The Experts below are selected from a list of 4440 Experts worldwide ranked by ideXlab platform
Bradford G Hill - One of the best experts on this subject based on the ideXlab platform.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
Toxicology and Applied Pharmacology, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:Abstract The limited availability of human Heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig Heart Slice biomimetic culture systems that preserve the viability and functionality of 300 μm Heart Slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on Heart Slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, Heart Slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, Slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that Heart Slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
bioRxiv, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:The limited availability of human Heart tissue and its complex cell composition are major limiting factors for reliable testing of drug efficacy, toxicity and understanding the mechanism. Recently, we developed a functional human and pig Heart Slice biomimetic culture system that fully preserves the viability and functionality of 300 micrometer Heart Slices for 6 days. Here, we validated the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three different anti-cancer drug categories associated with cardiomyopathy (doxorubicin, trastuzumab, and sunitinib). Heart Slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes (hiPSC-CMs); but they are superior to hiPSC-CMs in demonstrating sunitinib cardiotoxicity which is not detectable in hiPSC-CMs at low concentrations. These results indicate that Heart Slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanistic behavior.
Jessica M Miller - One of the best experts on this subject based on the ideXlab platform.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
Toxicology and Applied Pharmacology, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:Abstract The limited availability of human Heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig Heart Slice biomimetic culture systems that preserve the viability and functionality of 300 μm Heart Slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on Heart Slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, Heart Slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, Slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that Heart Slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
bioRxiv, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:The limited availability of human Heart tissue and its complex cell composition are major limiting factors for reliable testing of drug efficacy, toxicity and understanding the mechanism. Recently, we developed a functional human and pig Heart Slice biomimetic culture system that fully preserves the viability and functionality of 300 micrometer Heart Slices for 6 days. Here, we validated the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three different anti-cancer drug categories associated with cardiomyopathy (doxorubicin, trastuzumab, and sunitinib). Heart Slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes (hiPSC-CMs); but they are superior to hiPSC-CMs in demonstrating sunitinib cardiotoxicity which is not detectable in hiPSC-CMs at low concentrations. These results indicate that Heart Slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanistic behavior.
Moustafa Meki - One of the best experts on this subject based on the ideXlab platform.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
Toxicology and Applied Pharmacology, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:Abstract The limited availability of human Heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig Heart Slice biomimetic culture systems that preserve the viability and functionality of 300 μm Heart Slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on Heart Slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, Heart Slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, Slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that Heart Slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
bioRxiv, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:The limited availability of human Heart tissue and its complex cell composition are major limiting factors for reliable testing of drug efficacy, toxicity and understanding the mechanism. Recently, we developed a functional human and pig Heart Slice biomimetic culture system that fully preserves the viability and functionality of 300 micrometer Heart Slices for 6 days. Here, we validated the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three different anti-cancer drug categories associated with cardiomyopathy (doxorubicin, trastuzumab, and sunitinib). Heart Slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes (hiPSC-CMs); but they are superior to hiPSC-CMs in demonstrating sunitinib cardiotoxicity which is not detectable in hiPSC-CMs at low concentrations. These results indicate that Heart Slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanistic behavior.
Sharon A George - One of the best experts on this subject based on the ideXlab platform.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
Toxicology and Applied Pharmacology, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:Abstract The limited availability of human Heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig Heart Slice biomimetic culture systems that preserve the viability and functionality of 300 μm Heart Slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on Heart Slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, Heart Slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, Slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that Heart Slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
bioRxiv, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:The limited availability of human Heart tissue and its complex cell composition are major limiting factors for reliable testing of drug efficacy, toxicity and understanding the mechanism. Recently, we developed a functional human and pig Heart Slice biomimetic culture system that fully preserves the viability and functionality of 300 micrometer Heart Slices for 6 days. Here, we validated the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three different anti-cancer drug categories associated with cardiomyopathy (doxorubicin, trastuzumab, and sunitinib). Heart Slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes (hiPSC-CMs); but they are superior to hiPSC-CMs in demonstrating sunitinib cardiotoxicity which is not detectable in hiPSC-CMs at low concentrations. These results indicate that Heart Slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanistic behavior.
Anna Gams - One of the best experts on this subject based on the ideXlab platform.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
Toxicology and Applied Pharmacology, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:Abstract The limited availability of human Heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig Heart Slice biomimetic culture systems that preserve the viability and functionality of 300 μm Heart Slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on Heart Slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, Heart Slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, Slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1–1 μM. These results indicate that Heart Slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.
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Heart Slice culture system reliably demonstrates clinical drug related cardiotoxicity
bioRxiv, 2020Co-Authors: Jessica M Miller, Moustafa Meki, Sharon A George, Anna Gams, Riham Abouleisa, Xianliang Tang, Brooke M Ahern, Guruprasad A Giridharan, Ayman Elbaz, Bradford G HillAbstract:The limited availability of human Heart tissue and its complex cell composition are major limiting factors for reliable testing of drug efficacy, toxicity and understanding the mechanism. Recently, we developed a functional human and pig Heart Slice biomimetic culture system that fully preserves the viability and functionality of 300 micrometer Heart Slices for 6 days. Here, we validated the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three different anti-cancer drug categories associated with cardiomyopathy (doxorubicin, trastuzumab, and sunitinib). Heart Slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes (hiPSC-CMs); but they are superior to hiPSC-CMs in demonstrating sunitinib cardiotoxicity which is not detectable in hiPSC-CMs at low concentrations. These results indicate that Heart Slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanistic behavior.
