName":"Szigeti","initials":"B"},{"fullName":"Guedes J","firstName":"Jéssica","lastName":"Guedes","initials":"J"},{"fullName":"Woldmar N","firstName":"Nicole","lastName":"Woldmar","initials":"N"},{"fullName":"Oskolás H","firstName":"Henriett","lastName":"Oskolás","initials":"H"},{"fullName":"Marko-Varga M","firstName":"Matilda","lastName":"Marko-Varga","initials":"M"},{"fullName":"Appelqvist R","firstName":"Roger","lastName":"Appelqvist","initials":"R"},{"fullName":"Wieslander E","firstName":"Elisabet","lastName":"Wieslander","initials":"E"},{"fullName":"Pawlowski K","firstName":"Krysztof","lastName":"Pawlowski","initials":"K"},{"fullName":"Szadai L","firstName":"Leticia","lastName":"Szadai","initials":"L","authorId":{"type":"ORCID","value":"0000-0002-3605-839X"}},{"fullName":"Christersson L","firstName":"Lukas","lastName":"Christersson","initials":"L"},{"fullName":"Malm J","firstName":"Johan","lastName":"Malm","initials":"J"},{"fullName":"Németh IB","firstName":"István Balázs","lastName":"Németh","initials":"IB"},{"fullName":"Szasz MA","firstName":"Marcell","lastName":"Szasz","initials":"MA"},{"fullName":"Gil J","firstName":"Jeovanis","lastName":"Gil","initials":"J"},{"fullName":"Marko-Varga G","firstName":"György","lastName":"Marko-Varga","initials":"G"}]},"authorIdList":{"authorId":[{"type":"ORCID","value":"0000-0002-3605-839X"}]},"pubYear":"2026","abstractText":"Mucinous colorectal carcinoma (CRC) is a distinct histomorphological subtype characterized by abundant extracellular mucin that may promote immune evasion and chemoresistance. We describe a metastatic mucinous CRC case integrating digital pathology and proteomics to investigate disease progression and therapy resistance. Formalin-fixed paraffin-embedded samples from the primary tumor, peritoneal metastasis, and hepatoduodenal ligament metastasis of a 56-year-old patient were analyzed. Whole-slide imaging with QuPath-based AI enabled detailed histological annotation, while data-independent acquisition mass spectrometry identified over 6,000 proteins. Digital pathology revealed extensive mucin pools, architectural evolution from heterogeneous glandular patterns in the primary tumor to cribriform morphology in advanced metastases, and immune cell exclusion from mucin-rich regions. Proteomics revealed metabolic reprogramming, suppressed antigen presentation, and stage-specific activation of inflammatory, angiogenic, EMT, and PI3K/AKT/mTOR–MYC signaling pathways, consistent with proliferative and therapy-resistant phenotypes.Integration of AI-assisted histopathology with spatial proteomics highlighted the mucin barrier as a key mediator of immune evasion and chemoresistance. These findings support a personalized therapeutic framework targeting mucin-associated mechanisms alongside pathway-directed inhibitors, suggesting that spatial multi-omics may guide precision management strategies for aggressive mucinous colorectal cancer.","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"bioRxiv","yearOfPublication":2026},"grantsList":{"grant":[{"grantId":"FBKS-2025-18 - (671)","agency":"Berta Kamprad Foundation, Lund, Sweden","orderIn":0}]},"fullTextUrlList":{"fullTextUrl":[{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.64898/2026.03.02.709044"}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"Y","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"N","hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2026-05-19","firstIndexDate":"2026-05-19","firstPublicationDate":"2026-03-04"},{"id":"PPR1242577","source":"PPR","doi":"10.21203/rs.3.rs-9746720/v1","title":"Colorectal mucinous adenocarcinoma with signet-ring cells: a case report","authorString":"Liu Y, Zeng W, Ma S, Cao H.","authorList":{"author":[{"fullName":"Liu Y","firstName":"Yuan-sheng","lastName":"Liu","initials":"Y"},{"fullName":"Zeng W","firstName":"Wei-Ting","lastName":"Zeng","initials":"W"},{"fullName":"Ma S","firstName":"Song-Yan","lastName":"Ma","initials":"S"},{"fullName":"Cao H","firstName":"Hui-Qiong","lastName":"Cao","initials":"H"}]},"pubYear":"2026","abstractText":"Abstract

Background: In recent years, only a few cases of mucinous adenocarcinoma with signet-ring cell carcinoma (MAC-SRC) have been reported, and detailed endoscopic imaging features remain poorly characterized. This is likely because these tumors are often already at an advanced stage at diagnosis, rendering endoscopic examination infeasible. We herein report a young Asian male diagnosed with sigmoid colon MAC-SRC (60% mucinous adenocarcinoma, 40% signet-ring cell carcinoma). Case presentation: A 27-year-old male presented with recurrent vomiting for 20 days. Abdominal computed tomography showed marked thickening of the sigmoid colon wall. Colonoscopy demonstrated luminal stenosis and rigidity, with extensive erosive lesions covered by abundant, difficult-to-irrigate white mucus; the lesion measured 8 cm in length. Biopsy confirmed mucinous adenocarcinoma. The patient underwent left hemicolectomy, and postoperative pathology verified MAC-SRC. Two months after initiating chemotherapy, the patient was in good condition, with occasional abdominal distension and a weight gain of 2.5 kg. Conclusions: Compared with conventional adenocarcinoma, MAC-SRC in young patients shows distinct clinical features and carries a high risk of missed diagnosis. Colonoscopy with adequate biopsy is essential. This patient initially presented with upper gastrointestinal symptoms, leading to a delay in diagnosis. Timely intervention was initiated following endoscopic detection of mucosal abnormalities and confirmatory biopsy findings. The endoscopic characteristics we describe provide diagnostic evidence for MAC-SRC and have important clinical implications.

","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"Research Square","yearOfPublication":2026},"fullTextUrlList":{"fullTextUrl":[{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.21203/rs.3.rs-9746720/v1"}]},"commentCorrectionList":{"commentCorrection":[{"id":"42363138","source":"MED","reference":"BMC gastroenterology. 2026 Jun;:","type":"Preprint of","note":"CrossRef Pre-print loader","orderIn":10001}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"N","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"N","versionList":{"version":[{"id":"PPR1242577","source":"PPR","firstPublishDate":"2026-05-31","versionNumber":1,"pubTypeList":{"pubType":["preprint"]},"hasEvaluations":"N"}]},"versionNumber":1,"hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2026-06-03","firstIndexDate":"2026-06-03","firstPublicationDate":"2026-05-31"},{"id":"PPR944052","source":"PPR","doi":"10.1101/2024.11.20.624298","title":"Signaling downstream of tumor-stroma interaction regulates mucinous colorectal adenocarcinoma apicobasal polarity","authorString":"Pasquier N, Isomursu A, Hamidi H, Mathieu JR, Härkönen J, Follain G, Desterke C, Fusilier Z, Solis J, Belaya I, Kankaanpää P, Barresi V, Cartry J, Bedja S, Jaulin F, Ivaska J.","authorList":{"author":[{"fullName":"Pasquier N","firstName":"Nicolas","lastName":"Pasquier","initials":"N"},{"fullName":"Isomursu A","firstName":"Aleksi","lastName":"Isomursu","initials":"A","authorId":{"type":"ORCID","value":"0000-0001-6006-9163"}},{"fullName":"Hamidi H","firstName":"Hellyeh","lastName":"Hamidi","initials":"H","authorId":{"type":"ORCID","value":"0000-0003-4841-8927"}},{"fullName":"Mathieu JR","firstName":"Jacques R.R.","lastName":"Mathieu","initials":"JR","authorId":{"type":"ORCID","value":"0009-0005-2239-6303"}},{"fullName":"Härkönen J","firstName":"Jouni","lastName":"Härkönen","initials":"J"},{"fullName":"Follain G","firstName":"Gautier","lastName":"Follain","initials":"G","authorId":{"type":"ORCID","value":"0000-0003-0495-9529"}},{"fullName":"Desterke C","firstName":"Christophe","lastName":"Desterke","initials":"C","authorId":{"type":"ORCID","value":"0000-0001-7679-2524"}},{"fullName":"Fusilier Z","firstName":"Zoé","lastName":"Fusilier","initials":"Z"},{"fullName":"Solis J","firstName":"Junel","lastName":"Solis","initials":"J","authorId":{"type":"ORCID","value":"0000-0003-0972-5262"}},{"fullName":"Belaya I","firstName":"Irina","lastName":"Belaya","initials":"I"},{"fullName":"Kankaanpää P","firstName":"Pasi","lastName":"Kankaanpää","initials":"P"},{"fullName":"Barresi V","firstName":"Valeria","lastName":"Barresi","initials":"V"},{"fullName":"Cartry J","firstName":"Jérôme","lastName":"Cartry","initials":"J"},{"fullName":"Bedja S","firstName":"Sabrina","lastName":"Bedja","initials":"S"},{"fullName":"Jaulin F","firstName":"Fanny","lastName":"Jaulin","initials":"F"},{"fullName":"Ivaska J","firstName":"Johanna","lastName":"Ivaska","initials":"J"}]},"authorIdList":{"authorId":[{"type":"ORCID","value":"0000-0001-6006-9163"},{"type":"ORCID","value":"0000-0001-7594-0679"},{"type":"ORCID","value":"0000-0001-7679-2524"},{"type":"ORCID","value":"0000-0003-0495-9529"},{"type":"ORCID","value":"0000-0003-0972-5262"},{"type":"ORCID","value":"0000-0003-4841-8927"},{"type":"ORCID","value":"0009-0005-2239-6303"}]},"dataLinksTagsList":{"dataLinkstag":["altmetrics"]},"pubYear":"2024","abstractText":"Mucinous colorectal carcinoma (MUC CRC) dissemination into the tumor stroma and metastasis to multiple organs, including the peritoneum, is associated with poor prognosis. Disseminating MUC CRCs exhibit either a conventional ‘apical-in’ or an inverted ‘apical-out’ polarity phenotype that influence patient outcome. Identifying the mechanisms controlling MUC CRC polarity is critical to understand disease progression. Here, we analyze patient-derived MUC CRC xenografts, with apical-in or apical-out polarity, ex vivo or within collagen gels to mimic the peritumoral stroma. Single-cell analyses reveal α2β1-integrin as a key collagen-binding receptor in these models. Collagen–α2β1-integrin interaction activates Src and ERK/MAPK signaling and upregulates the expression of SorLA, an endosomal sorting receptor. SorLA supports apical-in polarity and carcinoma-stroma interactions by promoting integrin recycling to the plasma membrane and HER2/HER3 expression through a positive feedback mechanism. Accordingly, we observe positive correlation between HER2, HER3 and SorLA in patient samples with the highest HER2 expression in apical-in-presenting tissues. Treatment of tumor spheres with clinically relevant HER2/HER3-targeting antibodies reverts sphere polarity and impedes collagen remodeling and adhesion to mouse peritoneum. This SorLA—integrin—HER2/HER3 signaling axis may represent a basis for MUC CRC-patient stratification and shed light on other carcinomas with similar apical-out phenotypes.","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"bioRxiv","yearOfPublication":2024},"fullTextUrlList":{"fullTextUrl":[{"availability":"Open access","availabilityCode":"OA","documentStyle":"pdf","site":"Unpaywall","url":"https://www.biorxiv.org/content/biorxiv/early/2024/11/21/2024.11.20.624298.full.pdf"},{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.1101/2024.11.20.624298"}]},"commentCorrectionList":{"commentCorrection":[{"id":"42401587","source":"MED","reference":"Nature communications. \n 2026 Jul;:","type":"Preprint of","note":"Link created based on a title-first author match","orderIn":10001}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"N","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"Y","license":"cc by-nc-nd","hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2024-11-23","firstIndexDate":"2024-11-23","firstPublicationDate":"2024-11-21"},{"id":"PPR1009623","source":"PPR","doi":"10.1101/2025.04.21.25326138","title":"Age-specific trends in colorectal, appendiceal, and anal tumour incidence by histological subtype in Australia from 1990 to 2020: a population-based time-series analysis","authorString":"Meyers AL, Dowty JG, Mahmood K, Macrae FA, Rosty C, Buchanan DD, Jenkins MA.","authorList":{"author":[{"fullName":"Meyers AL","firstName":"Aaron","lastName":"Meyers","initials":"AL"},{"fullName":"Dowty JG","firstName":"James","lastName":"Dowty","initials":"JG"},{"fullName":"Mahmood K","firstName":"Khalid","lastName":"Mahmood","initials":"K"},{"fullName":"Macrae FA","firstName":"Finlay","lastName":"Macrae","initials":"FA"},{"fullName":"Rosty C","firstName":"Christophe","lastName":"Rosty","initials":"C"},{"fullName":"Buchanan DD","firstName":"Daniel","lastName":"Buchanan","initials":"DD"},{"fullName":"Jenkins MA","firstName":"Mark","lastName":"Jenkins","initials":"MA"}]},"pubYear":"2025","abstractText":"

Background

Early-onset bowel cancer incidence (age <50 years) has increased worldwide and is highest in Australia, but how this varies across histology and anatomical site remains unclear. We aimed to investigate appendiceal, proximal colon, distal colon, rectal, and anal cancer incidence trends by age and histology in Australia.

Methods

Cancer incidence rate data were obtained from all Australian cancer registries (1990-2020 period). Birth cohort-specific incidence rate ratios (IRRs) and annual percentage change in rates were estimated using age-period-cohort modelling and joinpoint regression.

Findings

After excluding neuroendocrine neoplasms, early-onset cancer incidence rose 5-9% annually, yielding 5,341 excess cases (2 per 100,000 person-years; 12% appendix, 45% colon, 36% rectum, 7% anus; 20-214% relative increase). Trends varied by site, period, and age: appendiceal cancer rose from 1990-2020 in 30-49-year-olds; colorectal cancers rose from around 1990-2010 in 20-29-year-olds and from 2010-2020 in 30-39-year-olds; anal cancer rose from 1990-2009 in 40-49-year-olds. Across all sites, IRRs increased with successive birth cohorts since 1960. Notably, adenocarcinoma incidence in the 1990s versus 1950s birth cohort was 2-3-fold for colorectum and 7-fold for appendix. The greatest subtype-specific increases occurred for appendiceal mucinous adenocarcinoma, colorectal non-mucinous adenocarcinoma, and anal squamous cell carcinoma. Only later-onset (age ≥50) colorectal and anal adenocarcinoma rates declined. Appendiceal tumours, neuroendocrine neoplasms (all sites), anorectal squamous cell carcinomas, and colon signet ring cell carcinomas rose across early-onset and later-onset strata.

Interpretation

Appendiceal, colorectal, and anal cancer incidence is rising in Australia with variation across age and histology, underscoring the need to identify factors driving these trends.

Funding

ALM is supported by an Australian Government Research Training Program Scholarship, Rowden White Scholarship, and WP Greene Scholarship. DDB is supported by a National Health and Medical Research Council of Australia (NHMRC) Investigator grant (GNT1194896), a University of Melbourne Dame Kate Campbell Fellowship, and by funding awarded to The Colon Cancer Family Registry (CCFR, www.coloncfr.org ) from the National Cancer Institute (NCI), National Institutes of Health (NIH) [award U01 CA167551]. MAJ is supported by an NHMRC Investigator grant (GNT1195099), a University of Melbourne Dame Kate Campbell Fellowship, and by funding awarded to the CCFR from NCI, NIH [award U01 CA167551].","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"medRxiv","yearOfPublication":2025},"fullTextUrlList":{"fullTextUrl":[{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.1101/2025.04.21.25326138"}]},"commentCorrectionList":{"commentCorrection":[{"id":"41292545","source":"MED","reference":"The Lancet regional health. Western Pacific. \n 2025 Nov;64:101728","type":"Preprint of","note":"Link created based on a title-first author match","orderIn":10001}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"Y","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"N","license":"cc by-nd","hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2025-04-26","firstIndexDate":"2025-04-26","firstPublicationDate":"2025-04-24"},{"id":"PPR801524","source":"PPR","doi":"10.1101/2024.02.01.578409","title":"Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer","authorString":"Ladaika CA, Ghobashi AH, Boulton WC, Miller SA, O’Hagan HM.","authorList":{"author":[{"fullName":"Ladaika CA","firstName":"Christopher","lastName":"Ladaika","initials":"CA"},{"fullName":"Ghobashi AH","firstName":"Ahmed","lastName":"Ghobashi","initials":"AH"},{"fullName":"Boulton WC","firstName":"William","lastName":"Boulton","initials":"WC"},{"fullName":"Miller SA","firstName":"Samuel","lastName":"Miller","initials":"SA","authorId":{"type":"ORCID","value":"0000-0002-0106-663X"}},{"fullName":"O’Hagan HM","firstName":"Heather","lastName":"O’Hagan","initials":"HM"}]},"authorIdList":{"authorId":[{"type":"ORCID","value":"0000-0002-0106-663X"}]},"pubYear":"2024","abstractText":"Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"bioRxiv","yearOfPublication":2024},"fullTextUrlList":{"fullTextUrl":[{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.1101/2024.02.01.578409"}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"Y","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"N","hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2024-02-07","firstIndexDate":"2024-02-07","firstPublicationDate":"2024-02-05"},{"id":"PPR709776","source":"PPR","doi":"10.21203/rs.3.rs-3212530/v1","title":"Clinical Treatment Of Colorectal Mucinous Adenocarcinoma Could Be Discriminate From Adenocarcinoma: Genesis And Immune Microenvironment Differences On Transcript Level","authorString":"Liu J, Qiu S, Fu X, Zhou B, Zu R, Lv Z, Li Y, Yang L, Zhou Z.","authorList":{"author":[{"fullName":"Liu J","firstName":"Jianbo","lastName":"Liu","initials":"J"},{"fullName":"Qiu S","firstName":"Siyuan","lastName":"Qiu","initials":"S"},{"fullName":"Fu X","firstName":"Xiaorui","lastName":"Fu","initials":"X"},{"fullName":"Zhou B","firstName":"Bin","lastName":"Zhou","initials":"B"},{"fullName":"Zu R","firstName":"Ruijuan","lastName":"Zu","initials":"R"},{"fullName":"Lv Z","firstName":"Zhaoying","lastName":"Lv","initials":"Z"},{"fullName":"Li Y","firstName":"Yuan","lastName":"Li","initials":"Y"},{"fullName":"Yang L","firstName":"Lie","lastName":"Yang","initials":"L"},{"fullName":"Zhou Z","firstName":"Zongguang","lastName":"Zhou","initials":"Z"}]},"pubYear":"2023","abstractText":"

Background:

Mucinous adenocarcinoma (MC) of colorectal cancer (CRC) differs from adenocarcinoma (AD) in clinical features and molecular characteristics. Current treatment of colorectal MC isn't precise enough and the molecular characteristics remain unclear. The study aims to explore the difference between MC and AD of CRC on transcriptome level, for possibility of treating colorectal MC precisely. Methods We accessed the data of CRC patients from The Cancer Genome Atlas (TCGA) database, then we performed differential analysis and weighted gene co-expression network analysis (WGCNA) to identify the differential hub RNAs between colorectal MC and AD. Functional enrichment analysis, RNAs co-expression networks, risk score based on least absolute shrinkage and selection operator (LASSO) regression model and validation in Gene Expression Omnibus (GEO) database, survival analysis were also performed. Finally, differential hub lncRNAs and hub RNA of significant module were validated by quantitative real time PCR (qRT-PCR) among different colon cancer cell lines. Results In total, we found 1680 differential expressed RNAs (DERs) and 4 significant modules (darkred, magenta, lightstellblue1, tan) comparing colorectal MC (52, 13.3%) with AD (340, 86.7%). From the functional enrichment analysis and RNAs co-expression networks, the darkred module was considered as a mucin-associated module, while some others may be associated with unique immune progress. Construction of logistic regression model and calculation of risk score based on differential hub RNAs in darkred module showed acceptable result in both TCGA and GEO data. Survival analysis suggested that many differential hub RNAs were positive and correlated with better survival. Finally, 8 differential hub RNAs in the darkred module (CTD-2547H18.1, CTD-2589M5.4, RP11-234B24.2, LA16c-321D4.2, LINC00261, RP11-25K19.1, COLCA1 and CAPN9) were validated by qRT-PCR. Except for LA16c-321D4.2 and COLCA1, all other RNAs showed higher expression levels in mucin-producing colorectal cell lines (Ls174T, HT-29 and T84). Conclusion This study suggests that clinical treatments for colorectal MC should be differentiated from AD. Further exploration of enterocyte (goblet cell) differentiation with tumor genesis and the distinct immune progression of MC may help to identify key therapeutic targets for colorectal MC. Further research into the application of immunotherapy to colorectal MC is needed.","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"Research Square","yearOfPublication":2023},"fullTextUrlList":{"fullTextUrl":[{"availability":"Open access","availabilityCode":"OA","documentStyle":"pdf","site":"Unpaywall","url":"https://www.researchsquare.com/article/rs-3212530/latest.pdf"},{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.21203/rs.3.rs-3212530/v1"}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"Y","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"N","license":"cc by","versionList":{"version":[{"id":"PPR709776","source":"PPR","firstPublishDate":"2023-08-23","versionNumber":1,"pubTypeList":{"pubType":["preprint"]},"hasEvaluations":"N"}]},"versionNumber":1,"hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2023-08-29","firstIndexDate":"2023-08-31","firstPublicationDate":"2023-08-23"},{"id":"PPR674705","source":"PPR","doi":"10.21203/rs.3.rs-3033737/v1","title":"Transcriptomic Landscape Of Colorectal Mucinous Adenocarcinoma Has Similarity With Intestinal Goblet Cells Differentiation","authorString":"Liu J, Qiu S, Fu X, Zhou B, Zu R, Lv Z, Li Y, Yang L, Zhou Z.","authorList":{"author":[{"fullName":"Liu J","firstName":"Jianbo","lastName":"Liu","initials":"J"},{"fullName":"Qiu S","firstName":"Siyuan","lastName":"Qiu","initials":"S"},{"fullName":"Fu X","firstName":"Xiaorui","lastName":"Fu","initials":"X"},{"fullName":"Zhou B","firstName":"Bin","lastName":"Zhou","initials":"B"},{"fullName":"Zu R","firstName":"Ruijuan","lastName":"Zu","initials":"R"},{"fullName":"Lv Z","firstName":"Zhaoying","lastName":"Lv","initials":"Z"},{"fullName":"Li Y","firstName":"Yuan","lastName":"Li","initials":"Y"},{"fullName":"Yang L","firstName":"Lie","lastName":"Yang","initials":"L"},{"fullName":"Zhou Z","firstName":"Zongguang","lastName":"Zhou","initials":"Z"}]},"pubYear":"2023","abstractText":"

Background:

Mucinous adenocarcinoma (MC) of colorectal cancer (CRC) differs from adenocarcinoma (AD) in clinical features and molecular characteristics. Current treatment of colorectal MC isn't precise enough and the molecular characteristics remain unclear. Methods We accessed the data of CRC patients from The Cancer Genome Atlas (TCGA) database, then we performed differential analysis and weighted gene co-expression network analysis (WGCNA) to identify the differential hub RNAs between colorectal MC and AD. Functional enrichment analysis, RNAs co-expression networks, risk score based on least absolute shrinkage and selection operator (LASSO) regression model and validation in Gene Expression Omnibus (GEO) database, survival analysis were also performed. Finally, differential hub lncRNAs and hub RNA of significant module were validated by quantitative real time PCR (qRT-PCR) among different colon cancer cell lines. Results In total, we found 1680 differential expressed RNAs (DERs) and 4 significant modules (darkred, magenta, lightstellblue1, tan) comparing colorectal MC (52, 13.3%) with AD (340, 86.7%). From the functional enrichment analysis and RNAs co-expression networks, the darkred module was considered as a mucin-associated module, while others may be associated with other features of colorectal MC. Construction of logistic regression model and calculation of risk score based on differential hub RNAs in darkred module showed acceptable result in both TCGA and GEO data. Survival analysis suggested that many differential hub RNAs were positive and correlated with better survival. Finally, 8 differential hub RNAs in the darkred module (CTD-2547H18.1, CTD-2589M5.4, RP11-234B24.2, LA16c-321D4.2, LINC00261, RP11-25K19.1, COLCA1 and CAPN9) were validated by qRT-PCR. Except for LA16c-321D4.2 and COLCA1, all other RNAs showed higher expression levels in mucin-producing colorectal cell lines (Ls174T, HT-29 and T84). Conclusion The study strengthens the findings of distinct molecular features between MC and AD in CRC and identifies potential marker RNAs making colorectal MC unique from AD. The genesis of colorectal MC may be related to the differentiation fate of intestinal goblet cells.","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"Research Square","yearOfPublication":2023},"fullTextUrlList":{"fullTextUrl":[{"availability":"Open access","availabilityCode":"OA","documentStyle":"pdf","site":"Unpaywall","url":"https://www.researchsquare.com/article/rs-3033737/latest.pdf"},{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.21203/rs.3.rs-3033737/v1"}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"N","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"N","license":"cc by","versionList":{"version":[{"id":"PPR674705","source":"PPR","firstPublishDate":"2023-06-12","versionNumber":1,"pubTypeList":{"pubType":["preprint"]},"hasEvaluations":"N"}]},"versionNumber":1,"hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2023-06-14","firstIndexDate":"2023-06-14","firstPublicationDate":"2023-06-12"},{"id":"PPR575984","source":"PPR","doi":"10.21203/rs.3.rs-2255993/v1","title":"Patients with Increased Levels of Fusobacterium Tumoral Abundance are Associated with Better Outcomes in Mucinous Colorectal Cancer.","authorString":"Duggan WP, Salvucci M, Kisakol B, Lindner AU, Reynolds IS, Dussmann H, Fay J, O'Grady T, Longley DB, Ginty F, McDonough E, Slade DJ, Burke JP, Prehn JHM.","authorList":{"author":[{"fullName":"Duggan WP","firstName":"William","lastName":"Duggan","initials":"WP","authorId":{"type":"ORCID","value":"0000-0001-7430-9973"}},{"fullName":"Salvucci M","firstName":"Manuela","lastName":"Salvucci","initials":"M"},{"fullName":"Kisakol B","firstName":"Batuhan","lastName":"Kisakol","initials":"B"},{"fullName":"Lindner AU","firstName":"Andreas","lastName":"Lindner","initials":"AU"},{"fullName":"Reynolds IS","firstName":"Ian","lastName":"Reynolds","initials":"IS"},{"fullName":"Dussmann H","firstName":"Heiko","lastName":"Dussmann","initials":"H"},{"fullName":"Fay J","firstName":"Joanna","lastName":"Fay","initials":"J"},{"fullName":"O'Grady T","firstName":"Tony","lastName":"O'Grady","initials":"T"},{"fullName":"Longley DB","firstName":"Daniel","lastName":"Longley","initials":"DB"},{"fullName":"Ginty F","firstName":"Fiona","lastName":"Ginty","initials":"F","authorId":{"type":"ORCID","value":"0000-0001-6638-683X"}},{"fullName":"McDonough E","firstName":"Elizabeth","lastName":"McDonough","initials":"E"},{"fullName":"Slade DJ","firstName":"Daniel","lastName":"Slade","initials":"DJ"},{"fullName":"Burke JP","firstName":"John","lastName":"Burke","initials":"JP"},{"fullName":"Prehn JHM","firstName":"Jochen","lastName":"Prehn","initials":"JHM"}]},"authorIdList":{"authorId":[{"type":"ORCID","value":"0000-0001-6638-683X"},{"type":"ORCID","value":"0000-0001-7430-9973"}]},"pubYear":"2022","abstractText":"Abstract

There is currently an urgent need to identify factors predictive of immunogenicity in colorectal cancer (CRC). Mucinous CRC is a distinct histological subtype of CRC, associated with a poor response to chemotherapy. Recent evidence suggests the commensal facultative anaerobe Fusobacterium may be especially prevalent in mucinous CRC. The objectives of this study were to assess the impact of Fusobacterium prevalence on immune cell expression and prognosis in mucinous CRC. Our study included two independent colorectal cancer patient cohorts, The Cancer Genome Atlas (TCGA) cohort, and a cohort of rectal cancers from the Beaumont RCSI Cancer Centre (BRCC). Multiplexed immunofluorescence staining of a tumor microarray (TMA) from the BRCC cohort was undertaken using Cell DIVE technology. Our cohorts included 87 cases (13.3%) of mucinous and 565 cases (86.7%) of non-mucinous CRC. Mucinous CRC in the TCGA dataset was associated with increased CD8 + lymphocyte (p = 0.018), regulatory T-cell (p = 0.001) and M2 macrophage (p = 0.001) expression. Similarly in the BRCC cohort, mucinous RC was associated with enhanced CD8 + lymphocyte (p = 0.022), regulatory T-cell (p = 0.047), and B-cell (p = 0.025) counts. Elevated Fusobacterium expression was associated with increased CD4+ (p = 0.031) and M1 macrophage (p = 0.006) expression, whilst M2 macrophages (p = 0.043) were under-expressed in the TCGA cohort. Increased Fusobacterium relative abundance in mucinous CRC was associated with improved clinical outcomes in our TCGA cohort despite having no association with MSI status (DSS: likelihood ratio p = 0.04, logrank p = 0.052). Fusobacterium abundance is associated with improved outcomes in mucinous CRC, possibly due its modulatory effect on the host immune response.

","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"Research Square","yearOfPublication":2022},"fullTextUrlList":{"fullTextUrl":[{"availability":"Open access","availabilityCode":"OA","documentStyle":"pdf","site":"Unpaywall","url":"https://www.researchsquare.com/article/rs-2255993/latest.pdf"},{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.21203/rs.3.rs-2255993/v1"}]},"commentCorrectionList":{"commentCorrection":[{"id":"37171483","source":"MED","reference":"Journal of molecular medicine (Berlin, Germany). 2023 Jul;101(7):829-841","type":"Preprint of","note":"CrossRef Pre-print loader","orderIn":10001}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"N","hasReferences":"Y","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"N","license":"cc by","versionList":{"version":[{"id":"PPR575984","source":"PPR","firstPublishDate":"2022-11-23","versionNumber":1,"pubTypeList":{"pubType":["preprint"]},"hasEvaluations":"N"}]},"versionNumber":1,"hasEvaluations":"N","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2022-11-26","firstIndexDate":"2022-11-26","firstPublicationDate":"2022-11-23"},{"id":"PPR396484","source":"PPR","doi":"10.1101/2021.09.17.460827","title":"Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion","authorString":"Cantero-Recasens G, Alonso-Marañón J, Lobo-Jarne T, Garrido M, Iglesias M, Espinosa L, Malhotra V.","authorList":{"author":[{"fullName":"Cantero-Recasens G","lastName":"Cantero-Recasens","initials":"G","authorId":{"type":"ORCID","value":"0000-0001-6452-782X"}},{"fullName":"Alonso-Marañón J","lastName":"Alonso-Marañón","initials":"J"},{"fullName":"Lobo-Jarne T","lastName":"Lobo-Jarne","initials":"T"},{"fullName":"Garrido M","lastName":"Garrido","initials":"M"},{"fullName":"Iglesias M","lastName":"Iglesias","initials":"M"},{"fullName":"Espinosa L","lastName":"Espinosa","initials":"L","authorId":{"type":"ORCID","value":"0000-0002-2897-4099"}},{"fullName":"Malhotra V","lastName":"Malhotra","initials":"V","authorId":{"type":"ORCID","value":"0000-0001-6198-7943"}}]},"authorIdList":{"authorId":[{"type":"ORCID","value":"0000-0001-6198-7943"},{"type":"ORCID","value":"0000-0001-6452-782X"},{"type":"ORCID","value":"0000-0002-2897-4099"}]},"dataLinksTagsList":{"dataLinkstag":["altmetrics","recommended_reviews"]},"pubYear":"2021","abstractText":"

ABSTRACT

15% of colorectal cancers (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that colorectal cancer cells build a barrier to chemotherapeutics by increasing mucins’ secretion. We show that low levels of KChIP3, a negative regulator of mucin secretion (Cantero-Recasens et al ., 2018), is a risk factor for CRC patients’ relapse in subset of untreated tumours. Our results also reveal that cells depleted of KChIP3 are four times more resistant (measured as cell viability and DNA damage) to chemotherapeutics 5-Fluorouracil plus Irinotecan (5-FU+iri.) compared to control cells, whereas KChIP3 overexpressing cells are 10 times more sensitive to killing by chemotherapeutics. Similar increase in tumour cell death is observed upon chemical inhibition of mucin secretion by the sodium/calcium exchanger (NCX) blockers (Mitrovic et al ., 2013). Finally, sensitivity of CRC patient-derived organoids to 5-FU+iri increases 40-fold upon mucin secretion inhibition. Reducing mucin secretion thus provides a means to control chemoresistance of mucinous colorectal cancer cells and other mucinous tumours.","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"bioRxiv","yearOfPublication":2021},"fullTextUrlList":{"fullTextUrl":[{"availability":"Open access","availabilityCode":"OA","documentStyle":"pdf","site":"Unpaywall","url":"https://www.biorxiv.org/content/biorxiv/early/2021/09/19/2021.09.17.460827.full.pdf"},{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.1101/2021.09.17.460827"}]},"commentCorrectionList":{"commentCorrection":[{"id":"35131032","source":"MED","reference":"eLife. 2022 Feb;11:e73926","type":"Preprint of","note":"CrossRef Pre-print loader","orderIn":10001}]},"isOpenAccess":"N","inEPMC":"N","inPMC":"N","hasPDF":"N","hasBook":"N","hasSuppl":"N","citedByCount":0,"hasData":"Y","hasReferences":"Y","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"Y","hasEvaluations":"Y","authMan":"N","epmcAuthMan":"N","nihAuthMan":"N","hasTMAccessionNumbers":"N","dateOfCreation":"2021-09-20","firstIndexDate":"2021-09-20","firstPublicationDate":"2021-09-19"},{"id":"PPR588446","source":"PPR","fullTextIdList":{"fullTextId":["PPR588446"]},"doi":"10.1101/2022.12.22.521159","title":"Mutation-induced phenotypic plasticity drives formation of a pro-metastatic tumour-intrinsic niche","authorString":"Bugter JM, El Bouazzaoui L, Küçükköse E, Mills ML, Hong Y, Sprangers J, Jordens I, Kokkinidi D, Plugge S, Venhuizen A, Bosman S, Hageman J, Fenderico N, Gilroy K, Montiel Gonzalez D, van Boxtel R, Suijkerbuijk SJ, Tejpar S, Campbell AD, Sansom OJ, Snippert HJ, Kranenburg O, Maurice MM.","authorList":{"author":[{"fullName":"Bugter JM","firstName":"Jeroen","lastName":"Bugter","initials":"JM","authorId":{"type":"ORCID","value":"0000-0001-9920-2937"},"authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands"}]}},{"fullName":"El Bouazzaoui L","firstName":"Layla","lastName":"El Bouazzaoui","initials":"L","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands"},{"affiliation":"Department of Surgical Oncology, Lab Translational Oncology, UMC Utrecht, the Netherlands"}]}},{"fullName":"Küçükköse E","firstName":"Emre","lastName":"Küçükköse","initials":"E","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Department of Surgical Oncology, Lab Translational Oncology, UMC Utrecht, the Netherlands"}]}},{"fullName":"Mills ML","firstName":"Megan","lastName":"Mills","initials":"ML","authorId":{"type":"ORCID","value":"0000-0001-6683-433X"},"authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Department of Oncology, Katholieke Universiteit Leuven, Belgium"}]}},{"fullName":"Hong Y","firstName":"Yourae","lastName":"Hong","initials":"Y","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands"}]}},{"fullName":"Sprangers J","firstName":"Joep","lastName":"Sprangers","initials":"J","authorId":{"type":"ORCID","value":"0000-0001-7865-2816"},"authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands"}]}},{"fullName":"Jordens I","firstName":"Ingrid","lastName":"Jordens","initials":"I","authorId":{"type":"ORCID","value":"0000-0003-3599-7931"},"authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands"}]}},{"fullName":"Kokkinidi D","firstName":"Danai","lastName":"Kokkinidi","initials":"D","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Princes Maxima Centre for Pediatric Oncology, Utrecht, the Netherlands"}]}},{"fullName":"Plugge S","firstName":"Susanna","lastName":"Plugge","initials":"S","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Princes Maxima Centre for Pediatric Oncology, Utrecht, the Netherlands"}]}},{"fullName":"Venhuizen A","firstName":"Anton","lastName":"Venhuizen","initials":"A","authorId":{"type":"ORCID","value":"0000-0002-3197-1307"},"authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, The Netherlands"}]}},{"fullName":"Bosman S","firstName":"Sabine","lastName":"Bosman","initials":"S","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Department of Oncology, Katholieke Universiteit Leuven, Belgium"}]}},{"fullName":"Hageman J","firstName":"Joris","lastName":"Hageman","initials":"J","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands"}]}},{"fullName":"Fenderico N","firstName":"Nicola","lastName":"Fenderico","initials":"N","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, The Netherlands"}]}},{"fullName":"Gilroy K","firstName":"Kathryn","lastName":"Gilroy","initials":"K","authorAffiliationDetailsList":{"authorAffiliation":[{"affiliation":"Oncode Institute and Centre for Molecular Medicine, UMC Utrecht, the Netherlands"}]}},{"fullName":"Montiel Gonzalez D","firstName":"Diego","lastName":"Montiel Gonzalez","initials":"D"},{"fullName":"van Boxtel R","firstName":"Ruben","lastName":"van Boxtel","initials":"R"},{"fullName":"Suijkerbuijk SJ","firstName":"Saskia J.E.","lastName":"Suijkerbuijk","initials":"SJ"},{"fullName":"Tejpar S","firstName":"Sabine","lastName":"Tejpar","initials":"S"},{"fullName":"Campbell AD","firstName":"Andrew","lastName":"Campbell","initials":"AD"},{"fullName":"Sansom OJ","firstName":"Owen","lastName":"Sansom","initials":"OJ"},{"fullName":"Snippert HJ","firstName":"Hugo J.G.","lastName":"Snippert","initials":"HJ"},{"fullName":"Kranenburg O","firstName":"Onno","lastName":"Kranenburg","initials":"O"},{"fullName":"Maurice MM","firstName":"Madelon","lastName":"Maurice","initials":"MM"}]},"authorIdList":{"authorId":[{"type":"ORCID","value":"0000-0001-6683-433X"},{"type":"ORCID","value":"0000-0001-7865-2816"},{"type":"ORCID","value":"0000-0001-9920-2937"},{"type":"ORCID","value":"0000-0002-3197-1307"},{"type":"ORCID","value":"0000-0002-8983-9464"},{"type":"ORCID","value":"0000-0003-3599-7931"}]},"dataLinksTagsList":{"dataLinkstag":["altmetrics","supporting_data"]},"pubYear":"2022","abstractText":"Colorectal cancer (CRC) progression is characterised by a remarkable increase in plasticity and cellular heterogeneity 1,2 . The ability of cells to shift states and adopt mixed lineage potential exacerbates during metastasis and associates with poor patient survival 3 . How these atypical differentiated states emerge and drive cancer progression however has remained unclear. Here, we investigate this issue for BRAF-mutant CRC that commonly arise via the serrated pathway 4 and are linked to poor prognosis via incompletely understood progression steps. Using patient-derived organoids, gene editing and murine tumour models, we show that mutations in RNF43, a regulator of WNT receptor abundance 5 , endow BRAF-mutant CRC with metastatic capacity by driving a non-dividing tumour-intrinsic niche cell (TINC) state that provides growth factor self-sufficiency to the cancer tissue. TINCs are enriched in RNF43 -mutant, mucinous and metastatic samples of human CRC, and ablation of TINCs lead to re-acquired external growth factor dependency during CRC organoid outgrowth. Together, our findings uncover a mechanism by which tumours leverage cellular plasticity to mediate self-organised stem– and niche-cell interactions. Our results argue that formation of a tumour-intrinsic niche is a prerequisite for BRAF-mutant CRC seeding to distant organs and that interference with niche formation may help avoid metastatic relapse.","pubTypeList":{"pubType":["Preprint"]},"bookOrReportDetails":{"publisher":"bioRxiv","yearOfPublication":2022},"grantsList":{"grant":[{"grantId":"91218050","agency":"ZonMw","orderIn":0}]},"fullTextUrlList":{"fullTextUrl":[{"availability":"Open access","availabilityCode":"OA","documentStyle":"pdf","site":"Unpaywall","url":"https://www.biorxiv.org/content/biorxiv/early/2023/04/15/2022.12.22.521159.full.pdf"},{"availability":"Free","availabilityCode":"F","documentStyle":"doi","site":"DOI","url":"https://doi.org/10.1101/2022.12.22.521159"},{"availability":"Open access","availabilityCode":"OA","documentStyle":"html","site":"Europe_PMC","url":"https://europepmc.org/article/PPR/PPR588446"},{"availability":"Open access","availabilityCode":"OA","documentStyle":"pdf","site":"Europe_PMC","url":"https://europepmc.org/api/fulltextRepo?pprId=PPR588446&type=FILE&fileName=EMS158981-pdf.pdf&mimeType=application/pdf"}]},"isOpenAccess":"Y","inEPMC":"Y","inPMC":"N","hasPDF":"Y","hasBook":"N","hasSuppl":"Y","citedByCount":0,"hasData":"Y","hasReferences":"Y","hasTextMinedTerms":"Y","hasDbCrossReferences":"N","hasLabsLinks":"Y","license":"cc by-nc-nd","hasEvaluations":"N","authMan":"N","epmcAuthMan":"Y","nihAuthMan":"N","manuscriptId":"EMS158981","hasTMAccessionNumbers":"Y","tmAccessionTypeList":{"accessionType":["doi"]},"dateOfCreation":"2022-12-24","firstIndexDate":"2022-12-24","fullTextReceivedDate":"2023-04-18","firstPublicationDate":"2022-12-23"}]}}