17 results on '"Davies, Jessica"'
Search Results
2. Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade
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Kaur, Gurman, Porter, Caroline BM, Ashenberg, Orr, Lee, Jack, Riesenfeld, Samantha J, Hofree, Matan, Aggelakopoulou, Maria, Subramanian, Ayshwarya, Kuttikkatte, Subita Balaram, Attfield, Kathrine E, Desel, Christiane AE, Davies, Jessica L, Evans, Hayley G, Avraham-Davidi, Inbal, Nguyen, Lan T, Dionne, Danielle A, Neumann, Anna E, Jensen, Lise Torp, Barber, Thomas R, Soilleux, Elizabeth, Carrington, Mary, McVean, Gil, Rozenblatt-Rosen, Orit, Regev, Aviv, Fugger, Lars, Kaur, Gurman [0000-0001-7722-3956], Riesenfeld, Samantha J [0000-0001-9144-021X], Hofree, Matan [0000-0001-8368-0299], Subramanian, Ayshwarya [0000-0002-4134-7612], Attfield, Kathrine E [0000-0003-3387-521X], Desel, Christiane AE [0000-0003-2029-3851], Davies, Jessica L [0000-0002-8888-1441], Avraham-Davidi, Inbal [0000-0001-7118-9179], Neumann, Anna E [0000-0001-7115-8305], Soilleux, Elizabeth [0000-0002-4032-7249], Carrington, Mary [0000-0002-2692-2180], McVean, Gil [0000-0002-5012-4162], Rozenblatt-Rosen, Orit [0000-0001-6313-3570], Fugger, Lars [0000-0003-2883-3226], and Apollo - University of Cambridge Repository
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123 ,631/250/2504 ,General Physics and Astronomy ,Cell Communication ,HLA-C Antigens ,General Biochemistry, Genetics and Molecular Biology ,14/32 ,Mice ,13/1 ,Fetus ,Pregnancy ,Animals ,45/91 ,Fetal Growth Retardation ,Multidisciplinary ,45 ,article ,General Chemistry ,631/208/248 ,Trophoblasts ,692/4017 ,13/31 ,631/250/1619/382 ,38/77 ,Female ,38/39 ,64/60 - Abstract
Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicateKIRandHLAgenes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.
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- 2022
- Full Text
- View/download PDF
3. The role of social cohesion and perceived access to public green space on health behaviours during summer 2020 of the COVID-19 pandemic
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Bessant, Thomas, Kelly, Kirsty, Davies, Jessica, Henderson, Rebecca, and Poortinga, Wouter
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- 2022
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4. Evidence of partner similarity for autistic traits, systemizing, and theory of mind via facial expressions
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Richards, Gareth, Baron-Cohen, Simon, Warrier, Varun, Mellor, Ben, Davies, Jessica, Gee, Laura, Galvin, John, Baron-Cohen, Simon [0000-0001-9217-2544], and Apollo - University of Cambridge Repository
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Facial Expression ,631/477/2811 ,Multidisciplinary ,mental disorders ,article ,Theory of Mind ,Humans ,631/477 ,Autistic Disorder ,Empathy ,behavioral disciplines and activities ,health care economics and organizations - Abstract
Funder: Autism Research Trust, Funder: Autistica; doi: http://dx.doi.org/10.13039/501100008161, Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265, Funder: Cambridge Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100018956, Funder: National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East of England at Cambridgeshire and Peterborough NHS Foundation Trust, Funder: Templeton World Charity Foundation; doi: http://dx.doi.org/10.13039/501100011730, It has been hypothesised that romantic partners are more similar than chance in relation to autistic traits. To test this theory, we recruited n = 105 heterosexual couples and examined within-couple correlations for autistic traits [measured using the Autism Spectrum Quotient (AQ)], empathizing [measured using the Empathy Quotient (EQ)], and systemizing [measured using the Systemizing Quotient-Revised (SQ-R)]. For a subsample that attended the lab (n = 58 couples), we also investigated theory of mind via facial expressions using the Reading the Mind in the Eyes Test (RMET) and attention to detail, a component within systemizing, using the Embedded Figures Task (EFT). Variable-centred analyses revealed positive within-couple correlations for all measures except EQ, although these effects were only statistically significant for unmarried couples and not for married/engaged couples. Follow-up analyses indicated that the observed couple similarity effects are likely consistent with people pairing with those more similar than chance (initial assortment) rather than becoming alike over time (convergence), and to seeking out self-resembling partners (active assortment) rather than pairing in this manner via social stratification processes (social homogamy). Additionally, a significant within-couple correlation for autistic traits was observed at the meta-analytic level. However, it should be noted that the meta-analytic effect size estimate was small (r = 0.153) and indicates that only ~ 2% of variance in a person’s score on a phenotypic measure of autistic traits can be predicted by that of their partner.
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- 2022
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5. Cross-reactivity of anti-HMGB1 antibodies for HMGB2
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Davies, Jessica E, Apta, Bonita HR, Harper, Matthew T, Harper, Matthew [0000-0002-4740-637X], and Apollo - University of Cambridge Repository
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Antigen-Antibody Reactions ,Human Umbilical Vein Endothelial Cells ,HMGB2 Protein ,Humans ,chemical and pharmacologic phenomena ,Cross Reactions ,HMGB1 Protein ,Article ,Antibodies ,Cells, Cultured ,Healthy Volunteers - Abstract
HMGB1 and HMGB2 are DNA-interacting proteins but can also have extracellular actions during inflammation. Despite their relatively high homology, they may have distinct roles, making it essential to be able to differentiate between the two. Here we examine the specificity of five commercially-available anti-HMGB1 antibodies. By Western blotting of recombinant proteins and HMGB1-/- mouse embryonic fibroblasts, we identified only one HMGB1 antibody that, under our experimental conditions, did not also detect HMGB2. Selecting specific antibodies for HMGB1 and HMGB2 allowed identification of distinct HMGB1 and HMGB2 subcellular pools in primary neutrophils.
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- 2018
6. Real-world anaplastic lymphoma kinase (ALK) rearrangement testing patterns, treatment sequences, and survival of ALK inhibitor-treated patients
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Davies, Jessica, Martinec, Michael, Coudert, Mathieu, Delmar, Paul, and Gracy Crane
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hemic and lymphatic diseases - Abstract
Background: The anaplastic lymphoma kinase (ALK) treatment landscape is crowded following recent ALK inhibitor approvals, and updated information on real-world treatment patterns in advanced non-small-cell lung cancer (aNSCLC) with ALK rearrangement (ALK+) is needed. Methods: This retrospective US cohort study used Flatiron Health’s longitudinal electronic health record (EHR)-derived database. Patients (≥18 years old) diagnosed with stage IIIB/IV aNSCLC, with documented ALK rearrangement and ≥2 visits after January 1, 2011 were followed until February 28, 2016. Patients enrolled on a clinical trial or exposed to ALK inhibitors other than crizotinib or ceritinib were excluded. Treatment patterns, time and type of biomarker testing, and overall survival (OS) were analyzed. Results: Median age (n = 300) was 62.5 years; 55% female; 48% non-smokers; 8.7% central nervous system (CNS) metastases at diagnosis. Overall, 73% and 86% received their first ALK biomarker test before/at diagnosis, or before/during first-line treatment, respectively. In total, 90.0%, 78.1% and 74.7% received first-, second- and third-line therapy, respectively. Most patients received ALK-targeted treatment; 62% received crizotinib of which 21% reported a dose reduction. Progression was the most common reason for crizotinib (78%) and ceritinib (41%) discontinuation. Median OS was 29.4 months (95% CI: 24.7–39.6) overall; 27.1 months (95% CI: 22.0–35.0) in patients with CNS metastases and 36.9 months (95% CI: 25.1–not reached) without. Conclusions: Despite widespread crizotinib use in patients with ALK+ aNSCLC, a high proportion of patients progressed. Ongoing analyses of EHR-derived cohorts are valuable in assessing real-world testing rates and therapeutic use of ALK inhibitors.
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- 2018
- Full Text
- View/download PDF
7. A Symbolic SAT-Based Algorithm for Almost-Sure Reachability with Small Strategies in POMDPs
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Chatterjee, Krishnendu, Chmelik, Martin, and Davies, Jessica
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FOS: Computer and information sciences ,Artificial Intelligence (cs.AI) ,Computer Science - Artificial Intelligence ,General Medicine - Abstract
POMDPs are standard models for probabilistic planning problems, where an agent interacts with an uncertain environment. We study the problem of almost-sure reachability, where given a set of target states, the question is to decide whether there is a policy to ensure that the target set is reached with probability 1 (almost-surely). While in general the problem is EXPTIME-complete, in many practical cases policies with a small amount of memory suffice. Moreover, the existing solution to the problem is explicit, which first requires to construct explicitly an exponential reduction to a belief-support MDP. In this work, we first study the existence of observation-stationary strategies, which is NP-complete, and then small-memory strategies. We present a symbolic algorithm by an efficient encoding to SAT and using a SAT solver for the problem. We report experimental results demonstrating the scalability of our symbolic (SAT-based) approach., Comment: Full version of "A Symbolic SAT-based Algorithm for Almost-sure Reachability with Small Strategies in POMDPs" AAAI 2016
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- 2016
8. A Symbolic SAT-based Algorithm for Almost-sure Reachability with Small Strategies in POMDPs
- Author
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Chatterjee, Krishnendu, Chmelík, Martin, and Davies, Jessica
- Subjects
000 Computer science, knowledge & systems - Abstract
POMDPs are standard models for probabilistic planning problems, where an agent interacts with an uncertain environment. We study the problem of almost-sure reachability, where given a set of target states, the question is to decide whether there is a policy to ensure that the target set is reached with probability 1 (almost-surely). While in general the problem is EXPTIME-complete, in many practical cases policies with a small amount of memory suffice. Moreover, the existing solution to the problem is explicit, which first requires to construct explicitly an exponential reduction to a belief-support MDP. In this work, we first study the existence of observation-stationary strategies, which is NP-complete, and then small-memory strategies. We present a symbolic algorithm by an efficient encoding to SAT and using a SAT solver for the problem. We report experimental results demonstrating the scalability of our symbolic (SAT-based) approach.
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- 2015
9. An Empirical Study of Borda Manipulation
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Davies, Jessica, Katsirelos, George, Narodystka, Nina, and Walsh, Toby
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FOS: Computer and information sciences ,Artificial Intelligence (cs.AI) ,I.2.4 ,Computer Science - Artificial Intelligence - Abstract
We study the problem of coalitional manipulation in elections using the unweighted Borda rule. We provide empirical evidence of the manipulability of Borda elections in the form of two new greedy manipulation algorithms based on intuitions from the bin-packing and multiprocessor scheduling domains. Although we have not been able to show that these algorithms beat existing methods in the worst-case, our empirical evaluation shows that they significantly outperform the existing method and are able to find optimal manipulations in the vast majority of the randomly generated elections that we tested. These empirical results provide further evidence that the Borda rule provides little defense against coalitional manipulation., Comment: To appear in Proceedings of the Third International Workshop on Computational Social Choice
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- 2010
- Full Text
- View/download PDF
10. 2-Aminoethoxydiphenylborate (2-APB) inhibits release of phosphatidylserine-exposing extracellular vesicles from platelets
- Author
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Wei, Hao, Davies, Jessica E, and Harper, Matthew T
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Drug Development ,Mechanism of action ,3. Good health - Abstract
Activated, procoagulant platelets shed phosphatidylserine (PS)-exposing extracellular vesicles (EVs) from their surface in a Ca2+- and calpain-dependent manner. These PS-exposing EVs are prothrombotic and proinflammatory and are found at elevated levels in many cardiovascular and metabolic diseases. How PS-exposing EVs are shed is not fully understood. A clearer understanding of this process may aid the development of drugs to selectively block their release. In this study we report that 2-aminoethoxydiphenylborate (2-APB) significantly inhibits the release of PS-exposing EVs from platelets stimulated with the Ca2+ ionophore, A23187, or the pore-forming toxin, streptolysin-O. Two analogues of 2-APB, diphenylboronic anhydride (DPBA) and 3-(diphenylphosphino)-1-propylamine (DP3A), inhibited PS-exposing EV release with similar potency. Although 2-APB and DPBA weakly inhibited platelet PS exposure and calpain activity, this was not seen with DP3A despite inhibiting PS-exposing EV release. These data suggest that there is a further target of 2-APB, independent of cytosolic Ca2+ signalling, PS exposure and calpain activity, that is required for PS-exposing EV release. DP3A is likely to inhibit the same target, without these other effects. Identifying the target of 2-APB, DPBA and DP3A may provide a new way to inhibit PS-exposing EV release from activated platelets and inhibit their contribution to thrombosis and inflammation.
11. Using Yoda-1 to mimic laminar flow in vitro: a tool to simplify drug testing
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Davies, Jessica E, Lopresto, Dora, Apta, Bonita HR, Lin, Zhiyuan, Ma, Wenxin, and Harper, Matthew T
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Inflammation ,Yoda-1 ,Shear stress ,Antibiotics, Antineoplastic ,Cell Survival ,Toxicology ,Laminar flow ,3. Good health ,Doxorubicin ,Pyrazines ,Thiadiazoles ,Human Umbilical Vein Endothelial Cells ,Humans ,Endothelium ,Stress, Mechanical ,Piezosurgery - Abstract
The endothelium is an attractive drug target and an important site of adverse drug reactions. Endothelial dysfunction is strongly associated with inflammation and contributes to drug-induced cardiovascular toxicity. Endothelial cells in the circulation are exposed to haemodynamic forces including shear stress. Including shear stress may improve future endothelial cell drug discovery or toxicity screening. Piezo-1 is required for endothelial cells to respond to shear stress. In this study, we investigated whether a small molecule activator of Piezo-1, Yoda-1, can mimic the effect of laminar flow-induced shear stress on endothelial cell inflammation, and endothelial cytotoxicity in response to the chemotherapy agent, doxorubicin. First, we tested whether Yoda-1 could mimic the effects of shear stress of expression of the endothelial adhesion molecules, ICAM-1 and VCAM-1. Human umbilical vein endothelial cells (HUVEC) were cultured in static conditions (with or without Yoda-1) or under laminar flow-induced shear stress (5 dyn/cm2). Yoda-1 and laminar flow had similar anti-inflammatory effects, reducing the ability of TNF-α to induce ICAM-1 and VCAM-1 expression. We then tested whether Yoda-1 could mimic the effect of shear stress on doxorubicin-induced cytotoxicity. Both laminar flow and Yoda-1 treatment of static cultures increased the cytotoxicity of doxorubicin. These findings show that Piezo-1 activation with Yoda-1 in static culture leads to an endothelial cell phenotype that mimics endothelial cells under laminar flow. Pharmacological activation of Piezo-1 may be a useful approach to mimic constant shear stress in static cultures, which may improve endothelial drug discovery and toxicity testing.
12. 2-Aminoethoxydiphenylborate (2-APB) inhibits release of phosphatidylserine-exposing extracellular vesicles from platelets
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Wei, Hao, Davies, Jessica E., and Harper, Matthew T.
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631/92/609 ,article ,692/308/153 ,3. Good health - Abstract
Activated, procoagulant platelets shed phosphatidylserine (PS)-exposing extracellular vesicles (EVs) from their surface in a Ca2+- and calpain-dependent manner. These PS-exposing EVs are prothrombotic and proinflammatory and are found at elevated levels in many cardiovascular and metabolic diseases. How PS-exposing EVs are shed is not fully understood. A clearer understanding of this process may aid the development of drugs to selectively block their release. In this study we report that 2-aminoethoxydiphenylborate (2-APB) significantly inhibits the release of PS-exposing EVs from platelets stimulated with the Ca2+ ionophore, A23187, or the pore-forming toxin, streptolysin-O. Two analogues of 2-APB, diphenylboronic anhydride (DPBA) and 3-(diphenylphosphino)-1-propylamine (DP3A), inhibited PS-exposing EV release with similar potency. Although 2-APB and DPBA weakly inhibited platelet PS exposure and calpain activity, this was not seen with DP3A despite inhibiting PS-exposing EV release. These data suggest that there is a further target of 2-APB, independent of cytosolic Ca2+ signalling, PS exposure and calpain activity, that is required for PS-exposing EV release. DP3A is likely to inhibit the same target, without these other effects. Identifying the target of 2-APB, DPBA and DP3A may provide a new way to inhibit PS-exposing EV release from activated platelets and inhibit their contribution to thrombosis and inflammation.
13. 2-Aminoethoxydiphenylborate (2-APB) inhibits release of phosphatidylserine-exposing extracellular vesicles from platelets
- Author
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Wei, Hao, Davies, Jessica E., and Harper, Matthew T.
- Subjects
631/92/609 ,article ,692/308/153 ,3. Good health - Abstract
Activated, procoagulant platelets shed phosphatidylserine (PS)-exposing extracellular vesicles (EVs) from their surface in a Ca2+- and calpain-dependent manner. These PS-exposing EVs are prothrombotic and proinflammatory and are found at elevated levels in many cardiovascular and metabolic diseases. How PS-exposing EVs are shed is not fully understood. A clearer understanding of this process may aid the development of drugs to selectively block their release. In this study we report that 2-aminoethoxydiphenylborate (2-APB) significantly inhibits the release of PS-exposing EVs from platelets stimulated with the Ca2+ ionophore, A23187, or the pore-forming toxin, streptolysin-O. Two analogues of 2-APB, diphenylboronic anhydride (DPBA) and 3-(diphenylphosphino)-1-propylamine (DP3A), inhibited PS-exposing EV release with similar potency. Although 2-APB and DPBA weakly inhibited platelet PS exposure and calpain activity, this was not seen with DP3A despite inhibiting PS-exposing EV release. These data suggest that there is a further target of 2-APB, independent of cytosolic Ca2+ signalling, PS exposure and calpain activity, that is required for PS-exposing EV release. DP3A is likely to inhibit the same target, without these other effects. Identifying the target of 2-APB, DPBA and DP3A may provide a new way to inhibit PS-exposing EV release from activated platelets and inhibit their contribution to thrombosis and inflammation.
14. Keratinocyte growth factor impairs human thymic recovery from lymphopenia
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Coles, Alasdair, Azzopardi, Laura, Kousin-Ezewu, Onajite, Mullay, Harpreet, Thompson, Sara, Jarvis, Lorna, Davies, Jessica, Howlett, Sarah, Rainbow, Daniel, Babar, Judith, Sadler, Timothy, Brown, William, Needham, Edward, May, Karen, Georgieva, Zoya, Handel, Adam, Maio, Stefano, Deadman, Mary, Rota, Ioanna, Hollander, Georg, Dawson, Sarah, Jayne, David, Seggewiss-Berhardt, Ruth, Douek, Daniel, Isaacs, John, and Jones, Joanne
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Fibroblast Growth Factor 7 ,Adolescent ,Autoimmune diseases ,FOS: Clinical medicine ,Immunology ,T cell development ,T cells ,Therapeutics ,Middle Aged ,3. Good health ,Disease Models, Animal ,Mice ,Young Adult ,Multiple Sclerosis, Relapsing-Remitting ,CD52 Antigen ,Lymphopenia ,Animals ,Humans ,Female ,10. No inequality - Abstract
Background: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates. Methods: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signaljoint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30. Findings: At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107 /L vs. 7.733x107 /L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocoldefined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groups Conclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime., Trial - MRC and Moulton Trust Funding Me (senior Author) - Wellcome Trust Funding.
15. Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73
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Jarvis, Lorna B., Rainbow, Daniel B., Coppard, Valerie, Howlett, Sarah K., Georgieva, Zoya, Davies, Jessica L., Mullay, Harpreet Kaur, Hester, Joanna, Ashmore, Tom, Van Den Bosch, Aletta, Grist, James T., Coles, Alasdair J., Mousa, Hani S., Pluchino, Stefano, Mahbubani, Krishnaa T., Griffin, Julian L., Saeb-Parsy, Kourosh, Issa, Fadi, Peruzzotti-Jametti, Luca, Wicker, Linda S., and Jones, Joanne L.
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82 ,82/58 ,631/250/24/1529 ,article ,hemic and immune systems ,chemical and pharmacologic phenomena ,631/250/251/1574 ,13/106 ,3. Good health ,13/31 ,13/1 ,13/21 ,631/250/1619/554/1898/1271 ,38/39 ,64/60 ,631/250/24/1313 - Abstract
The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.
16. Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73
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Jarvis, Lorna B, Rainbow, Daniel B, Coppard, Valerie, Howlett, Sarah K, Georgieva, Zoya, Davies, Jessica L, Mullay, Harpreet Kaur, Hester, Joanna, Ashmore, Tom, Van Den Bosch, Aletta, Grist, James T, Coles, Alasdair J, Mousa, Hani S, Pluchino, Stefano, Mahbubani, Krishnaa T, Griffin, Julian L, Saeb-Parsy, Kourosh, Issa, Fadi, Peruzzotti-Jametti, Luca, Wicker, Linda S, and Jones, Joanne L
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Male ,Gene Expression Regulation ,Humans ,hemic and immune systems ,chemical and pharmacologic phenomena ,Female ,GPI-Linked Proteins ,Hypoxia-Inducible Factor 1, alpha Subunit ,5'-Nucleotidase ,T-Lymphocytes, Regulatory ,3. Good health - Abstract
The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.
17. Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73
- Author
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Daniel B. Rainbow, Lorna B. Jarvis, Valerie Coppard, Hani S Mousa, Joanne L. Jones, Alasdair Coles, Zoya Georgieva, Fadi Issa, Kourosh Saeb-Parsy, Krishnaa T. Mahbubani, Stefano Pluchino, Tom Ashmore, Sarah Howlett, Julian L. Griffin, Luca Peruzzotti-Jametti, Linda S. Wicker, Aletta Van Den Bosch, Joanna Hester, Harpreet Kaur Mullay, James T. Grist, Jessica L. Davies, Jarvis, Lorna B [0000-0002-5760-0125], Rainbow, Daniel B [0000-0003-4931-3289], Davies, Jessica L [0000-0002-8888-1441], Hester, Joanna [0000-0002-7466-3849], Pluchino, Stefano [0000-0002-6267-9472], Mahbubani, Krishnaa T [0000-0002-1327-2334], Griffin, Julian L [0000-0003-1336-7744], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Issa, Fadi [0000-0002-8279-7732], Wicker, Linda S [0000-0001-7771-0324], Jones, Joanne L [0000-0003-4974-1371], Apollo - University of Cambridge Repository, Mousa, Hani S [0000-0002-8327-7114], Jarvis, Lorna B. [0000-0002-5760-0125], Rainbow, Daniel B. [0000-0003-4931-3289], Davies, Jessica L. [0000-0002-8888-1441], Mahbubani, Krishnaa T. [0000-0002-1327-2334], Griffin, Julian L. [0000-0003-1336-7744], Wicker, Linda S. [0000-0001-7771-0324], and Jones, Joanne L. [0000-0003-4974-1371]
- Subjects
Male ,Adoptive cell transfer ,Autoimmune diseases ,Medicine (miscellaneous) ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Graft-versus-host disease ,Autoimmunity ,Transcriptome ,13/1 ,0302 clinical medicine ,Biology (General) ,631/250/24/1313 ,5'-Nucleotidase ,0303 health sciences ,631/250/24/1529 ,631/250/251/1574 ,hemic and immune systems ,Regulatory T cells ,3. Good health ,13/31 ,030220 oncology & carcinogenesis ,631/250/1619/554/1898/1271 ,38/39 ,64/60 ,Female ,General Agricultural and Biological Sciences ,medicine.drug ,QH301-705.5 ,13/106 ,chemical and pharmacologic phenomena ,Biology ,GPI-Linked Proteins ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,13/21 ,medicine ,Humans ,030304 developmental biology ,82 ,82/58 ,Hypoxia-Inducible Factor 1, alpha Subunit ,Adenosine ,Transplantation ,HIF1A ,Gene Expression Regulation ,Anaerobic glycolysis ,Cancer research ,Ex vivo ,Immunosuppression - Abstract
The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression., Jarvis et al demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A)-driven acquisition of CD73 expression, which along with CD39, enables expanded Tregs to convert ATP to immunosuppressive adenosine. Given this, the data suggests that Treg expansion protocols should be optimised for CD39/CD73 co-expression to enhance therapeutic potential.
- Published
- 2020
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