المؤلفون: Chrisochoidou, Yakinthi, Roy, Rajat, Farahmand, Pooyeh, Gonzalez, Guadalupe, Doig, Jennifer, Krasny, Lukas, Rimmer, Ella F, Willis, Anne E, MacFarlane, Marion, Huang, Paul H, Carragher, Neil O, Munro, Alison F, Murphy, Daniel J, Veselkov, Kirill, Seckl, Michael J, Moffatt, Miriam F, Cookson, William OC, Pardo, Olivier E

مصطلحات موضوعية: Animals, Mice, Humans, Mesothelioma, Malignant, Fibroblasts, Cancer-Associated Fibroblasts, Lung

الوصف: Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients.

وصف الملف: application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/363261Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/363261Test

المؤلفون: De Lorenzo, Giuditta, Tandavanitj, Rapeepat, Doig, Jennifer, Setthapramote, Chayanee, Poggianella, Monica, Sanchez Velazquez, Ricardo, Scales, Hannah, Edgar, Julia M., Kohl, Alain, Brewer, James, Burrone, Oscar R., Patel, Arvind

الوصف: Zika virus (ZIKV) envelope (E) protein is the major target of neutralizing antibodies in infected host, and thus represents a candidate of interest for vaccine design. However, a major concern in the development of vaccines against ZIKV and the related dengue virus is the induction of cross-reactive poorly neutralizing antibodies that can cause antibody-dependent enhancement (ADE) of infection. This risk necessitates particular care in vaccine design. Specifically, the engineered immunogens should have their cross-reactive epitopes masked, and they should be optimized for eliciting virus-specific strongly neutralizing antibodies upon vaccination. Here, we developed ZIKV subunit- and virus-like particle (VLP)-based vaccines displaying E in its wild type form, or E locked in a covalently linked dimeric (cvD) conformation to enhance the exposure of E dimers to the immune system. Compared with their wild-type derivatives, cvD immunogens elicited antibody with higher capacity of neutralizing virus infection of cultured cells. More importantly, these immunogens protected animals from lethal challenge with both the African and Asian lineages of ZIKV, impairing virus dissemination to brain and sexual organs. Moreover, the locked conformation of E reduced the exposure of epitopes recognized by cross-reactive antibodies and therefore showed a lower potential to induce ADE in vitro. Our data demonstrated a higher efficacy of the VLPs in comparison with the soluble dimer and support VLP-cvD as a promising ZIKV vaccine.

وصف الملف: text

العلاقة: https://eprints.gla.ac.uk/223806/2/223806.pdfTest; De Lorenzo, G. et al. (2021) Zika virus-like particles bearing covalent dimer of envelope protein protect mice from lethal challenge. Journal of Virology , 95(1), e01415-20. (doi:10.1128/JVI.01415-20 ) (PMID:33028720) (PMCID:PMCID: PMC7737734)

الإتاحة: https://doi.org/10.1128/JVI.01415-20Test
https://eprints.gla.ac.uk/223806Test/
https://eprints.gla.ac.uk/223806/2/223806.pdfTest

المؤلفون: Uggenti, Carolina, Lepelley, Alice, Depp, Marine, Badrock, Andrew, Rodero, Mathieu P, El-Daher, Marie-Thérèse, Rice, Gillian, Dhir, Somdutta, Wheeler, Ann, Dhir, Ashish, Albawardi, Waad, Frémond, Marie-Louise, Seabra, Luis, Doig, Jennifer, Blair, Natalie, Martin-Niclos, Maria José, Della Mina, Erika, Rubio-Roldán, Alejandro, García-Pérez, Jose, Sproul, Duncan, Rehwinkel, Jan, Hertzog, Jonny, Boland-Auge, Anne, Olaso, Robert, Deleuze, Jean-François, Baruteau, Julien, Brochard, Karine, Buckley, Jonathan, Cavallera, Vanessa, Cereda, Cristina, de Waele, Liesbeth, Dobbie, Angus, Doummar, Diane, Elmslie, Frances, Koch-Hogrebe, Margarete, Kumar, Ram, Lamb, Kate, Livingston, John, Majumdar, Anirban, Lorenço, Charles Marques, Orcesi, Simona, Peudenier, Sylviane, Rostasy, Kevin, Salmon, Caroline, Scott, Christiaan, Tonduti, Davide, Touati, Guy, Valente, Marialuisa, van Der Linden, Hélio, van Esch, Hilde, Vermelle, Marie, Webb, Kate, Jackson, Andrew, Reijns, Martin, Gilbert, Nick, Crow, Yanick

المساهمون: University of Edinburgh (Edin.), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Manchester Manchester, Centre for Genomics and Oncological Research Pfizer Granada, Spain, Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government Granada, Spain, University of Oxford, Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, University College of London London (UCL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Cape Town, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), University Hospitals Leuven Leuven, Chapel Allerton Hospital, Sorbonne Université (SU), CHU Trousseau APHP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of London London, Universität Witten/Herdecke, Alder Hey Children's Hospital, Gloucestershire Hospitals, Partenaires INRAE, Leeds Teaching Hospitals NHS Trust, Bristol Royal Hospital for Children, Università degli Studi di Pavia = University of Pavia (UNIPV), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Royal Surrey County Hospital (NHS Royal Surrey), Children's Hospital "V. Buzzi" Milan, Italy, Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven), CH Dunkerque, ANR-10-INBS-0009,France Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

المصدر: ISSN: 1061-4036.

مصطلحات موضوعية: [SDV]Life Sciences [q-bio]

الوصف: International audience ; Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.

العلاقة: hal-03367600; https://hal.science/hal-03367600Test; https://hal.science/hal-03367600/documentTest; https://hal.science/hal-03367600/file/Baruteau_AGS8-9%2520main_NG%2520resubmission_v4.pdfTest

الإتاحة: https://doi.org/10.1038/s41588-020-00737-3Test
https://hal.science/hal-03367600Test
https://hal.science/hal-03367600/documentTest
https://hal.science/hal-03367600/file/Baruteau_AGS8-9%2520main_NG%2520resubmission_v4.pdfTest

المؤلفون: Patek, Charles E., Little, Melissa H., Fleming, Stewart, Miles, Colin, Charlieu, Jean-Paul, Clarke, Alan R., Miyagawa, Kiyoshi, Christie, Sheila, Doig, Jennifer, Harrison, David J., Porteous, David J., Brookes, Anthony J., Hooper, Martin L., Hastie, Nicholas D.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 1999 Mar . 96(6), 2931-2936.

الوصول الحر: https://www.jstor.org/stable/47466Test

المؤلفون: López-Camacho, César, Abbink, Peter, Larocca, Rafael A., Dejnirattisai, Wanwisa, Boyd, Michael, Badamchi-Zadeh, Alex, Wallace, Zoë R., Doig, Jennifer, Sanchez Velazquez, Ricardo, Neto, Roberto Dias Lins, Coelho, Danilo F., Kim, Young Chan, Donald, Claire L., Owsianka, Ania, De Lorenzo, Giuditta, Kohl, Alain, Gilbert, Sarah C., Dorrell, Lucy, Mongkolsapaya, Juthathip, Patel, Arvind H., Screaton, Gavin R., Barouch, Dan H., Hill, Adrian V.S., Reyes-Sandoval, Arturo

الوصف: Zika virus (ZIKV) emerged on a global scale and no licensed vaccine ensures long-lasting anti-ZIKV immunity. Here we report the design and comparative evaluation of four replication-deficient chimpanzee adenoviral (ChAdOx1) ZIKV vaccine candidates comprising the addition or deletion of precursor membrane (prM) and envelope, with or without its transmembrane domain (TM). A single, non-adjuvanted vaccination of ChAdOx1 ZIKV vaccines elicits suitable levels of protective responses in mice challenged with ZIKV. ChAdOx1 prME ∆TM encoding prM and envelope without TM provides 100% protection, as well as long-lasting anti-envelope immune responses and no evidence of in vitro antibody-dependent enhancement to dengue virus. Deletion of prM and addition of TM reduces protective efficacy and yields lower anti-envelope responses. Our finding that immunity against ZIKV can be enhanced by modulating antigen membrane anchoring highlights important parameters in the design of viral vectored ZIKV vaccines to support further clinical assessments.

وصف الملف: text

العلاقة: https://eprints.gla.ac.uk/162866/1/162866.pdfTest; López-Camacho, C. et al. (2018) Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors. Nature Communications , 9, 2441. (doi:10.1038/s41467-018-04859-5 ) (PMID:29934593) (PMCID:PMC6015009)

الإتاحة: https://doi.org/10.1038/s41467-018-04859-5Test
https://eprints.gla.ac.uk/162866Test/
https://eprints.gla.ac.uk/162866/1/162866.pdfTest

المؤلفون: Davies, Faith C. J., Hope, Jilly E., McLachlan, Fiona, Nunez, Francis, Doig, Jennifer, Bengani, Hemant, Smith, Colin, Abbott, Catherine M.

المصدر: Scientific Reports ; volume 7, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: De novo heterozygous missense mutations in the gene encoding translation elongation factor eEF1A2 have recently been found to give rise to neurodevelopmental disorders. Children with mutations in this gene have developmental delay, epilepsy, intellectual disability and often autism; the most frequently occurring mutation is G70S. It has been known for many years that complete loss of eEF1A2 in mice causes motor neuron degeneration and early death; on the other hand heterozygous null mice are apparently normal. We have used CRISPR/Cas9 gene editing in the mouse to mutate the gene encoding eEF1A2, obtaining a high frequency of biallelic mutations. Whilst many of the resulting founder (F0) mice developed motor neuron degeneration, others displayed phenotypes consistent with a severe neurodevelopmental disorder, including sudden unexplained deaths and audiogenic seizures. The presence of G70S protein was not sufficient to protect mice from neurodegeneration in G70S/− mice, showing that the mutant protein is essentially non-functional.

الإتاحة: https://doi.org/10.1038/srep46019Test
https://www.nature.com/articles/srep46019.pdfTest
https://www.nature.com/articles/srep46019Test

المؤلفون: Cao, Yuan, Portela, Miriam, Janikiewicz, Justyna, Doig, Jennifer, Abbott, Catherine M.

المساهمون: Chen, Jin-Gui

المصدر: PLoS ONE ; volume 9, issue 12, page e114117 ; ISSN 1932-6203

الإتاحة: https://doi.org/10.1371/journal.pone.0114117Test

المؤلفون: Doig, Jennifer, Griffiths, Lowri A., Peberdy, David, Dharmasaroja, Permphan, Vera, Maria, Davies, Faith J. C., Newbery, Helen J., Brownstein, David, Abbott, Catherine M.

المصدر: The FEBS Journal ; volume 280, issue 24, page 6528-6540 ; ISSN 1742-464X 1742-4658

الإتاحة: https://doi.org/10.1111/febs.12554Test

المؤلفون: Griffiths, Lowri A., Doig, Jennifer, Churchhouse, Antonia M. D., Davies, Faith C. J., Squires, Charlotte E., Newbery, Helen J., Abbott, Catherine M.

المساهمون: Cai, Huaibin

المصدر: PLoS ONE ; volume 7, issue 7, page e41917 ; ISSN 1932-6203

الإتاحة: https://doi.org/10.1371/journal.pone.0041917Test

المؤلفون: Plowman, Sarah J, Williamson, D James, O'Sullivan, Maureen J, Doig, Jennifer, Ritchie, Ann-Marie, Harrison, David J, Melton, David W, Arends, Mark J, Hooper, Martin L, Patek, Charles E

المصدر: Plowman , S J , Williamson , D J , O'Sullivan , M J , Doig , J , Ritchie , A-M , Harrison , D J , Melton , D W , Arends , M J , Hooper , M L & Patek , C E 2003 , ' While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable ' , Molecular and Cellular Biology , vol. 23 , no. 24 , pp. 9245-9250 . https://doi.org/10.1128/MCB.23.24.9245-9250.2003Test

مصطلحات موضوعية: Alternative splicing, Animals, Base sequence, DNA, Female, Fertility, Gene expression regulation, Developmental, Genes, Ras, Male, Mice, Inbred C57BL, knockout, Phenotype, Protein Isoforms, Tissue distribution

الوصف: In mammals, the three classical ras genes encode four highly homologous proteins, N-Ras, H-Ras, and the isoforms K-Ras 4A and 4B. Previous studies have shown that K-ras is essential for mouse development and that while K-ras 4A and 4B are expressed during development, K-ras 4A expression is regulated temporally and spatially and occurs in adult kidney, intestine, stomach, and liver. In the present study, the pattern of K-ras 4A expression was examined in a wide range of wild-type adult mouse tissues, and gene targeting was used to generate K-ras 4A-deficient mice to examine its role in development. It was found that K-ras 4A is also expressed in uterus, lung, pancreas, salivary glands, seminal vesicles, bone marrow cells, and cecum, where it was the major K-Ras isoform expressed. Mating between K-ras(tmDelta4A/+) mice produced viable K-ras(tmDelta4A/tmDelta4A) offspring with the expected Mendelian ratios of inheritance, and these mice expressed the K-ras 4B splice variant only. K-ras(tmDelta4A/tmDelta4A) mice were fertile and showed no histopathological abnormalities on inbred (129/Ola) or crossbred (129/Ola x C57BL/6) genetic backgrounds. The results demonstrate that K-Ras 4A, like H- and N-Ras, is dispensable for normal mouse development, at least in the presence of functional K-Ras 4B.

وصف الملف: application/pdf

العلاقة: https://research-portal.st-andrews.ac.uk/en/researchoutput/while-kras-is-essential-for-mouse-development-expression-of-the-kras-4a-splice-variant-is-dispensableTest(d6fc3ec4-8d02-4feb-b874-381866cc8e30).html

الإتاحة: https://doi.org/10.1128/MCB.23.24.9245-9250.2003Test
https://research-portal.st-andrews.ac.uk/en/researchoutput/while-kras-is-essential-for-mouse-development-expression-of-the-kras-4a-splice-variant-is-dispensableTest(d6fc3ec4-8d02-4feb-b874-381866cc8e30).html
https://research-repository.st-andrews.ac.uk/bitstream/10023/6244/1/plowman2003molcellbiol9245.pdfTest
http://mcb.asm.org/content/23/24/9245Test