المؤلفون: Montorsi, Lucia, Pitcher, Michael J, Zhao, Yuan, Dionisi, Chiara, Demonti, Alicia, Tull, Thomas J, Dhami, Pawan, Ellis, Richard J, Bishop, Cynthia, Sanderson, Jeremy D, Jain, Sahil, D'Cruz, David, Gibbons, Deena L, Winkler, Thomas H, Bemark, Mats, Ciccarelli, Francesca D, Spencer, Jo

المصدر: Nature Communications. 15(1):4051-4051

مصطلحات موضوعية: Animals, Humans, Mice, B-Lymphocytes/immunology, Gastrointestinal Microbiome/immunology, Endodeoxyribonucleases/metabolism, Dendritic Cells/immunology, Lymphoid Tissue/immunology, Female, Inbred C57BL, Intestinal Mucosa/immunology, Male, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Immunologi inom det medicinska området, Medical and Health Sciences, Basic Medicine, Immunology in the medical area

الوصف: Intestinal homeostasis is maintained by the response of gut-associated lymphoid tissue to bacteria transported across the follicle associated epithelium into the subepithelial dome. The initial response to antigens and how bacteria are handled is incompletely understood. By iterative application of spatial transcriptomics and multiplexed single-cell technologies, we identify that the double negative 2 subset of B cells, previously associated with autoimmune diseases, is present in the subepithelial dome in health. We show that in this location double negative 2 B cells interact with dendritic cells co-expressing the lupus autoantigens DNASE1L3 and C1q and microbicides. We observe that in humans, but not in mice, dendritic cells expressing DNASE1L3 are associated with sampled bacteria but not DNA derived from apoptotic cells. We propose that fundamental features of autoimmune diseases are microbiota-associated, interacting components of normal intestinal immunity.

الوصول الحر: https://lup.lub.lu.se/record/014dee57-9974-4752-82b6-dee36c38f5f4Test
http://dx.doi.org/10.1038/s41467-024-48267-4Test

المؤلفون: Steele, Christopher D, Abbasi, Ammal, Islam, S M Ashiqul, Bowes, Amy L, Khandekar, Azhar, Haase, Kerstin, Hames-Fathi, Shadi, Ajayi, Dolapo, Verfaillie, Annelien, Dhami, Pawan, McLatchie, Alex, Lechner, Matt, Light, Nicholas, Shlien, Adam, Malkin, David, Feber, Andrew, Proszek, Paula, Lesluyes, Tom, Mertens, Fredrik, Flanagan, Adrienne M, Tarabichi, Maxime, Van Loo, Peter, Alexandrov, Ludmil B, Pillay, Nischalan

المصدر: Nature. 606(7916):984-991

مصطلحات موضوعية: Medicin och hälsovetenskap, Klinisk medicin, Cancer och onkologi, Medical and Health Sciences, Clinical Medicine, Cancer and Oncology, Medicinska och farmaceutiska grundvetenskaper, Medicinsk genetik, Basic Medicine, Medical Genetics

الوصف: Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.

الوصول الحر: https://lup.lub.lu.se/record/8eb51002-b2ce-475a-a2bd-8457f53c4fd1Test
http://dx.doi.org/10.1038/s41586-022-04738-6Test

المؤلفون: Durham, Lucy E., Humby, Frances C, Ng, Nora, Ryan, Sarah, Nuamah, Rosamond, Fung, Kathy, Kallayil, Athul Menon, Dhami, Pawan, Kirkham, Bruce W., Taams, Leonie S.

المصدر: Arthritis & Rheumatology ; ISSN 2326-5191 2326-5205

الوصف: Objective Synovial fluid (SF) derived T‐cells are frequently studied as a proxy for investigating the synovial tissue (ST) T‐cell infiltrate in inflammatory arthritis. However, since ST is the primary site of inflammatory activity, there is debate as to whether SF provides a true reflection of the ST T‐cell population. Methods In this study, we used single cell RNA sequencing paired with single cell T‐cell receptor (TCR) sequencing to directly compare memory T‐cells from paired samples of SF and ST from 6 patients with inflammatory arthritis to investigate their similarity in terms of TCR repertoire and T‐cell subset composition. Results The TCR repertoires of SF and ST T‐cells were strikingly similar, particularly for CD8+ T‐cells. A median of 49% of the total CD8+ TCR repertoire in SF was shared with ST, compared to 20% shared with blood. Similarly, 47% of the ST CD8+ TCR repertoire was shared with SF compared to 25% with blood. Furthermore, once the effect of collagenase digestion on gene expression by ST T‐cells had been accounted for, the frequencies of specific CD8+ and CD4+ T‐cell subsets were, in general, similar in SF and ST and were distinct from blood. Conclusion Our results suggest that T‐cells migrate and equilibrate between SF and ST and maintain similar phenotypes in both sites. We conclude that SF is an appropriate proxy for investigating the T‐cell infiltrate in inflamed synovium, particularly in terms of investigating the TCR repertoire. image

الإتاحة: https://doi.org/10.1002/art.42949Test

المؤلفون: Webster, Amy P, Ecker, Simone, Moghul, Ismail, Liu, Xiaohong, Dhami, Pawan, Marzi, Sarah, Paul, Dirk S, Kuxhausen, Michelle, Lee, Stephanie J, Spellman, Stephen R, Wang, Tao, Feber, Andrew, Rakyan, Vardhman, Peggs, Karl S, Beck, Stephan

المصدر: Frontiers in Genetics , 15 , Article 1242636. (2024)

مصطلحات موضوعية: DNA methylation, haematopoietic stem cell transplant, epigenetics, machine learning, biomarker identification and validation, HCT (hematopoietic cell transplant)

الوصف: Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10190831/1/Moghul_Donor%20whole%20blood%20DNA%20methylation%20is%20not%20a%20strong%20predictor%20of%20acute%20graft%20versus%20host%20disease%20in%20unrelated%20donor%20allogeneic%20haematopoietic%20cell%20transplantation_VoR.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10190831Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10190831/1/Moghul_Donor%20whole%20blood%20DNA%20methylation%20is%20not%20a%20strong%20predictor%20of%20acute%20graft%20versus%20host%20disease%20in%20unrelated%20donor%20allogeneic%20haematopoietic%20cell%20transplantation_VoR.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10190831Test/

المؤلفون: Francis, Luc, McCluskey, Daniel, Ganier, Clarisse, Jiang, Treasa, Du-Harpur, Xinyi, Gabriel, Jeyrroy, Dhami, Pawan, Kamra, Yogesh, Visvanathan, Sudha, Barker, Jonathan N., Smith, Catherine H., Capon, Francesca, Mahil, Satveer K.

المساهمون: Psoriasis Association, RCUK | Medical Research Council, DH | National Institute for Health Research

المصدر: Nature Communications ; volume 15, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Biologic therapies targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis. However, the early mechanisms of action of these drugs remain poorly understood. Here, we perform longitudinal single-cell RNA-sequencing in affected individuals receiving IL-23 inhibitor therapy. By profiling skin at baseline, day 3 and day 14 of treatment, we demonstrate that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We also identify a transient WNT5A + /IL24+ fibroblast state, which is only detectable in lesional skin. In-silico and in-vitro studies indicate that signals stemming from these WNT5A + /IL24+ fibroblasts upregulate multiple inflammatory genes in keratinocytes. Importantly, the abundance of WNT5A + /IL24+ fibroblasts is significantly reduced after treatment. This observation is validated in-silico , by deconvolution of multiple transcriptomic datasets, and experimentally, by RNA in-situ hybridization. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.

الإتاحة: https://doi.org/10.1038/s41467-024-44994-wTest
https://www.nature.com/articles/s41467-024-44994-w.pdfTest
https://www.nature.com/articles/s41467-024-44994-wTest

المؤلفون: Webster, Amy P., Ecker, Simone, Moghul, Ismail, Liu, Xiaohong, Dhami, Pawan, Marzi, Sarah, Paul, Dirk S., Kuxhausen, Michelle, Lee, Stephanie J., Spellman, Stephen R., Wang, Tao, Feber, Andrew, Rakyan, Vardhman, Peggs, Karl S., Beck, Stephan

المصدر: Frontiers in Genetics ; volume 15 ; ISSN 1664-8021

الوصف: Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use.

الإتاحة: https://doi.org/10.3389/fgene.2024.1242636Test

المؤلفون: Crescioli, Silvia, Correa, Isabel, Ng, Joseph, Willsmore, Zena N, Laddach, Roman, Chenoweth, Alicia, Chauhan, Jitesh, Di Meo, Ashley, Stewart, Alexander, Kalliolia, Eleni, Alberts, Elena, Adams, Rebecca, Harris, Robert J, Mele, Silvia, Pellizzari, Giulia, Black, Anna BM, Bax, Heather J, Cheung, Anthony, Nakamura, Mano, Hoffmann, Ricarda M, Terranova-Barberio, Manuela, Ali, Niwa, Batruch, Ihor, Soosaipillai, Antoninus, Prassas, Ioannis, Ulndreaj, Antigona, Chatanaka, Miyo K, Nuamah, Rosamund, Kannambath, Shichina, Dhami, Pawan, Geh, Jenny LC, MacKenzie Ross, Alastair D, Healy, Ciaran, Grigoriadis, Anita, Kipling, David, Karagiannis, Panagiotis, Dunn-Walters, Deborah K, Diamandis, Eleftherios P, Tsoka, Sophia, Spicer, James, Lacy, Katie E, Fraternali, Franca, Karagiannis, Sophia N

المصدر: Nature Communications , 14 (1) , Article 3378. (2023)

الوصف: B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10171871/1/s41467-023-39042-y.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10171871Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10171871/1/s41467-023-39042-y.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10171871Test/

المؤلفون: Owen, Nicholas, Toms, Maria, Tian, Yuan, Toualbi, Lyes, Richardson, Rose, Young, Rodrigo, Tracey-White, Dhani, Dhami, Pawan, Beck, Stephan, Moosajee, Mariya

المصدر: The Journal of Pathology , 259 pp. 441-454. (2023)

مصطلحات موضوعية: DNA methylation, Polarity complex, RNA-seq, epigenome, iPSC, retina, transcriptome, zebrafish

الوصف: The crumbs cell polarity complex plays a crucial role in apical-basal epithelial polarity, cellular adhesion, and morphogenesis. Homozygous variants in human CRB1 result in autosomal recessive Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP), with no established genotype-phenotype correlation. The associated protein complexes have key functions in developmental pathways; however the underlying disease mechanism remains unclear. Using the oko meduzym289/m289 (crb2a-/- ) zebrafish, we performed integrative transcriptomic (RNA-seq data) and methylomic (reduced representation bisulphite sequencing, RRBS) analysis of whole retina to identify dysregulated genes and pathways. Delayed retinal cell specification was identified in both the crb2a-/- zebrafish and CRB1 patient-derived retinal organoids, highlighting dysfunction of cell cycle modulation and epigenetic transcriptional control. Differential DNA methylation analysis revealed novel hypermethylated pathways involving biological adhesion, Hippo and transforming growth factor β (TGFβ) signalling. By integrating gene expression with DNA methylation using functional epigenetic modules (FEM), we identified 6 key modules involving cell cycle control and disturbance of TGFβ, BMP, Hippo, and SMAD protein signal transduction pathways, revealing significant interactome hotspots relevant to crb2a function, confirming the epigenetic control of gene regulation in early retinal development and points to a novel mechanism underlying CRB1-retinopathies.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/10163680/7/Beck_The%20Journal%20of%20Pathology%20-%202023%20-%20Owen%20-%20Loss%20of%20the%20crumbs%20cell%20polarity%20complex%20disrupts%20epigenetic%20transcriptional.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10163680Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/10163680/7/Beck_The%20Journal%20of%20Pathology%20-%202023%20-%20Owen%20-%20Loss%20of%20the%20crumbs%20cell%20polarity%20complex%20disrupts%20epigenetic%20transcriptional.pdfTest
https://discovery.ucl.ac.uk/id/eprint/10163680Test/

المؤلفون: Neves, Vitor CM, Satie Okajima, Luciana, Elbahtety, Eyad, Joseph, Susan, Daly, James, Menon, Athul, Fan, Di, Volkyte, Ayste, Mainas, Giuseppe, Fung, Kathy, Dhami, Pawan, Pelegrine, Andre A, Sharpe, Paul, Nibali, Luigi, Ide, Mark

الوصف: BACKGROUND: Despite the improvements in treatment over the last decades, periodontal disease (PD) affects millions of people around the world and the only treatment available is based on controlling microbial load. Diabetes is known to increase the risk of PD establishment and progression, and recently, glucose metabolism modulation by pharmaceutical or dietarian means has been emphasised as a significant modulator of non-communicable disease development. METHODS: The impact of pharmaceutically controlling glucose metabolism in non-diabetic animals and humans (REBEC, UTN code: U1111-1276-1942) was investigated by repurposing Metformin, as a mean to manage periodontal disease and its associated systemic risk factors. RESULTS: We found that glucose metabolism control via use of Metformin aimed at PD management resulted in significant prevention of bone loss during induced periodontal disease and age-related bone loss in vivo. Metformin also influenced the bacterial species present in the oral environment and impacted the metabolic epithelial and stromal responses to bacterial dysbiosis at a single cell level. Systemically, Metformin controlled blood glucose levels and age-related weight gain when used long-term. Translationally, our pilot randomized control trial indicated that systemic Metformin was safe to use in non-diabetic patients and affected the periodontal tissues. During the medication window, patients showed stable levels of systemic blood glucose, lower circulating hsCRP and lower insulin levels after periodontal treatment when compared to placebo. Finally, patients treated with Metformin had improved periodontal parameters when compared to placebo treated patients. CONCLUSION: This is the first study to demonstrate that systemic interventions using Metformin in non-diabetic individuals aimed at PD prevention have oral-systemic effects constituting a possible novel form of preventive medicine for oral-systemic disease management.

وصف الملف: text

العلاقة: https://researchonline.lshtm.ac.uk/id/eprint/4671303/1/Neves-etal-2023-Repurposing-Metformin-for-periodontal-disease-management-as-a-form-of-oral-systemic-preventive-medicine.pdfTest; Neves, Vitor CM; Satie Okajima, Luciana; Elbahtety, Eyad ; Joseph, Susan; Daly, James; Menon, Athul; Fan, Di; Volkyte, Ayste; Mainas, Giuseppe; Fung, Kathy; +5 more. Dhami, Pawan; Pelegrine, Andre A; Sharpe, Paul; Nibali, Luigi; Ide, Mark; (2023) Repurposing Metformin for periodontal disease management as a form of oral-systemic preventive medicine. Journal of translational medicine, 21 (1). 655-. ISSN 1479-5876 DOI: https://doi.org/10.1186/s12967-023-04456-1Test

الإتاحة: https://doi.org/10.1186/s12967-023-04456-1Test
https://researchonline.lshtm.ac.uk/id/eprint/4671303Test/
https://researchonline.lshtm.ac.uk/id/eprint/4671303/1/Neves-etal-2023-Repurposing-Metformin-for-periodontal-disease-management-as-a-form-of-oral-systemic-preventive-medicine.pdfTest

المؤلفون: Caetano, Ana J, Redhead, Yushi, Karim, Farah, Dhami, Pawan, Kannambath, Shichina, Nuamah, Rosamond, Volponi, Ana A, Nibali, Luigi, Booth, Veronica, D'Agostino, Eleanor M, Sharpe, Paul T

المساهمون: Biotechnology and Biological Sciences Research Council, NIHR Biomedical Research Centre Guy's and St Thomas' NHS Foundation Trust and King's College London, Czech Science Foundation

المصدر: eLife ; volume 12 ; ISSN 2050-084X

الوصف: The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP . Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.

الإتاحة: https://doi.org/10.7554/elife.81525Test
https://cdn.elifesciences.org/articles/81525/elife-81525-v2.pdfTest
https://cdn.elifesciences.org/articles/81525/elife-81525-v2.xmlTest
https://elifesciences.org/articles/81525Test