The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Craig Fisher - One of the best experts on this subject based on the ideXlab platform.
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The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of Pancreatic Toxicity in the rat and dog
BMC Genomics, 2016Co-Authors: Aaron Smith, John Calley, Sachin Mathur, Hui-rong Qian, Mark Farmen, Florian Caiment, Pierre R. Bushel, Craig Fisher, Patrick Kirby, Erik KoenigAbstract:Background MicroRNAs (miRNA) are ~19–25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein Toxicity studies utilizing both species. Results A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas Toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of Pancreatic injury in the rat and dog. Conclusions A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ Toxicity in 2 toxicologically relevant species.
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The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of Pancreatic Toxicity in the rat and dog
BMC genomics, 2016Co-Authors: Aaron P. Smith, John Calley, Sachin Mathur, Hui-rong Qian, Mark Farmen, Florian Caiment, Pierre R. Bushel, Craig FisherAbstract:MicroRNAs (miRNA) are ~19–25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein Toxicity studies utilizing both species. A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas Toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of Pancreatic injury in the rat and dog. A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ Toxicity in 2 toxicologically relevant species.
Daniele Santini - One of the best experts on this subject based on the ideXlab platform.
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Pazopanib and Pancreatic Toxicity: a case report
BMC Research Notes, 2015Co-Authors: Marco Russano, Olga Venditti, Loretta D’onofrio, Raffaele Ratta, Francesco Maria Guida, Giuseppe Tonini, Bruno Vincenzi, Daniele SantiniAbstract:Pazopanib is an oral multitargeted tyrosine-kinase inhibitor, used as a single agent to treat advanced renal cell carcinoma. Treatment with other tyrosine-kinase inhibitors is known to be associated with asymptomatic elevations of serum amylase and lipase levels. As regards the pazopanib, data are lacking in literature. We report one case of Pancreatic Toxicity associated with pazopanib administration. Before starting treatment, patient had no risk factors for pancreatitis. The patient, an Italian 68 years old woman, started pazopanib at doses of 800 mg daily as first-line therapy for metastatic renal cell carcinoma. Six months after the start of treatment, blood tests showed for the first time a significant increase in serum lipase and amylase in the absence of symptoms and radiological findings of pancreatitis. The patient continued treatment without interruptions or dose reductions. However, the continuation of the treatment led to a further increase of Pancreatic enzymes. We tried to continue the treatment by reducing the dose but only the discontinuation was associated with normalization of amylase and lipase’s levels. On the other hand the treatment with pazopanib got prolonged response of the disease in the absence of signs of pancreatitis. We therefore decided to continue treatment with pazopanib 400 mg daily with close monitoring of blood levels of Pancreatic enzymes. We hypothesize that the increase of Pancreatic enzymes is not a dose-dependent event. The mechanism for Pancreatic Toxicity induced by tyrosine-kinase inhibitors is unknown and no predictive factors have been identified. There are no clear guidelines on the management of the drug in the presence of Pancreatic enzyme increase. In any case, we believe that a careful monitoring of Pancreatic enzymes during treatment with pazopanib is advisable.
Erik Koenig - One of the best experts on this subject based on the ideXlab platform.
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The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of Pancreatic Toxicity in the rat and dog
BMC Genomics, 2016Co-Authors: Aaron Smith, John Calley, Sachin Mathur, Hui-rong Qian, Mark Farmen, Florian Caiment, Pierre R. Bushel, Craig Fisher, Patrick Kirby, Erik KoenigAbstract:Background MicroRNAs (miRNA) are ~19–25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein Toxicity studies utilizing both species. Results A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas Toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of Pancreatic injury in the rat and dog. Conclusions A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ Toxicity in 2 toxicologically relevant species.
Richard A. D. Carano - One of the best experts on this subject based on the ideXlab platform.
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bruton s tyrosine kinase small molecule inhibitors induce a distinct Pancreatic Toxicity in rats
Journal of Pharmacology and Experimental Therapeutics, 2017Co-Authors: Rebecca Erickson, Leah Schutt, Jacqueline M. Tarrant, Michelle Mcdowell, Lichuan Liu, Adam R. Johnson, Jed Ross, Sockcheng Lewinkoh, Maj Hedehus, Richard A. D. CaranoAbstract:Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused Pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of Pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine Pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that Pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.
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Bruton’s Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats
The Journal of pharmacology and experimental therapeutics, 2016Co-Authors: Rebecca Erickson, Leah Schutt, Jacqueline M. Tarrant, Michelle Mcdowell, Lichuan Liu, Adam R. Johnson, Sock-cheng Lewin-koh, Hedehus, Jed Ross, Richard A. D. CaranoAbstract:Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused Pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of Pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine Pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that Pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.
Sachin Mathur - One of the best experts on this subject based on the ideXlab platform.
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The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of Pancreatic Toxicity in the rat and dog
BMC Genomics, 2016Co-Authors: Aaron Smith, John Calley, Sachin Mathur, Hui-rong Qian, Mark Farmen, Florian Caiment, Pierre R. Bushel, Craig Fisher, Patrick Kirby, Erik KoenigAbstract:Background MicroRNAs (miRNA) are ~19–25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein Toxicity studies utilizing both species. Results A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas Toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of Pancreatic injury in the rat and dog. Conclusions A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ Toxicity in 2 toxicologically relevant species.
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The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of Pancreatic Toxicity in the rat and dog
BMC genomics, 2016Co-Authors: Aaron P. Smith, John Calley, Sachin Mathur, Hui-rong Qian, Mark Farmen, Florian Caiment, Pierre R. Bushel, Craig FisherAbstract:MicroRNAs (miRNA) are ~19–25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein Toxicity studies utilizing both species. A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas Toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of Pancreatic injury in the rat and dog. A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ Toxicity in 2 toxicologically relevant species.
