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2. The genomic landscape of 2,023 colorectal cancers

Author

Cornish, Alex J., Gruber, Andreas J., Kinnersley, Ben, Chubb, Daniel, Frangou, Anna, Caravagna, Giulio, Noyvert, Boris, Lakatos, Eszter, Wood, Henry M., Thorn, Steve, Culliford, Richard, Arnedo-Pac, Claudia, Househam, Jacob, Cross, William, Sud, Amit, Law, Philip, Leathlobhair, Maire Ni, Hawari, Aliah, Woolley, Connor, Sherwood, Kitty, Feeley, Nathalie, Gül, Güler, Fernandez-Tajes, Juan, Zapata, Luis, Alexandrov, Ludmil B., Murugaesu, Nirupa, Sosinsky, Alona, Mitchell, Jonathan, Lopez-Bigas, Nuria, Quirke, Philip, Church, David N., Tomlinson, Ian P. M., Sottoriva, Andrea, Graham, Trevor A., Wedge, David C., and Houlston, Richard S.

Published
2024
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3. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer

Author

Kayhanian, Hamzeh, Cross, William, van der Horst, Suzanne E. M., Barmpoutis, Panagiotis, Lakatos, Eszter, Caravagna, Giulio, Zapata, Luis, Van Hoeck, Arne, Middelkamp, Sjors, Litchfield, Kevin, Steele, Christopher, Waddingham, William, Patel, Dominic, Milite, Salvatore, Jin, Chen, Baker, Ann-Marie, Alexander, Daniel C., Khan, Khurum, Hochhauser, Daniel, Novelli, Marco, Werner, Benjamin, van Boxtel, Ruben, Hageman, Joris H., Buissant des Amorie, Julian R., Linares, Josep, Ligtenberg, Marjolijn J. L., Nagtegaal, Iris D., Laclé, Miangela M., Moons, Leon M. G., Brosens, Lodewijk A. A., Pillay, Nischalan, Sottoriva, Andrea, Graham, Trevor A., Rodriguez-Justo, Manuel, Shiu, Kai-Keen, Snippert, Hugo J. G., and Jansen, Marnix

Published
2024
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4. Bridging clinic and wildlife care with AI-powered pan-species computational pathology

Author

AbdulJabbar, Khalid, Castillo, Simon P, Hughes, Katherine, Davidson, Hannah, Boddy, Amy M, Abegglen, Lisa M, Minoli, Lucia, Iussich, Selina, Murchison, Elizabeth P, Graham, Trevor A, Spiro, Simon, Maley, Carlo C, Aresu, Luca, Palmieri, Chiara, and Yuan, Yinyin

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Life on Land, Male, Animals, Humans, Dogs, Animals, Wild, Artificial Intelligence, Prostatic Neoplasms, Neural Networks, Computer, Pan troglodytes
Abstract

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves = 2, and amphibia = 1), accuracy (range 0.57-0.94) is influenced by cell morphological similarity preserved across different taxonomic groups, tumour sites, and variations in the immune compartment. Furthermore, a spatial immune score based on artificial intelligence and spatial statistics is associated with prognosis in canine melanoma and prostate tumours. A metric, named morphospace overlap, is developed to guide veterinary pathologists towards rational deployment of this technology on new samples. This study provides the foundation and guidelines for transferring artificial intelligence technologies to veterinary pathology based on understanding of morphological conservation, which could vastly accelerate developments in veterinary medicine and comparative oncology.

Published
2023

5. Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease

Author

van Bodegraven, Adriaan A., Fidder, Herma H., Hirdes, Meike M.C., Hoentjen, Frank, Jansen, Jeroen M., Mahmmod, Nofel, van der Meulen-de Jong, Andrea E., Ponsioen, Cyriel Y., van Schaik, Fiona D.M., van der Woude, C. Janneke, Wijnands, Anouk M., Penning de Vries, Bas B.L., Lutgens, Maurice W.M.D., Bakhshi, Zeinab, Al Bakir, Ibrahim, Beaugerie, Laurent, Bernstein, Charles N., Chang-ho Choi, Ryan, Coelho-Prabhu, Nayantara, Graham, Trevor A., Hart, Ailsa L., ten Hove, Joren R., Itzkowitz, Steven H., Kirchgesner, Julien, Mooiweer, Erik, Shaffer, Seth R., Shah, Shailja C., Elias, Sjoerd G., and Oldenburg, Bas

Published
2024
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10. Profiling of Copy Number Alterations Using Low-Coverage Whole-Genome Sequencing Informs Differential Diagnosis and Prognosis in Primary Cutaneous Follicle Center Lymphoma

Author

Bátai, Bence, Kiss, Laura, Varga, Luca, Nagy, Ákos, Househam, Jacob, Baker, Ann-Marie, László, Tamás, Udvari, Anna, Horváth, Róbert, Nagy, Tibor, Csomor, Judit, Szakonyi, József, Schneider, Tamás, Graham, Trevor A., Alpár, Donát, Fitzgibbon, Jude, Szepesi, Ágota, and Bödör, Csaba

Published
2024
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13. Tellurium and selenium in black shales and related lithologies

Author

Armstrong, Joseph Graham Trevor, Bowden, Stephen, and Panell, John

Subjects
Black shales, Tellurium, Selenium, Petrology
Abstract

Increasing interest and potential demand for the elements tellurium (Te) and selenium (Se), requires an improved understanding of the mechanisms controlling their mobility in the Earth's crust. Black shales are known to contain elevated concentrations of Te and Se and as such act as a potentially large sink of these elements in the crust. In this thesis, whole rock geochemistry and detailed mineralogical analysis of black shales and related lithologies is undertaken to gain a better understanding the factors controlling Te and Se enrichment. Whole rock analysis of black shales and pelites from Britain and Ireland identifies mean concentrations of 0.07 ppm (Te) and 2.03 ppm (Se) in the majority of deposits with significantly elevated concentrations in certain samples. Mineralogical, isotopic and correlation analysis indicate that the depositional enrichment of Te and Se within black shales is controlled by the availability of Te and Se in the depositional waters. Periodic increases in atmospheric O2 concentrations through geological time, specifically during the Ediacaran and the Carboniferous, resulted in a higher flux of Te and Se to oceanic basins and higher concentrations of Te and Se in the resultant shales. Within black shales, Te is concentrated within organic matter, while Se is concentrated within diagenetic pyrite and organic matter. Both Te and Se are readily liberated from black shales at surface through oxidation and leaching by groundwater. During metamorphic recrystallisation of black shales, mobilisation of Te and Se occurs, forming concentrated enrichments associated with pyrite. Magmatic assimilation provides a potential enrichment mechanism for Te and Se from shales and pelites. Assimilation of Dalradian pelites within Ordovician intrusions has formed Te and Se enriched graphitic deposits. A similar crustal assimilation mechanism may have occurred in other deposits, producing hyper-enriched Te and Se deposits based on shale protoliths.

Published
2021

15. The co-evolution of the genome and epigenome in colorectal cancer

Author

Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., and Sottoriva, Andrea

Published
2022
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16. Phenotypic plasticity and genetic control in colorectal cancer evolution

Author

Househam, Jacob, Heide, Timon, Cresswell, George D., Spiteri, Inmaculada, Kimberley, Chris, Zapata, Luis, Lynn, Claire, James, Chela, Mossner, Maximilian, Fernandez-Mateos, Javier, Vinceti, Alessandro, Baker, Ann-Marie, Gabbutt, Calum, Berner, Alison, Schmidt, Melissa, Chen, Bingjie, Lakatos, Eszter, Gunasri, Vinaya, Nichol, Daniel, Costa, Helena, Mitchinson, Miriam, Ramazzotti, Daniele, Werner, Benjamin, Iorio, Francesco, Jansen, Marnix, Caravagna, Giulio, Barnes, Chris P., Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Sottoriva, Andrea, and Graham, Trevor A.

Published
2022
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19. Immunosuppressive niche engineering at the onset of human colorectal cancer

Author

Gatenbee, Chandler D., Baker, Ann-Marie, Schenck, Ryan O., Strobl, Maximilian, West, Jeffrey, Neves, Margarida P., Hasan, Sara Yakub, Lakatos, Eszter, Martinez, Pierre, Cross, William C. H., Jansen, Marnix, Rodriguez-Justo, Manuel, Whelan, Christopher J., Sottoriva, Andrea, Leedham, Simon, Robertson-Tessi, Mark, Graham, Trevor A., and Anderson, Alexander R. A.

Published
2022
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20. Performative Speech Act Verbs and Sincerity in Anglo-Norman and Middle English Letters

Author

Williams, Graham Trevor

Abstract

This paper investigates performative manifestations of sincerity across Anglo-Norman and Middle English. In particular, it locates adverbial sincerity markers used to qualify performative speech act verbs in late medieval letters (fourteenth and fifteenth centuries), at a point when Middle English was rapidly replacing Anglo-Norman as the vernacular of epistolarity in England. Employing historical dictionaries and corpora, the study (1) locates the range of words for 'sincerity' from a time when the modern lexeme had yet to be borrowed in either vernacular, and (2) demonstrates that while it is clear that Middle English epistolarity was greatly influenced by Anglo-Norman, quantitative and qualitative analyses suggest that sincerity markers were much less commonplace in Middle English performatives, which further suggests ways in which the communicative ideal and practice of sincerity were reanalyzed from one language to the next.

Published
2020
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22. Figure 5 from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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23. Figure 6 from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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24. Supplementary Data from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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25. Figure 1 from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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26. Data from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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27. Figure 3 from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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28. Figure 4 from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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29. Figure 2 from FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA

Author

Baker, Ann-Marie, primary, Nageswaran, Gayathri, primary, Nenclares, Pablo, primary, Ronel, Tahel, primary, Smith, Kane, primary, Kimberley, Christopher, primary, Laclé, Miangela M., primary, Bhide, Shreerang, primary, Harrington, Kevin J., primary, Melcher, Alan, primary, Rodriguez-Justo, Manuel, primary, Chain, Benny, primary, and Graham, Trevor A., primary

Published
2024
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32. Classifying the evolutionary and ecological features of neoplasms

Author

Maley, Carlo C, Aktipis, Athena, Graham, Trevor A, Sottoriva, Andrea, Boddy, Amy M, Janiszewska, Michalina, Silva, Ariosto S, Gerlinger, Marco, Yuan, Yinyin, Pienta, Kenneth J, Anderson, Karen S, Gatenby, Robert, Swanton, Charles, Posada, David, Wu, Chung-I, Schiffman, Joshua D, Hwang, E Shelley, Polyak, Kornelia, Anderson, Alexander RA, Brown, Joel S, Greaves, Mel, and Shibata, Darryl

Subjects
Biomedical and Clinical Sciences, Health Sciences, Cancer, Antigens, Neoplasm, Biological Evolution, Ecological and Environmental Phenomena, Gene Expression, Genetic Variation, Humans, Microbiota, Neoplasms, Phenotype, Reactive Oxygen Species, Time Factors, Tumor Hypoxia, Tumor Microenvironment, Medical and Health Sciences, Oncology & Carcinogenesis, Biomedical and clinical sciences, Health sciences
Abstract

Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.

Published
2017

33. Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

Author

Bollen, Yannik, Stelloo, Ellen, van Leenen, Petra, van den Bos, Myrna, Ponsioen, Bas, Lu, Bingxin, van Roosmalen, Markus J., Bolhaqueiro, Ana C. F., Kimberley, Christopher, Mossner, Maximilian, Cross, William C. H., Besselink, Nicolle J. M., van der Roest, Bastiaan, Boymans, Sander, Oost, Koen C., de Vries, Sippe G., Rehmann, Holger, Cuppen, Edwin, Lens, Susanne M. A., Kops, Geert J. P. L., Kloosterman, Wigard P., Terstappen, Leon W. M. M., Barnes, Chris P., Sottoriva, Andrea, Graham, Trevor A., and Snippert, Hugo J. G.

Published
2021
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34. Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease.

Author

Wijnands, Anouk M., Penning de Vries, Bas B.L., Lutgens, Maurice W.M.D., Bakhshi, Zeinab, Al Bakir, Ibrahim, Beaugerie, Laurent, Bernstein, Charles N., Chang-ho Choi, Ryan, Coelho-Prabhu, Nayantara, Graham, Trevor A., Hart, Ailsa L., ten Hove, Joren R., Itzkowitz, Steven H., Kirchgesner, Julien, Mooiweer, Erik, Shaffer, Seth R., Shah, Shailja C., Elias, Sjoerd G., and Oldenburg, Bas

Abstract

Colonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD. We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal–external cross-validation. The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal–external cross-validation results showed medium discrimination and reasonable to good calibration. The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application. [Display omitted] [ABSTRACT FROM AUTHOR]

Published
2024
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36. Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer

Author

Lakatos, Eszter, primary, Gunasri, Vinaya, additional, Zapata, Luis, additional, Househam, Jacob, additional, Heide, Timon, additional, Trahearn, Nicholas, additional, Swinyard, Ottilie, additional, Cisneros, Luis, additional, Lynn, Claire, additional, Mossner, Maximilian, additional, Kimberley, Chris, additional, Spiteri, Inmaculada, additional, Cresswell, George D., additional, Llibre-Palomar, Gerard, additional, Mitchison, Miriam, additional, Maley, Carlo C., additional, Jansen, Marnix, additional, Rodriguez-Justo, Manuel, additional, Bridgewater, John, additional, Baker, Ann-Marie, additional, Sottoriva, Andrea, additional, and Graham, Trevor A., additional

Published
2024
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37. Phenotypic plasticity mediates colorectal cancer metastasis

Author

Efremova, Mirjana, primary, Ogden, Samuel, additional, Metic, Nasrine, additional, Smith, Elise, additional, Berner, Alison, additional, Baker, Ann-Marie, additional, Uddin, Imran, additional, Chelala, Claude, additional, Ullah, Dayem, additional, Saad, Amina, additional, Aleong, Jo-Anne Chin, additional, Graham, Trevor, additional, and Kocher, Hemant, additional

Published
2024
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40. Molecular characteristics of early‐onset pancreatic ductal adenocarcinoma

Author

Debernardi, Silvana, primary, Liszka, Lukasz, additional, Ntala, Chara, additional, Steiger, Katja, additional, Esposito, Irene, additional, Carlotti, Emanuela, additional, Baker, Ann‐Marie, additional, McDonald, Stuart, additional, Graham, Trevor, additional, Dmitrovic, Branko, additional, Feakins, Roger M., additional, and Crnogorac‐Jurcevic, Tatjana, additional

Published
2023
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41. Poor diagnostic reproducibility in the identification of non-conventional dysplasia in colitis impacts the application of histological stratification tools

Author

Nasreddin, Nadia, primary, Jansen, Marnix, additional, Loughrey, Maurice B., additional, Wang, Lai Mun, additional, Koelzar, Viktor H., additional, Rodriguez-Justo, Manuel, additional, Novelli, Marco, additional, Fisher, Jennifer, additional, Brown, Matthew W., additional, Al Bakir, Ibrahim, additional, Hart, Ailsa, additional, Dunne, Philip, additional, Graham, Trevor A., additional, and Leedham, Simon J., additional

Published
2023
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42. Evolutionary dynamics of neoantigens in growing tumors

Author

Lakatos, Eszter, Williams, Marc J., Schenck, Ryan O., Cross, William C. H., Househam, Jacob, Zapata, Luis, Werner, Benjamin, Gatenbee, Chandler, Robertson-Tessi, Mark, Barnes, Chris P., Anderson, Alexander R. A., Sottoriva, Andrea, and Graham, Trevor A.

Published
2020
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44. Gremlin 1 Identifies a Skeletal Stem Cell with Bone, Cartilage, and Reticular Stromal Potential

Author

Worthley, Daniel L, Churchill, Michael, Compton, Jocelyn T, Tailor, Yagnesh, Rao, Meenakshi, Si, Yiling, Levin, Daniel, Schwartz, Matthew G, Uygur, Aysu, Hayakawa, Yoku, Gross, Stefanie, Renz, Bernhard W, Setlik, Wanda, Martinez, Ashley N, Chen, Xiaowei, Nizami, Saqib, Lee, Heon Goo, Kang, H Paco, Caldwell, Jon-Michael, Asfaha, Samuel, Westphalen, C Benedikt, Graham, Trevor, Jin, Guangchun, Nagar, Karan, Wang, Hongshan, Kheirbek, Mazen A, Kolhe, Alka, Carpenter, Jared, Glaire, Mark, Nair, Abhinav, Renders, Simon, Manieri, Nicholas, Muthupalani, Sureshkumar, Fox, James G, Reichert, Maximilian, Giraud, Andrew S, Schwabe, Robert F, Pradere, Jean-Phillipe, Walton, Katherine, Prakash, Ajay, Gumucio, Deborah, Rustgi, Anil K, Stappenbeck, Thaddeus S, Friedman, Richard A, Gershon, Michael D, Sims, Peter, Grikscheit, Tracy, Lee, Francis Y, Karsenty, Gerard, Mukherjee, Siddhartha, and Wang, Timothy C

Subjects
Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research - Nonembryonic - Human, Regenerative Medicine, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Musculoskeletal, Animals, Bone and Bones, Cartilage, Intercellular Signaling Peptides and Proteins, Intestine, Small, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).

Published
2015

46. Molecular characteristics of early‐onset pancreatic ductal adenocarcinoma.

Author

Debernardi, Silvana, Liszka, Lukasz, Ntala, Chara, Steiger, Katja, Esposito, Irene, Carlotti, Emanuela, Baker, Ann‐Marie, McDonald, Stuart, Graham, Trevor, Dmitrovic, Branko, Feakins, Roger M., and Crnogorac‐Jurcevic, Tatjana

Abstract

The median age of patients with pancreatic ductal adenocarcinoma (PDAC) at diagnosis is 71 years; however, around 10% present with early‐onset pancreatic cancer (EOPC), i.e., before age 50. The molecular mechanisms underlying such an early onset are unknown. We assessed the role of common PDAC drivers (KRAS, TP53, CDKN2A and SMAD4) and determined their mutational status and protein expression in 90 formalin‐fixed, paraffin‐embedded tissues, including multiple primary and matched metastases, from 37 EOPC patients. KRAS was mutated in 88% of patients; p53 was altered in 94%, and p16 and SMAD4 were lost in 86% and 71% of patients, respectively. Meta‐synthesis showed a higher rate of p53 alterations in EOPC than in late‐onset PDAC (94% vs. 69%, P = 0.0009) and significantly higher loss of SMAD4 (71% vs. 44%, P = 0.0025). The majority of EOPC patients accumulated aberrations in all four drivers; in addition, high tumour heterogeneity was observed across all tissues. The cumulative effect of an exceptionally high rate of alterations in all common PDAC driver genes combined with high tumour heterogeneity suggests an important mechanism underlying the early onset of PDAC. [ABSTRACT FROM AUTHOR]

Published
2024
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48. Evolutionary dynamics of 1,976 lymphoid malignancies predict clinical outcome

Author

Gabbutt, Calum, primary, Duran-Ferrer, Marti, additional, Grant, Heather, additional, Mallo, Diego, additional, Nadeu, Ferran, additional, Househam, Jacob, additional, Villamor, Neus, additional, Krali, Olga, additional, Nordlund, Jessica, additional, Zenz, Thorsten, additional, Campo, Elias, additional, Lopez-Guillermo, Armando, additional, Fitzgibbon, Jude, additional, Barnes, Chris P, additional, Shibata, Darryl, additional, Martin-Subero, Jose I, additional, and Graham, Trevor A, additional

Published
2023
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