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1. Exploring the effects of nutrient deprivation and waste accumulation on T cells and oncolytic adenoviruses in order to create immune activators for tumour therapy

Author

Frost, Sally Claire, D'Angiolella, Vincenzo, and Seymour, Leonard

Subjects
Cancer--Immunotherapy, Virology, Oncolytic virotherapy, Oncology
Abstract

High metabolic stress is a hallmark of cancer. Tumours are characterised by a depletion of amino acids and accumulation of lactic acid, both promote an immunosuppressive milieu and may limit success of cancer immunotherapy. One such therapeutic approach is represented by an oncolytic adenovirus, EnAdenotucirev (EnAd), engineered to express a bispecific T cell engager (BiTE) targeting EpCAM. This platform offers a multi-pronged strategy to directly lyse cancer cells and elicit T cell-mediated cytotoxicity, demonstrating anti-cancer activity in ex vivo tumour models. However, the impact of nutrient depletion and lactic acid upon EnAd and the EpCAM BiTE are yet to be explored. Here, we show that the EpCAM BiTE is able to overcome nutrient depletion, likely due to its ability to hyper-activate T cells. By contrast, EnAd replication and cytolytic activity is severely impacted. This was demonstrated using artificial amino acid-depleted media and malignant ascites fluids. The opposite held true for therapeutic activity in accumulated lactic acid; BiTE functionality was severely limited due to acidification, while EnAd was less susceptible and retained its ability to replicate. The use of different BiTE formats did not relieve the inhibition observed. This work is the first to describe the impact of low pH on the activity of BiTEs, and serves to highlight the importance of utilising clinically-relevant models during the pre-clinical development of immunotherapies. Acidosis represents a hurdle for T cell-activating therapies. We propose that using EnAd to express shRNAs targeting lactic acid production in tumour cells, may reverse pH-induced immune suppression. We targeted LDHA and MCT-4, two components required to extrude lactic acid. We showed that knockdown of LDHA following infection was possible and that the shRNA-encoded EnAd retained its oncolytic and replicative capabilities. Arming oncolytic viruses with anti-acidity agents, alongside those with T cell-activating abilities, may offer a novel approach to overcome metabolic barriers of the tumour microenvironment and combat immune evasion.

Published
2020

4. Integrating Industry Resources and Community Development: A Vision for the Future.

Author

Frost, Sally Joy

Abstract

The Adult Basic Education Program at Umgeni Water, a water authority in South Africa, is a workplace literacy program that seeks to impart skills within the workplace that can be used in community development, benefiting both the business and community involved. From a pilot project in 1989, the adult education program at Umgeni Water has grown into a holistic development program targeted at the 540 employees assessed to be below a level of functional literacy (42 percent of the work force). At present, 342 learners are in the program, organized into 21 classes at 11 sites. Learners attend classes for 4 hours per week during work time. The program is run by a team of six facilitators experienced in adult education. In 3 years, the program has increased the functional literacy rate among the target group by 12 percent. The program takes a consultative approach, encouraging input from all stakeholders. Learning is experiential and relevant to the life experiences of adults. The learning the adults acquire at work empowers them to participate in community development efforts that benefit themselves as well as the wider community. (KC)

Published
1996

7. A rapid review of children and young people's views of poverty and welfare in the context of Universal Credit

Author

Bidmead, Elaine, Zerbi, Catherine El, Cheetham, Mandy, Frost, Sally, Bidmead, Elaine, Zerbi, Catherine El, Cheetham, Mandy, and Frost, Sally

Abstract

Children and young people's (CYP) life chances depend heavily on family resources. This paper reports a rapid review of qualitative/mixed method studies about Universal Credit undertaken with CYP in the UK; subsequently expanded to include additional descriptors of economic disadvantage. Sixteen studies were reviewed; narrative synthesis was used to explore themes. Most recruited CYP with experience of economic disadvantage; none explicitly reported perspectives of CYP experiencing disability or rurality. Findings show growing up in poverty has significant, negative impacts on health and well-being, causing feelings of exclusion, shame and unfairness; raising important questions about the adequacy of welfare support in the UK.

Published
2023

10. Common Origin of Pigment Cells

Author

Bagnara, Joseph T., Matsumoto, Jiro, Ferris, Wayne, Frost, Sally K., Turner,, William A., Tchen, T. T., and Taylor, John D.

Published
1979

17. External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase

Author

Pokrovska, Tzveta D., primary, Jacobus, Egon J., additional, Puliyadi, Rathi, additional, Prevo, Remko, additional, Frost, Sally, additional, Dyer, Arthur, additional, Baugh, Richard, additional, Rodriguez-Berriguete, Gonzalo, additional, Fisher, Kerry, additional, Granata, Giovanna, additional, Herbert, Katharine, additional, Taverner, William K., additional, Champion, Brian R., additional, Higgins, Geoff S., additional, Seymour, Len W., additional, and Lei-Rossmann, Janet, additional

Published
2020
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18. MOESM5 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Abstract

Additional file 5. A CD206-targeting TriTE outperforms the parental BiTE at an E:T ratio of 2:1. MDMs were polarised, CFSE-stained, and co-cultured for 96 h with T cells at a fixed E:T ratio of 2:1, in the presence of increasing BiTE/TriTE concentrations. % Live cells were calculated with propidium iodide staining and Celigo image cytometry. Data show mean ± SD of biological triplicates. Statistical significance was assessed by two-way ANOVA followed by Bonferroni post-hoc analysis, with each treatment being compared to the relevant “Mock” condition (*, P

Published
2019
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24. Drug-Induced and Genetic Hypermelanism: Effects on Pigment Cell Differentiation.

Author

FROST, SALLY K., BORCHERT, MONIKA, and CARSON, MARY KAY

Abstract

Allopurinol, a drug that inhibits the enzyme xanthine dehydrogenase (XDH), is known to cause hypermelanism in the axolotl. The hypermelanistic condition that results from allopurinol treatment is similar in most respects to the phenotype that results from the action of the melanoid ( m) gene in axolotls. On the basis of structural and biochemical studies, it now seems clear that genetic and drug-induced hypermelanism are the same in the following ways. 1) Both types of melanism result in the production of more than normal amounts of melanin and more melanin-containing cells (melanophores). 2) In both cases the amount of pteridine-associated yellow pigment declines during development, and this is associated directly with fine structural changes that occur within the pigment organelles (pterinosomes) of yellow pigment cells (xanthophores). 3) In both cases the hypermelanistic condition results in the suppression of reflecting pigment cell (iridophore) differentiation. 4) Both conditions have now been linked directly to depressed levels of XDH activity. Thus both genetic and drug-induced hypermelanism result in alterations in the normal differentiation of all three pigment cell types and the subsequent disruption of normal pigment pattern formation. The possible significance of these findings with regard to factors known or suspected to direct the migration and/or differentiation of neural crest-derived pigment cells is discussed. [ABSTRACT FROM AUTHOR]

Published
1989
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25. Effects of Exogenous Guanosine on Chromatophore Differentiation in the Axolotl.

Author

FROST, SALLY K., ROBINSON, SCOTT J., CARSON, MARY KAY, THORSTEINSDOTTIR, SOLVEIG, and GIESLER, JAMES

Abstract

Guanosine is shown to dramatically alter the pigment phenotype of axolotls by suppressing melanization and enhancing the biosynthesis and deposition of purine-derived pigments. Phenotypic changes caused by guanosine are manifested by altered chromatophore differentiation patterns such that few black pigment cells (melanophores) differentiate (and those that do are punctate and necrotic in appearance), whereas the development of yellow (xanthophore) and reflecting (iridophore) pigment cells is enhanced. Mechanisms for changes in chromatophore differentiation, and thus pattern formation, are discussed, including the possibility that pigment cells may undergo transdifferentiation in vivo. [ABSTRACT FROM AUTHOR]

Published
1987
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27. MOESM8 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 8. 3FR BiTE treatment triggers wide-ranging increases in immunomodulatory cytokines and chemokines. Cell-free supernatants from two ascites samples treated (or not) for five days with 3Ctrl or 3FR BiTE were assessed using a 13-plex immunoassay. Fold-increases in cytokine/chemokine levels were calculated relative to “Mock”-treated samples. Data show mean ± SD of biological triplicates.

28. MOESM8 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 8. 3FR BiTE treatment triggers wide-ranging increases in immunomodulatory cytokines and chemokines. Cell-free supernatants from two ascites samples treated (or not) for five days with 3Ctrl or 3FR BiTE were assessed using a 13-plex immunoassay. Fold-increases in cytokine/chemokine levels were calculated relative to “Mock”-treated samples. Data show mean ± SD of biological triplicates.

29. MOESM4 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 4. CD206- and FRβ BiTE-induced T cell-mediated killing of MDMs is dependent on the perforin pathway. T cells were co-cultured with autologous CFSE-stained MDMs and treated (or not) with the indicated BiTEs for 96 h, at which point % Live cells were calculated with Celigo image cytometry. For inhibition of perforin, T cells were pre-treated for 2 h with Concanamycin A (100 ng/mL), or an equivalent concentration of vehicle control (DMSO), then washed prior to BiTE addition. Inhibitors of Fas/FasL (anti-Fas antibody, clone ZB4, 2 μg/mL) and TRAIL (TRAIL-R1-Fc, 1 μg/mL) were added at the point of BiTE treatment and not removed. Data show mean ± SD of biological triplicates. Statistical significance was assessed by two-way ANOVA followed by Bonferroni post-hoc analysis, with each treatment being compared to the relevant “Mock” condition (*, P

30. MOESM1 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 1. Dot blot analysis of BiTE/TriTEs. A-C, Two-fold serial dilutions of BiTE/TriTE-containing supernatants from transfected HEK293A cells were concentrated and applied to a nitrocellulose membrane, alongside a 10xHis-tagged protein of known concentration. Membranes were probed with anti-His primary antibody and HRP-conjugated anti-mouse secondary antibody. A, An exemplary dot blot of a 10xHis-tagged protein of known concentration. B, An exemplary standard curve to determine BiTE/TriTE concentration, as generated by measuring dot intensity with ImageJ software. C, Dot blot analyses BiTE/TriTE-containing supernatants.

31. MOESM7 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
integumentary system, 3. Good health
Abstract

Additional file 7. Representative flow cytometric dot plots of CD206 and FRβ expression by whole ascites cells from five cancer patients.

32. MOESM11 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 11. Expression of M1 macrophage markers on ascites from individual patient samples following virus treatment. Total unpurified ascites cells from different patients were infected with 100 vp/cell parental or BiTE-expressing EnAd for 5 days in the presence or absence of autologous fluid. Cells were stained with anti-CD11b, anti-CD64, anti-CD80 and anti-CD86 antibodies, as well as a LIVE/DEAD fixable stain, then analysed by flow cytometry. Fold-changes in geometric mean fluorescence intensity (MFI) values of CD64, CD80 and CD86 on live CD11b+CD64+ ascites cells were calculated relative to “Mock”-treated samples. Data show mean ± SD of biological triplicates. Statistical significance was assessed by two-way ANOVA followed by Bonferroni post-hoc analysis, with each treatment being compared to either “EnAd” alone or, in the case of EnAd, “Mock”. (*, P

33. MOESM9 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
parasitic diseases, 3. Good health
Abstract

Additional file 9. A schematic representation of the EnAd genome encoding a BiTE transgene under the control of the CMV promoter.

35. MOESM10 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 10. Supernatants from cells infected with BiTE-armed EnAd trigger T cell-mediated cytotoxicity of macrophages. A,B, DLD-1 cells were infected with the indicated viruses at a dose of 100 virus particles/cell. 72 h later, supernatants were harvested and applied at the indicated dilutions to co-cultures of PBMC-derived T cells and CFSE-stained monocyte-derived macrophages (MDM). A, After four days’ co-culture, MDM killing was assessed with propidium iodide staining and Celigo image cytometry. B, T cell activation was assessed by measuring CD25 expression with flow cytometry. Data show mean ± SD of biological triplicates (A,B). Statistical analysis was performed by two-way ANOVA with Bonferroni post-hoc tests comparing with the relevant “Mock” condition (A), or with one-way ANOVA followed by Dunnett’s post-hoc analysis compared with “Mock”-treated cells (B). (*, P

36. MOESM7 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
integumentary system, 3. Good health
Abstract

Additional file 7. Representative flow cytometric dot plots of CD206 and FRβ expression by whole ascites cells from five cancer patients.

40. MOESM11 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 11. Expression of M1 macrophage markers on ascites from individual patient samples following virus treatment. Total unpurified ascites cells from different patients were infected with 100 vp/cell parental or BiTE-expressing EnAd for 5 days in the presence or absence of autologous fluid. Cells were stained with anti-CD11b, anti-CD64, anti-CD80 and anti-CD86 antibodies, as well as a LIVE/DEAD fixable stain, then analysed by flow cytometry. Fold-changes in geometric mean fluorescence intensity (MFI) values of CD64, CD80 and CD86 on live CD11b+CD64+ ascites cells were calculated relative to “Mock”-treated samples. Data show mean ± SD of biological triplicates. Statistical significance was assessed by two-way ANOVA followed by Bonferroni post-hoc analysis, with each treatment being compared to either “EnAd” alone or, in the case of EnAd, “Mock”. (*, P

43. MOESM2 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
integumentary system, 3. Good health
Abstract

Additional file 2. CD206 and FRβ expression by MDMs. MDMs from healthy donor PBMCs were polarised as indicated and stained with PE-conjugated anti-CD206 or anti-FRβ antibodies, or isotype controls, then analysed by flow cytometry. Representative histograms are displayed.

44. MOESM9 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
parasitic diseases, 3. Good health
Abstract

Additional file 9. A schematic representation of the EnAd genome encoding a BiTE transgene under the control of the CMV promoter.

45. MOESM1 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
3. Good health
Abstract

Additional file 1. Dot blot analysis of BiTE/TriTEs. A-C, Two-fold serial dilutions of BiTE/TriTE-containing supernatants from transfected HEK293A cells were concentrated and applied to a nitrocellulose membrane, alongside a 10xHis-tagged protein of known concentration. Membranes were probed with anti-His primary antibody and HRP-conjugated anti-mouse secondary antibody. A, An exemplary dot blot of a 10xHis-tagged protein of known concentration. B, An exemplary standard curve to determine BiTE/TriTE concentration, as generated by measuring dot intensity with ImageJ software. C, Dot blot analyses BiTE/TriTE-containing supernatants.

46. MOESM2 of Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples

Author

Scott, Eleanor, Jacobus, Egon J., Lyons, Brian, Frost, Sally, Freedman, Joshua, Dyer, Arthur, Hena Khalique, Taverner, William, Carr, Alison, Champion, Brian, Fisher, Kerry, Seymour, Len, and Duffy, Margaret

Subjects
integumentary system, 3. Good health
Abstract

Additional file 2. CD206 and FRβ expression by MDMs. MDMs from healthy donor PBMCs were polarised as indicated and stained with PE-conjugated anti-CD206 or anti-FRβ antibodies, or isotype controls, then analysed by flow cytometry. Representative histograms are displayed.

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