The Experts below are selected from a list of 54921 Experts worldwide ranked by ideXlab platform
Michelle Krogsgaard - One of the best experts on this subject based on the ideXlab platform.
-
Specific increase in T Cell Potency via structure-based design of a T Cell receptor for adoptive immunotherapy
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Karolina Malecek, Arsen Grigoryan, Wei Jun Gu, Laura A. Johnson, Timothy Cardozo, Shi Zhong, Steven A Rosenberg, Michelle KrogsgaardAbstract:Adoptive immunotherapy with antigen-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor antigens are non-reactive "self" proteins, which presents an immunotherapy design challenge. Studies have shown that tumor-specific T Cell receptors (TCRs) can be transduced into normal peripheral blood lymphocytes, which persist after transfer in about 30% of patients and effectively destroy tumor Cells. Still, recent clinical trial with affinity-enhanced TCRs has resulted in severe effects due to cross reactivity to an unrelated peptide. Thus, the challenge for targeted T Cell therapy remains to increase T Cell Potency in order to improve clinical responses and ensure on-target specificity by avoiding unwanted cross reactivity. We used structure-based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor differentiation antigen-major histocompatibility complex (pMHC), Mart-1(27L)-HLA-A2, which elicits full T Cell activation to trigger immune responses. Structural based approaches have been used to increase TCR affinity, however their potential cross-reactivity has not been reported. Here, we analyzed the effects of selected TCR point mutations alone and in combination on T Cell activation Potency. Further, we analyzed their specificity and cross-reactivity with related antigens presented by different melanoma Cell lines and donor-derived antigen presenting Cells. Our structure-based approach allowed us to rationally design sequence substitutions that improve binding in contact areas between the TCR and pMHC without increasing cross-reactivity with a wide variety of self-antigens. We identified and evaluated point mutations in critical TCR positions resulting in more potent T Cell activation but maintaining overall specificity. When double and triple combination mutations were introduced, they exhibited an additive enhancement that further improved T Cell activation while retaining a high degree of specificity.
-
Specific increase in T-Cell Potency via structure-based design of a T-Cell receptor for adoptive immunotherapy.
Journal of Clinical Oncology, 2014Co-Authors: Karolina Malecek, Arsen Grigoryan, Wei Jun Gu, Laura A. Johnson, Timothy Cardozo, Shi Zhong, Steven A Rosenberg, Michelle KrogsgaardAbstract:3063 Background: Adoptive immunotherapy with antigen-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor antigens are non-reactive “self” proteins, which presents an immunotherapy design challenge. Studies have shown that tumor-specific T Cell receptors (TCRs) can be transduced into normal peripheral blood lymphocytes, which persist after transfer in about 30% of patients and effectively destroy tumor Cells. Still, recent clinical trial with affinity-enhanced TCRs has resulted in severe effects due to cross reactivity to an unrelated peptide. Thus, the challenge for targeted T Cell therapy remains to increase T-Cell Potency in order to improve clinical responses and ensure on-target specificity by avoiding unwanted cross reactivity. Methods: We used structure based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor differentiation antigen-major histocompatibility complex (pMHC), Mart-1(27L) HLA-A2, which elicits full...
Roeland Nusse - One of the best experts on this subject based on the ideXlab platform.
-
axin2 marks quiescent hair follicle bulge stem Cells that are maintained by autocrine wnt β catenin signaling
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Xinhong Lim, Si Hui Tan, Sophia Beng Hui Lim, Roeland NusseAbstract:How stem Cells maintain their identity and Potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem Cells can enter an extended period of quiescence during the resting phase but retain stem Cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem Cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge Cells causes them to lose their stem Cell Potency to contribute to hair growth and undergo premature differentiation instead. Bulge Cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated Cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem Cell Potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge Cells reinforces differentiation.
-
Axin2 marks quiescent hair follicle bulge stem Cells that are maintained by autocrine Wnt/β-catenin signaling
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Xinhong Lim, Si Hui Tan, Sophia Beng Hui Lim, Roeland NusseAbstract:How stem Cells maintain their identity and Potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem Cells can enter an extended period of quiescence during the resting phase but retain stem Cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem Cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge Cells causes them to lose their stem Cell Potency to contribute to hair growth and undergo premature differentiation instead. Bulge Cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated Cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem Cell Potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge Cells reinforces differentiation.
Marcela V. Maus - One of the best experts on this subject based on the ideXlab platform.
-
Current approaches to increase CAR T Cell Potency in solid tumors: targeting the tumor microenvironment
Journal for ImmunoTherapy of Cancer, 2017Co-Authors: Irene Scarfo, Marcela V. MausAbstract:Chimeric antigen receptor (CAR) T-Cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy. Understanding the role of the TME and its interaction with CAR T-Cells is crucial to improve the Potency of adoptive immunotherapy. In this review, we discuss the strategies and potential combinatorial approaches recently developed in mouse models to enhance the efficacy of CAR T-Cells, with particular emphasis on the translational potential of these approaches.
Jackson B Gibbs - One of the best experts on this subject based on the ideXlab platform.
-
Design and Biological Activity of (S)-4-(5-{[1-(3-Chlorobenzyl)-2- oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile, a 3-Aminopyrrolidinone Farnesyltransferase Inhibitor with ExCellent Cell Potency
Journal of medicinal chemistry, 2001Co-Authors: Ian M. Bell, Steven N Gallicchio, Douglas C Beshore, Carolyn A Buser, Joseph P Davide, Christine Fernandes, Marc Abrams, J. Christopher Culberson, Michelle Ellis-hutchings, Jackson B GibbsAbstract:The synthesis, structure−activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with exCellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of Cell Potency to intrinsic Potency, compared with other known FTIs. It exhibited exCellent Potency against a range of tumor Cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
-
design and biological activity of s 4 5 1 3 chlorobenzyl 2 oxopyrrolidin 3 ylamino methyl imidazol 1 ylmethyl benzonitrile a 3 aminopyrrolidinone farnesyltransferase inhibitor with exCellent Cell Potency
Journal of Medicinal Chemistry, 2001Co-Authors: Ian M. Bell, Steven N Gallicchio, Marc T Abrams, Douglas C Beshore, Carolyn A Buser, Christopher J Culberson, Joseph P Davide, Michelle Ellishutchings, Christine Fernandes, Jackson B GibbsAbstract:The synthesis, structure−activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with exCellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of Cell Potency to intrinsic Potency, compared with other known FTIs. It exhibited exCellent Potency against a range of tumor Cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
Luonan Chen - One of the best experts on this subject based on the ideXlab platform.
-
Quantifying Waddington's epigenetic landscape: a comparison of single-Cell Potency measures.
Briefings in bioinformatics, 2018Co-Authors: Jifan Shi, Andrew E. Teschendorff, Weiyan Chen, Luonan ChenAbstract:MOTIVATION Estimating differentiation Potency of single Cells is a task of great biological and clinical significance, as it may allow identification of normal and cancer stem Cell phenotypes. However, very few single-Cell Potency models have been proposed, and their robustness and reliability across independent studies have not yet been fully assessed. RESULTS Using nine independent single-Cell RNA-Seq experiments, we here compare four different single-Cell Potency models to each other, in their ability to discriminate Cells that ought to differ in terms of differentiation Potency. Two of the Potency models approximate Potency via network entropy measures that integrate the single-Cell RNA-Seq profile of a Cell with a protein interaction network. The comparison between the four models reveals that integration of RNA-Seq data with a protein interaction network dramatically improves the robustness and reliability of single-Cell Potency estimates. We demonstrate that underlying this robustness is a correlation relationship, according to which high differentiation Potency is positively associated with overexpression of network hubs. We further show that overexpressed network hubs are strongly enriched for ribosomal mitochondrial proteins, suggesting that their mRNA levels may provide a universal marker of a Cell's Potency. Thus, this study provides novel systems-biological insight into Cellular Potency and may provide a foundation for improved models of differentiation Potency with far-reaching implications for the discovery of novel stem Cell or progenitor Cell phenotypes.
-
Quantifying Waddington's epigenetic landscape: a comparison of single-Cell Potency measures
2018Co-Authors: Jifan Shi, Andrew E. Teschendorff, Weiyan Chen, Luonan ChenAbstract:Over 60 years ago Waddington proposed an epigenetic landscape model of Cellular differentiation, whereby Cell-fate transitions are modelled as canalization events, with stable Cell states occupying the basins or attractor states. A key ingredient of this landscape is the energy potential, or height, which correlates with Cell-Potency. To date, very few explicit biophysical models for estimating single-Cell Potency have been proposed. Using 9 independent experiments, encompassing over 6,600 high-quality single-Cell RNA-Seq profiles, we here demonstrate that single-Cell Potency can be approximated as the graph entropy of a Markov Chain process on a model signaling network. Our analysis highlights that other proposed single-Cell Potency measures are not robust, whilst also revealing that integration with orthogonal systems-level information improves Potency estimates. Thus, this study provides a foundation for an improved systems-level understanding of single-Cell Potency, which may have profound implications for the discovery of novel stem-and progenitor Cell phenotypes.