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Toward rapid, high-sensitivity, volume-constrained biomarker quantification and validation using backscattering interferometry.
Olmsted IR, Hassanein M, Kussrow A, Hoeksema M, Li M, Massion PP, Bornhop DJ
(2014) Anal Chem 86: 7566-74
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Calibration, Enzyme-Linked Immunosorbent Assay, Galectins, Humans, Keratin-19, Limit of Detection, Lung Neoplasms
Show Abstract · Added February 2, 2015
Realizing personalized medicine, which promises to enable early disease detection, efficient diagnostic staging, and therapeutic efficacy monitoring, hinges on biomarker quantification in patient samples. Yet, the lack of a sensitive technology and assay methodology to rapidly validate biomarker candidates continues to be a bottleneck for clinical translation. In our first direct and quantitative comparison of backscattering interferometry (BSI) to fluorescence sensing by ELISA, we show that BSI could aid in overcoming this limitation. The analytical validation study was performed against ELISA for two biomarkers for lung cancer detection: Cyfra 21-1 and Galectin-7. Spiked serum was used for calibration and comparison of analytical figures of merit, followed by analysis of blinded patient samples. Using the ELISA antibody as the probe chemistry in a mix-and-read assay, BSI provided significantly lower detection limits for spiked serum samples with each of the biomarkers. The limit of quantification (LOQ) for Cyrfa-21-1 was measured to be 230 pg/mL for BSI versus 4000 pg/mL for ELISA, and for Galectin-7, it was 13 pg/mL versus 500 pg/mL. The coefficient of variation for 5 day, triplicate determinations was <15% for BSI and <10% for ELISA. The two techniques correlated well, ranging from 3-29% difference for Cyfra 21-1 in a blinded patient sample analysis. The label-free and free-solution operation of BSI allowed for a significant improvement in analysis speed, with greater ease, improved LOQ values, and excellent day-to-day reproducibility. In this unoptimized format, BSI required 5.5-fold less sample quantity needed for ELISA (a 10 point calibration curve measured in triplicate required 36 μL of serum for BSI vs 200 μL for ELISA). The results indicate that the BSI platform can enable rapid, sensitive analytical validation of serum biomarkers and should significantly impact the validation bottleneck of biomarkers.
0 Communities
2 Members
0 Resources
9 MeSH Terms
Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj.
Walter TJ, Vanderpool C, Cast AE, Huppert SS
(2014) Am J Pathol 184: 1479-88
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Epithelial Cells, Hepatocyte Nuclear Factor 6, Hepatocytes, Imaging, Three-Dimensional, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Immunohistochemistry, Keratin-19, Mice, Knockout, Plant Lectins, Portal Vein, Receptors, Notch, Regeneration, SOX9 Transcription Factor
Show Abstract · Added May 27, 2014
The potential for intrahepatic bile duct (IHBD) regeneration in patients with bile duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of bile duct insufficiency with liver epithelial cell-specific deficiencies in Hnf6 and Rbpj, a mediator of canonical Notch signaling. Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice initially developed no peripheral bile ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice mounted a ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6.
Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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1 Members
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15 MeSH Terms
Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice.
Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, Kisseleva T
(2010) Gastroenterology 139: 987-98
MeSH Terms: Animals, Bile Ducts, Biomarkers, Calcium-Binding Proteins, Carbon Tetrachloride, Cell Lineage, Cell Transdifferentiation, Chemical and Drug Induced Liver Injury, Collagen Type II, Crosses, Genetic, Disease Models, Animal, Epithelial Cells, Fibroblasts, Genes, Reporter, Glial Fibrillary Acidic Protein, Hepatic Stellate Cells, Immunohistochemistry, Keratin-19, Ligation, Liver, Liver Cirrhosis, Liver Regeneration, Luminescent Proteins, Mice, Mice, Transgenic, Promoter Regions, Genetic, Proteins, RNA, Untranslated, S100 Calcium-Binding Protein A4, S100 Proteins
Show Abstract · Added December 4, 2012
BACKGROUND & AIMS - Chronic injury changes the fate of certain cellular populations, inducing epithelial cells to generate fibroblasts by epithelial-to-mesenchymal transition (EMT) and mesenchymal cells to generate epithelial cells by mesenchymal-to-epithelial transition (MET). Although contribution of EMT/MET to embryogenesis, renal fibrosis, and lung fibrosis is well documented, role of EMT/MET in liver fibrosis is unclear. We determined whether cytokeratin-19 positive (K19(+)) cholangiocytes give rise to myofibroblasts (EMT) and/or whether glial fibrillary acidic protein positive (GFAP(+)) hepatic stellate cells (HSCs) can express epithelial markers (MET) in response to experimental liver injury.
METHODS - EMT was studied with Cre-loxP system to map cell fate of K19(+) cholangiocytes in K19(YFP) or fibroblast-specific protein-1 (FSP-1)(YFP) mice, generated by crossing tamoxifen-inducible K19(CreERT) mice or FSP-1(Cre) mice with Rosa26(f/f-YFP) mice. MET of GFAP(+) HSCs was studied in GFAP(GFP) mice. Mice were subjected to bile duct ligation or CCl(4)-liver injury, and livers were analyzed for expression of mesodermal and epithelial markers.
RESULTS - On Cre-loxP recombination, >40% of genetically labeled K19(+) cholangiocytes expressed yellow fluorescent protein (YFP). All mice developed liver fibrosis. However, specific immunostaining of K19(YFP) cholangiocytes showed no expression of EMT markers alpha-smooth muscle actin, desmin, or FSP-1. Moreover, cells genetically labeled by FSP-1(YFP) expression did not coexpress cholangiocyte markers K19 or E-cadherin. Genetically labeled GFAP(GFP) HSCs did not express epithelial or liver progenitor markers in response to liver injury.
CONCLUSION - EMT of cholangiocytes identified by genetic labeling does not contribute to hepatic fibrosis in mice. Likewise, GFAP(Cre)-labeled HSCs showed no coexpression of epithelial markers, providing no evidence for MET in HSCs in response to fibrogenic liver injury.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
30 MeSH Terms
Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice.
Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS
(2010) Hepatology 51: 1391-400
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Keratin-19, Mice, Mice, Knockout, Receptor, Notch1, Receptor, Notch2, Signal Transduction
Show Abstract · Added February 11, 2011
UNLABELLED - Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization, we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bipotential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. Although Notch2 has a dominant role in IHBD formation, there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Because changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs.
CONCLUSION - There is a threshold requirement for Notch signaling at multiple steps, including IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture.
1 Communities
4 Members
0 Resources
8 MeSH Terms
A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs.
Means AL, Xu Y, Zhao A, Ray KC, Gu G
(2008) Genesis 46: 318-23
MeSH Terms: Alleles, Animals, Cell Lineage, DNA, Dose-Response Relationship, Drug, Epithelial Cells, Gene Targeting, Genes, Reporter, Immunohistochemistry, Integrases, Intestine, Small, Keratin-19, Mice, Mice, Inbred C57BL, Mice, Transgenic, Organ Specificity, Recombination, Genetic, Stem Cells, Tamoxifen
Show Abstract · Added February 3, 2014
Cre/LoxP-mediated DNA recombination allows for gene function and cell lineage analyses during embryonic development and tissue regeneration. Here, we describe the derivation of a K19(CreERT) mouse line in which the tamoxifen-activable CreER(T) was knocked into the endogenous cytokeratin 19 locus. In the absence of tamoxifen, leaky Cre activity could be detected only in less than 1% of stomach and intestinal epithelial cells, but not in pancreatic or hepatic epithelial tissues. Tamoxifen administration in postnatal animals induced widespread DNA recombination in epithelial cells of pancreatic ducts, hepatic ducts, stomach, and intestine in a dose-dependent manner. Significantly, we found that Cre activity could be induced in the putative gut stem/progenitor cells that sustained long-term gut epithelial expression of a Cre reporter. This mouse line should therefore provide a valuable reagent for manipulating gene activity and for cell lineage marking in multiorgans during normal tissue homeostasis and regeneration.
(c) 2008 Wiley-Liss, Inc.
2 Communities
2 Members
0 Resources
19 MeSH Terms