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Article ; Online: Flow Cytometry Reveals the Nature of Oncotic Cells

Anna Vossenkamper / Gary Warnes

International Journal of Molecular Sciences, Vol 20, Iss 18, p

2019 Volume 4379

Abstract: The term necrosis is commonly applied to cells that have died via a non-specific pathway or mechanism but strictly is the description of the degradation processes involved once the plasma membrane of the cell has lost integrity. The signalling pathways ... ...

Abstract	The term necrosis is commonly applied to cells that have died via a non-specific pathway or mechanism but strictly is the description of the degradation processes involved once the plasma membrane of the cell has lost integrity. The signalling pathways potentially involved in accidental cell death (ACD) or oncosis are under-studied. In this study, the flow cytometric analysis of the intracellular antigens involved in regulated cell death (RCD) revealed the phenotypic nature of cells undergoing oncosis or necrosis. Sodium azide induced oncosis but also classic apoptosis, which was blocked by zVAD (z-Vla-Ala-Asp(OMe)-fluoromethylketone). Oncotic cells were found to be viability +ve /caspase-3 −ve /RIP3 +ve/−ve (Receptor-interacting serine/threonine protein kinase 3). These two cell populations also displayed a DNA damage response (DDR) phenotype pH2AX +ve /PARP −ve , cleaved PARP induced caspase independent apoptosis H2AX −ve /PARP +ve and hyper-activation or parthanatos H2AX +ve /PARP +ve . Oncotic cells with phenotype cell viability +ve /RIP3 −ve /caspase-3 −ve showed increased DDR and parthanatos. Necrostatin-1 down-regulated DDR in oncotic cells and increased sodium azide induced apoptosis. This flow cytometric approach to cell death research highlights the link between ACD and the RCD processes of programmed apoptosis and necrosis.
Keywords	accidental cell death ; oncosis ; DDR ; parthanatos ; flow cytometry ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease

Kevin J. Roberts / Marion F. Cubitt / Timothy M. Carlton / Lurdes Rodrigues-Duarte / Luana Maggiore / Ray Chai / Simon Clare / Katherine Harcourt / Thomas T. MacDonald / Keith P. Ray / Anna Vossenkämper / Michael R. West / J. Scott Crowe

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 14

Abstract: Abstract Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, ... ...

Abstract	Abstract Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease

J. Scott Crowe / Kevin J. Roberts / Timothy M. Carlton / Luana Maggiore / Marion F. Cubitt / Simon Clare / Katherine Harcourt / Jill Reckless / Thomas T. MacDonald / Keith P. Ray / Anna Vossenkämper / Michael R. West

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 13

Abstract: Abstract TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease ... ...

Abstract	Abstract TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. Although sensitive to pepsin, V565 retained activity after lengthy incubations with trypsin, chymotrypsin, and pancreatin, as well as mouse small intestinal and human ileal and faecal supernatants. In orally dosed naïve and DSS colitis mice, high V565 concentrations were observed in intestinal contents and faeces and immunostaining revealed V565 localisation in mouse colon tissue. V565 was detected by ELISA in post-dose serum of colitis mice, but not naïve mice, demonstrating penetration of disrupted epithelium. In an ex vivo human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Aryl Hydrocarbon Receptor Interacting Protein Maintains Germinal Center B Cells through Suppression of BCL6 Degradation

Dijue Sun / Urszula Stopka-Farooqui / Sayka Barry / Ezra Aksoy / Gregory Parsonage / Anna Vossenkämper / Melania Capasso / Xinyu Wan / Sherine Norris / Jennifer L. Marshall / Andrew Clear / John Gribben / Thomas T. MacDonald / Christopher D. Buckley / Márta Korbonits / Oliver Haworth

Cell Reports, Vol 27, Iss 5, Pp 1461-1471.e

2019 Volume 4

Abstract: Summary: B cell lymphoma-6 (BCL6) is highly expressed in germinal center B cells, but how its expression is maintained is still not completely clear. Aryl hydrocarbon receptor interacting protein (AIP) is a co-chaperone of heat shock protein 90. Deletion ...

Abstract	Summary: B cell lymphoma-6 (BCL6) is highly expressed in germinal center B cells, but how its expression is maintained is still not completely clear. Aryl hydrocarbon receptor interacting protein (AIP) is a co-chaperone of heat shock protein 90. Deletion of Aip in B cells decreased BCL6 expression, reducing germinal center B cells and diminishing adaptive immune responses. AIP was required for optimal AKT signaling in response to B cell receptor stimulation, and AIP protected BCL6 from ubiquitin-mediated proteasomal degradation by the E3-ubiquitin ligase FBXO11 by binding to the deubiquitinase UCHL1, thus helping to maintain the expression of BCL6. AIP was highly expressed in primary diffuse large B cell lymphomas compared to healthy tissue and other tumors. Our findings describe AIP as a positive regulator of BCL6 expression with implications for the pathobiology of diffuse large B cell lymphoma. : BCL6 overexpression contributes to the pathobiology of diffuse large B cell lymphoma (DLBCL). Sun et al. find that the co-chaperone aryl hydrocarbon receptor interacting protein (AIP), whose high expression is associated with reduced survival of DLBCL patients, helps maintain BCL6 expression by facilitating the removal of ubiquitin from BCL6. Keywords: AIP, BCL6, FBXO11, UCHL1, ubiquitination, lymphoma
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients

Suhail Nurbhai / Kevin J. Roberts / Timothy M. Carlton / Luana Maggiore / Marion F. Cubitt / Keith P. Ray / Jill Reckless / Hafeez Mohammed / Peter Irving / Thomas T. MacDonald / Anna Vossenkämper / Michael R. West / Gareth C. Parkes / J. Scott Crowe

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following ... ...

Abstract	Abstract V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn’s disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn’s patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3+ T-lymphocytes and CD14+ macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease.

William C Reisdorf / Qing Xie / Xin Zeng / Wensheng Xie / Neetu Rajpal / Bao Hoang / Mark E Burgert / Vinod Kumar / Mark R Hurle / Deepak K Rajpal / Sarah O'Donnell / Thomas T MacDonald / Anna Vossenkämper / Lin Wang / Mike Reilly / Bart J Votta / Yolanda Sanchez / Pankaj Agarwal

PLoS ONE, Vol 14, Iss 4, p e

2019 Volume 0215033

Abstract: Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including ... ...

Abstract	Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1β in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3

Michela Borghesan / Juan Fafián-Labora / Olga Eleftheriadou / Paula Carpintero-Fernández / Marta Paez-Ribes / Gema Vizcay-Barrena / Avital Swisa / Dror Kolodkin-Gal / Pilar Ximénez-Embún / Robert Lowe / Belen Martín-Martín / Hector Peinado / Javier Muñoz / Roland A. Fleck / Yuval Dor / Ittai Ben-Porath / Anna Vossenkamper / Daniel Muñoz-Espin / Ana O’Loghlen

Cell Reports, Vol 27, Iss 13, Pp 3956-3971.e

2019 Volume 6

Abstract: Summary: Senescence is a cellular phenotype present in health and disease, characterized by a stable cell-cycle arrest and an inflammatory response called senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior ...

Abstract	Summary: Senescence is a cellular phenotype present in health and disease, characterized by a stable cell-cycle arrest and an inflammatory response called senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior of neighboring cells and altering the microenvironment; yet, this role has been mainly attributed to soluble factors. Here, we show that both the soluble factors and small extracellular vesicles (sEVs) are capable of transmitting paracrine senescence to nearby cells. Analysis of individual cells internalizing sEVs, using a Cre-reporter system, show a positive correlation between sEV uptake and senescence activation. We find an increase in the number of multivesicular bodies during senescence in vivo. sEV protein characterization by mass spectrometry (MS) followed by a functional siRNA screen identify interferon-induced transmembrane protein 3 (IFITM3) as being partially responsible for transmitting senescence to normal cells. We find that sEVs contribute to paracrine senescence. : Borghesan et al. show that the soluble fraction and small extracellular vesicles (sEVs) mediate paracrine senescence. RNA sequencing and loxP reporter systems confirm sEV-mediated paracrine senescence, while preventing sEV release averts senescence. Mass spectrometry and functional analysis show that the IFN protein, IFITM3, is partially responsible for this phenotype. Keywords: exosomes, small extracellular vesicles, EV, paracrine senescence, OIS, DDIS, aging, interferon, IFITM3, fragilis
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis

David Díaz-Jiménez / Lucía Núñez / Marjorie De la Fuente / Karen Dubois-Camacho / Hugo Sepúlveda / Martín Montecino / Alejandro Torres-Riquelme / Paulina García-González / Jonás Chnaiderman / Anna Vossenkamper / Thomas T. MacDonald / Daniela Simian / María-Julieta González / John A. Cidlowski / Rodrigo Quera / Marcela A. Hermoso

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 14

Abstract: Abstract The ST2/IL33 signalling pathway has been associated with ulcerative colitis (UC). ST2, encoded by the IL1RL1 gene, is expressed as both a membrane-anchored receptor (ST2L) activated by IL33 and as a soluble receptor (sST2) with anti-inflammatory ...

Abstract	Abstract The ST2/IL33 signalling pathway has been associated with ulcerative colitis (UC). ST2, encoded by the IL1RL1 gene, is expressed as both a membrane-anchored receptor (ST2L) activated by IL33 and as a soluble receptor (sST2) with anti-inflammatory properties. In UC patients, sST2 is further increased by corticosteroid treatment; however, the glucocorticoid-mediated molecular regulation remains unknown. We therefore tested whether genetic variants in the IL1RL1 distal promoter are involved in UC and affect glucocorticoid-mediated ST2 expression. Serum ST2 levels and genetic variants in the IL1RL1 distal promoter were examined by ELISA and PCR sequencing in UC patients receiving corticosteroids. Glucocorticoid-mediated ST2 production was evaluated in intestinal mucosa cultures. Molecular regulation of glucocorticoid-mediated ST2 was assessed by RT-qPCR, ChIP assay and luciferase reporter assay. Dexamethasone effect on ST2 transcript expression was analyzed in leukocytes and related to IL1RL1 variants. Sequencing of a distal IL1RL1 promoter region demonstrated that SNPs rs6543115(C) and rs6543116(A) are associated with increased sST2 in UC patients on corticosteroids. Dexamethasone up-regulated sST2 transcription through interaction with the glucocorticoid-response element (GRE) carrying rs6543115(C) variant. Our data indicate that IL1RL1 SNPs rs6543115(C) confer susceptibility to UC and is contained in the GRE, which may modulate glucocorticoid-induced sST2 expression.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue

Yuan Zhao / Mohamed Uduman / Jacqueline H. Y. Siu / Thomas J. Tull / Jeremy D. Sanderson / Yu-Chang Bryan Wu / Julian Q. Zhou / Nedyalko Petrov / Richard Ellis / Katrina Todd / Konstantia-Maria Chavele / William Guesdon / Anna Vossenkamper / Wayel Jassem / David P. D’Cruz / David J. Fear / Susan John / Dagmar Scheel-Toellner / Claire Hopkins /

Estefania Moreno / Natalie L. Woodman / Francesca Ciccarelli / Susanne Heck / Steven H. Kleinstein / Mats Bemark / Jo Spencer

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 15

Abstract: Human memory and marginal zone B cells share some features including CD27 expression and somatic hypermutation, but their lineage relationship is still unclear. Here the authors use mass cytometry and sequential clustering methods to show that, despite ... ...

Abstract	Human memory and marginal zone B cells share some features including CD27 expression and somatic hypermutation, but their lineage relationship is still unclear. Here the authors use mass cytometry and sequential clustering methods to show that, despite their shared features, memory and marginal zone B cells represent distinct lineage choices.
Keywords	Science ; Q
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue

Estefania Moreno / Natalie L. Woodman / Francesca Ciccarelli / Susanne Heck / Steven H. Kleinstein / Mats Bemark / Jo Spencer

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 15

Abstract	Human memory and marginal zone B cells share some features including CD27 expression and somatic hypermutation, but their lineage relationship is still unclear. Here the authors use mass cytometry and sequential clustering methods to show that, despite their shared features, memory and marginal zone B cells represent distinct lineage choices.
Keywords	Science ; Q
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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