The Experts below are selected from a list of 88071 Experts worldwide ranked by ideXlab platform
Sharon Wei Ling Lee - One of the best experts on this subject based on the ideXlab platform.
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integrated in silico and 3d in vitro model of Macrophage migration in response to physical and chemical factors in the tumor microenvironment
Integrative Biology, 2020Co-Authors: Sharon Wei Ling Lee, R J Seager, Felix Litvak, Fabian Spill, Je Lin Sieow, Hweixian Leong PennyAbstract:Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor Macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and Macrophages to study how IF affects Macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased Macrophage migration directedness and speed. Interestingly, there was no additive effect on Macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro Macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of Tumor-Associated Macrophage-based immunotherapeutic strategies.
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integrated in silico and 3d in vitro model of Macrophage migration in response to physical and chemical factors in the tumor microenvironment
bioRxiv, 2020Co-Authors: Sharon Wei Ling Lee, R J Seager, Felix Litvak, Fabian Spill, Je Lin Sieow, Hweixian Leong PennyAbstract:Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor Macrophage functions, however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and Macrophages to study how IF affects Macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased Macrophage migration directedness and speed. Interestingly, there was no additive effect on Macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. The model proposes IL-8, CCL2 and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro Macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2, or to the co-addition of a sub-optimal concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of Tumor-Associated Macrophage-based immunotherapeutic strategies.
Fabian Spill - One of the best experts on this subject based on the ideXlab platform.
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integrated in silico and 3d in vitro model of Macrophage migration in response to physical and chemical factors in the tumor microenvironment
Integrative Biology, 2020Co-Authors: Sharon Wei Ling Lee, R J Seager, Felix Litvak, Fabian Spill, Je Lin Sieow, Hweixian Leong PennyAbstract:Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor Macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and Macrophages to study how IF affects Macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased Macrophage migration directedness and speed. Interestingly, there was no additive effect on Macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro Macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of Tumor-Associated Macrophage-based immunotherapeutic strategies.
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integrated in silico and 3d in vitro model of Macrophage migration in response to physical and chemical factors in the tumor microenvironment
bioRxiv, 2020Co-Authors: Sharon Wei Ling Lee, R J Seager, Felix Litvak, Fabian Spill, Je Lin Sieow, Hweixian Leong PennyAbstract:Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor Macrophage functions, however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and Macrophages to study how IF affects Macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased Macrophage migration directedness and speed. Interestingly, there was no additive effect on Macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. The model proposes IL-8, CCL2 and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro Macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2, or to the co-addition of a sub-optimal concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of Tumor-Associated Macrophage-based immunotherapeutic strategies.
Hweixian Leong Penny - One of the best experts on this subject based on the ideXlab platform.
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integrated in silico and 3d in vitro model of Macrophage migration in response to physical and chemical factors in the tumor microenvironment
Integrative Biology, 2020Co-Authors: Sharon Wei Ling Lee, R J Seager, Felix Litvak, Fabian Spill, Je Lin Sieow, Hweixian Leong PennyAbstract:Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor Macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and Macrophages to study how IF affects Macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased Macrophage migration directedness and speed. Interestingly, there was no additive effect on Macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro Macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of Tumor-Associated Macrophage-based immunotherapeutic strategies.
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integrated in silico and 3d in vitro model of Macrophage migration in response to physical and chemical factors in the tumor microenvironment
bioRxiv, 2020Co-Authors: Sharon Wei Ling Lee, R J Seager, Felix Litvak, Fabian Spill, Je Lin Sieow, Hweixian Leong PennyAbstract:Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor Macrophage functions, however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and Macrophages to study how IF affects Macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased Macrophage migration directedness and speed. Interestingly, there was no additive effect on Macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. The model proposes IL-8, CCL2 and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro Macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2, or to the co-addition of a sub-optimal concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of Tumor-Associated Macrophage-based immunotherapeutic strategies.
Ralph Weissleder - One of the best experts on this subject based on the ideXlab platform.
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radiation induced targeted nanoparticle based gene delivery for brain tumor therapy
ACS Nano, 2019Co-Authors: Gulsah Erelakbaba, Litia Carvalho, Tian Tian, Max Zinter, Hasan Akbaba, Pierre J Obeid, Antonio E Chiocca, Ralph WeisslederAbstract:Targeted therapy against the programmed cell death ligand-1 (PD-L1) blockade holds considerable promise for the treatment of different tumor types; however, little effect has been observed against gliomas thus far. Effective glioma therapy requires a delivery vehicle that can reach tumor cells in the central nervous system, with limited systemic side effect. In this study, we developed a cyclic peptide iRGD (CCRGDKGPDC)-conjugated solid lipid nanoparticle (SLN) to deliver small interfering RNAs (siRNAs) against both epidermal growth factor receptor (EGFR) and PD-L1 for combined targeted and immunotherapy against glioblastoma, the most aggressive type of brain tumors. Building on recent studies showing that radiation therapy alters tumors for enhanced nanotherapeutic delivery in Tumor-Associated Macrophage-dependent fashion, we showed that low-dose radiation primes targeted SLN uptake into the brain tumor region, leading to enhanced downregulation of PD-L1 and EGFR. Bioluminescence imaging revealed that ra...
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89Zr-Labeled Dextran Nanoparticles Allow in Vivo Macrophage Imaging
Bioconjugate Chemistry, 2011Co-Authors: Edmund J. Keliher, Matthias Nahrendorf, Jason S. Lewis, Brett Marinelli, Andita Newton, Mikael J. Pittet, Ralph WeisslederAbstract:Tissue Macrophages play a critical role both in normal physiology and in disease states. However, because of a lack of specific imaging agents, we continue to have a poor understanding of their absolute numbers, flux rates, and functional states in different tissues. Here, we describe a new Macrophage specific positron emission tomography imaging agent, labeled with zirconium-89 (89Zr), that was based on a cross-linked, short chain dextran nanoparticle (13 nm). Following systemic administration, the particle demonstrated a vascular half-life of 3.9 h and was found to be located primarily in tissue resident Macrophages rather than other white blood cells. Subsequent imaging of the probe using a xenograft mouse model of cancer allowed for quantitation of Tumor-Associated Macrophage numbers, which are of major interest in emerging molecular targeting strategies. It is likely that the material described, which allows the visualization of Macrophage biology in vivo, will likewise be useful for a multitude of h...
Isabelle Dussault - One of the best experts on this subject based on the ideXlab platform.
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Data_Sheet_1_Observational Study of PD-L1, TGF-β, and Immune Cell Infiltrates in Hepatocellular Carcinoma.DOCX
2019Co-Authors: Christian Ihling, Bartholomew Naughton, Yue Zhang, Alexander P. Rolfe, Eveline Frick-krieger, Luigi M. Terracciano, Isabelle DussaultAbstract:Introduction: Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers, with increased programed death ligand 1 (PD-L1) and transforming growth factor beta (TGF-β) activity implicated in immunosuppression.Methods: In an observational study of HCC liver samples, we determined the incidence of PD-L1 and immune cell (IC) infiltrates, and signs of TGF-β activity. HCCs were characterized by the incidence and distribution of PD-L1+ cells, and CD8+, CD68+, and FoxP3+ infiltrating ICs in HCC and surrounding liver. Gene expression signatures (GESs) associated with TGF-β activity and ICs were evaluated by RNAseq.Results: In non-neoplastic cirrhotic and non-cirrhotic liver, PD-L1 occurred on sinusoidal lining cells (mostly Kupffer cells), endothelial cells and ICs. In HCC, PD-L1+ tumor cells were rare. Most PD-L1+ cells were identified as ICs. CD8+, CD68+, and FoxP3+ ICs were associated with HCC, particularly in the invasive margin. CD8+ cell incidence correlated with PD-L1+ cells, consistent with PD-L1 being upregulated in response to pre-existing cytotoxic T-lymphocyte activity. TGFB1 mRNA levels and TGF-β activation GES correlated with the strength of the Tumor-Associated Macrophage GES.Conclusion: Inhibition of PD-L1+ ICs and TGF-β activity and their respective immunomodulatory pathways may contribute to antitumor effects in HCC.
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Observational Study of PD-L1, TGF-β, and Immune Cell Infiltrates in Hepatocellular Carcinoma
Frontiers Media S.A., 2019Co-Authors: Christian Ihling, Bartholomew Naughton, Yue Zhang, Alexander P. Rolfe, Eveline Frick-krieger, Luigi M. Terracciano, Isabelle DussaultAbstract:Introduction: Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers, with increased programed death ligand 1 (PD-L1) and transforming growth factor beta (TGF-β) activity implicated in immunosuppression.Methods: In an observational study of HCC liver samples, we determined the incidence of PD-L1 and immune cell (IC) infiltrates, and signs of TGF-β activity. HCCs were characterized by the incidence and distribution of PD-L1+ cells, and CD8+, CD68+, and FoxP3+ infiltrating ICs in HCC and surrounding liver. Gene expression signatures (GESs) associated with TGF-β activity and ICs were evaluated by RNAseq.Results: In non-neoplastic cirrhotic and non-cirrhotic liver, PD-L1 occurred on sinusoidal lining cells (mostly Kupffer cells), endothelial cells and ICs. In HCC, PD-L1+ tumor cells were rare. Most PD-L1+ cells were identified as ICs. CD8+, CD68+, and FoxP3+ ICs were associated with HCC, particularly in the invasive margin. CD8+ cell incidence correlated with PD-L1+ cells, consistent with PD-L1 being upregulated in response to pre-existing cytotoxic T-lymphocyte activity. TGFB1 mRNA levels and TGF-β activation GES correlated with the strength of the Tumor-Associated Macrophage GES.Conclusion: Inhibition of PD-L1+ ICs and TGF-β activity and their respective immunomodulatory pathways may contribute to antitumor effects in HCC
