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Diagnostic utility of PAX8, TTF-1 and napsin A for discriminating metastatic carcinoma from primary adenocarcinoma of the lung.
Ye J, Hameed O, Findeis-Hosey JJ, Fan L, Li F, McMahon LA, Yang Q, Wang HL, Xu H
(2012) Biotech Histochem 87: 30-4
MeSH Terms: Adenocarcinoma, Aspartic Acid Endopeptidases, Biomarkers, Tumor, DNA-Binding Proteins, Diagnosis, Differential, Humans, Immunohistochemistry, Lung Neoplasms, PAX8 Transcription Factor, Paired Box Transcription Factors, Transcription Factors
Show Abstract · Added March 21, 2014
TTF-1 and napsin A are useful biomarkers for differentiating primary lung adenocarcinoma from metastatic tumors. Studies have shown, however, that TTF-1 and napsin A also can be expressed in extrapulmonary carcinomas, and that a small fraction of primary lung adenocarcinomas do not co-express these two markers. We attempted to determine whether a tissue-specific transcriptional factor, PAX8, can help determine primary sites of lung carcinomas. Immunohistochemical stains for PAX8, TTF-1 and napsin A were performed on 103 cases of metastatic lung carcinomas from a variety of origins and 120 cases of primary lung adenocarcinomas. Our data demonstrated that all 103 metastatic carcinomas were negative for napsin A, while 14 (13.6%; four thyroid, two endometrium, three colon, one prostate, one salivary adenoid cystic, two renal cell carcinomas, and one ovary) showed weak to strong TTF-1 nuclear staining in 5-60% of the tumor cells. All primary lung adenocarcinomas were negative for PAX8, whereas 46 (44.7%) metastatic carcinomas from the kidney (29/33), ovary (6/8), endometrium (5/5), endocervix (1/1), thyroid (4/5) and urinary tract (1/3) were positive for PAX8. Our data demonstrate that of combined use of PAX8, TTF-1 and napsin A is reliable to separate reliably lung primary from metastatic tumors.
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11 MeSH Terms
Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model.
Ray KC, Bell KM, Yan J, Gu G, Chung CH, Washington MK, Means AL
(2011) PLoS One 6: e16786
MeSH Terms: Amino Acid Substitution, Animals, Aspartic Acid, Carcinoma in Situ, Carcinoma, Pancreatic Ductal, Cell Transformation, Neoplastic, Disease Models, Animal, Disease Susceptibility, Epithelium, Glycine, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mouth Neoplasms, Mutation, Missense, Pancreatic Neoplasms, Papilloma, Proto-Oncogene Proteins p21(ras)
Show Abstract · Added February 3, 2014
Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, Kras(G12D), broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the Kras(G12D) mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes Kras(G12D)-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer.
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18 MeSH Terms
Anterior cingulate and cerebellar GABA and Glu correlations measured by ¹H J-difference spectroscopy.
Waddell KW, Zanjanipour P, Pradhan S, Xu L, Welch EB, Joers JM, Martin PR, Avison MJ, Gore JC
(2011) Magn Reson Imaging 29: 19-24
MeSH Terms: Adult, Aspartic Acid, Cerebellum, Creatine, Female, Glutamic Acid, Gyrus Cinguli, Humans, Magnetic Resonance Spectroscopy, Male, Protons, Statistics as Topic, Tissue Distribution, gamma-Aminobutyric Acid
Show Abstract · Added May 29, 2013
Gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, normalized to total creatine (tCr), were measured in the anterior cingulate and cerebellar vermis in healthy adults (n=19, age=24.6±6.4 years) using ¹H MRS at 3 T, and metabolite correlations across regions and subjects were determined. Mean anterior cingulate and cerebellar GABA/tCr ratios were 0.31 (0.08) and 0.23 (0.06), respectively, while corresponding Glu levels were 1.16 (0.10) and 0.70 (0.07), respectively. Anterior cingulate and cerebellar glutamate levels were correlated (r=0.6103, P=.0140), although it is noted that when adjusted for multiple comparisons, all correlations reported here cluster to a P value of .0583. It is unlikely that this correlation is driven by correlations in tCr, since interregional correlations were not observed for other metabolites referenced to tCr. Correlations were also observed among metabolites in both the anterior cingulate and cerebellar vermis. In the former, N-acetylasparate was linearly dependent on glutamate (r=0.6577, P=.0063) and, at or below this significance threshold, four metabolites were correlated in the cerebellar vermis (Ins/tCh: r=0.6261, P=.0109. NAA/tCh: r=0.6426, P=.0082. NAA/Glu: r=0.6412, P=.0085. tCh/Glu: r=0.6193, P=0.0122).
Copyright © 2011 Elsevier Inc. All rights reserved.
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14 MeSH Terms
BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension.
Talati M, West J, Blackwell TR, Loyd JE, Meyrick B
(2010) Am J Physiol Lung Cell Mol Physiol 299: L363-73
MeSH Terms: Adolescent, Adult, Aged, Animals, Aspartic Acid Endopeptidases, Bone Morphogenetic Protein Receptors, Type II, Endothelin-1, Endothelin-Converting Enzymes, Female, Gene Expression, Humans, Hypertension, Pulmonary, Macrophages, Macrophages, Alveolar, Male, Metalloendopeptidases, Mice, Mice, Mutant Strains, Microscopy, Confocal, Middle Aged, Mutation, Receptor, Endothelin A, Receptor, Endothelin B, Tissue Distribution, Young Adult
Show Abstract · Added March 5, 2014
Macrophage derived-endothelin-1 (ET-1) has been suggested to contribute to a number of chronic lung diseases. Whether the ET-1 cascade from non-vascular sources (inflammatory cells) also contributes to pulmonary artery hypertension (PAH) and in particular to heritable PAH (HPAH) with known bone morphogenetic protein type 2 receptor (BMPR2) mutations is not known. We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH). At baseline ET(A) and ET(B) receptors and endothelin converting enzyme (ECE) gene expression was reduced in BMPR2 mutant BMDM compared with controls. In control BMDM, LPS resulted in increased ppET-1 gene expression and ET-1 in culture media, whereas ET(A) and ET(B) receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ET(B) receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ET(B) receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ET(A) and ET(B) expression was decreased in the HPAH, but not IPAH, patients compared with controls. We conclude that reduced expression of macrophage ET-1 receptors in HPAH increases lung ET-1 and may contribute to the pathogenesis and maintenance of HPAH. This is the first description of protein expression that distinguishes HPAH from IPAH in patients.
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25 MeSH Terms
Posttranslational modifications of the bovine lens beaded filament proteins filensin and CP49.
Wang Z, Obidike JE, Schey KL
(2010) Invest Ophthalmol Vis Sci 51: 1565-74
MeSH Terms: Amino Acid Sequence, Animals, Aspartic Acid, Cattle, Chromatography, High Pressure Liquid, Eye Proteins, Intermediate Filament Proteins, Isoaspartic Acid, Isomerism, Lens, Crystalline, Molecular Sequence Data, Phosphorylation, Protein Processing, Post-Translational, Tandem Mass Spectrometry
Show Abstract · Added May 27, 2014
PURPOSE - The lens beaded filament proteins filensin and CP49 are phosphorylated proteins that undergo proteolytic degradation with fiber cell age; however, the specific sites of modifications remain largely unknown. The purpose of this study was to identify posttranslational modifications (PTMs) in bovine lens beaded filament proteins.
METHODS - Filensin and CP49 were enriched by urea extraction of lens fiber cell homogenates after the water-soluble fraction was removed. The urea-soluble fraction was separated by SDS-PAGE, and the corresponding filensin and CP49 bands were digested by trypsin, Lys C, or Glu C. The enzymatic digests were analyzed by HPLC mass spectrometry.
RESULTS - The sequences of lens beaded filament proteins were systematically mapped, and putative database sequence errors of filensin were identified. The data also indicated that Met-1 of CP49 was removed and Ser2 was acetylated. Nine phosphorylation sites on filensin and seven phosphorylation sites on CP49 were identified. Filensin was found to be truncated at D431 and L39, and the resulting new N termini were N-myristoylated and N-acetylated, respectively. Truncation of CP49 occurred at D37. Aspartic acid isomerization to isoaspartic acid occurs at the major truncation sites of filensin (D431) and of CP49 (D37).
CONCLUSIONS - This study identified sites of phosphorylation and truncation in filensin and CP49 and revealed two unusual PTMs: postproteolytic N-acetylation and N-myristoylation of filensin. The detailed knowledge about these PTMs provides important information for further study of their functional consequences-for example protein redistribution during lens fiber cell differentiation and aging.
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14 MeSH Terms
Glutamate spillover augments GABA synthesis and release from axodendritic synapses in rat hippocampus.
Stafford MM, Brown MN, Mishra P, Stanwood GD, Mathews GC
(2010) Hippocampus 20: 134-44
MeSH Terms: Animals, Axons, CA1 Region, Hippocampal, D-Aspartic Acid, Dendrites, Excitatory Amino Acid Transporter 3, Glutamic Acid, In Vitro Techniques, Interneurons, Neural Inhibition, Neuroglia, Neurons, Presynaptic Terminals, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Synapses, Synaptic Transmission, gamma-Aminobutyric Acid
Show Abstract · Added January 20, 2015
Tight coupling between gamma-aminobutyric acid (GABA) synthesis and vesicle filling suggests that the presynaptic supply of precursor glutamate could dynamically regulate inhibitory synapses. Although the neuronal glutamate transporter excitatory amino acid transporter 3 (EAAT3) has been proposed to mediate such a metabolic role, highly efficient astrocytic uptake of synaptically released glutamate normally maintains low-extracellular glutamate levels. We examined whether axodendritic inhibitory synapses in stratum radiatum of hippocampal area CA1, which are closely positioned among excitatory glutamatergic synapses, are regulated by synaptic glutamate release via presynaptic uptake. Under conditions of spatially and temporally coordinated release of glutamate and GABA within pyramidal cell dendrites, blocking glial glutamate uptake enhanced quantal release of GABA in a transporter-dependent manner. These physiological findings correlated with immunohistochemical studies revealing expression of EAAT3 by interneurons and uptake of D-asparate into putative axodendritic inhibitory terminals only when glial uptake was blocked. These results indicate that spillover of glutamate between adjacent excitatory and inhibitory synapses can occur under conditions when glial uptake incompletely clears synaptically released glutamate. Our anatomical studies also suggest that perisomatic inhibitory synapses, unlike synapses within dendritic layers of hippocampus, are not capable of glutamate uptake and therefore transporter-mediated dynamic regulation of inhibition is a unique feature of axodendritic synapses that may play a role in maintaining a homeostatic balance of inhibition and excitation.
Copyright 2009 Wiley-Liss, Inc.
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19 MeSH Terms
Biochemical abnormalities of the medial temporal lobe and medial prefrontal cortex in late-life depression.
Venkatraman TN, Krishnan RR, Steffens DC, Song AW, Taylor WD
(2009) Psychiatry Res 172: 49-54
MeSH Terms: Aspartic Acid, Choline, Creatine, Depressive Disorder, Major, Energy Metabolism, Functional Laterality, Humans, Image Processing, Computer-Assisted, Inositol, Magnetic Resonance Spectroscopy, Prefrontal Cortex, Temporal Lobe, Whole Body Imaging
Show Abstract · Added May 20, 2014
We utilized single-voxel (1)H magnetic resonance spectroscopy (MRS) to investigate biochemical abnormalities related to late-life depression in the medial prefrontal cortex and medial temporal lobe. Fourteen elderly subjects whose depression responded to treatment and 12 nondepressed subjects were enrolled. Subjects were scanned using a GE 3.0 Tesla whole body MR scanner. Metabolite concentrations were quantified using the LC Model software and adjusted for CSF and ratio of gray to white matter. ANCOVA models tested for group differences while controlling for age and sex. Older previously depressed individuals showed significantly reduced concentrations of total N-acetyl aspartate (NAA), choline, and creatine in the prefrontal cortex and significantly elevated left medial temporal lobe concentrations of NAA and myo-inositol. There were no significant group differences in right temporal metabolite concentrations. The prefrontal cortex observations suggest that reduced neuronal, phospolipid, and energy metabolism is present even in clinically improved depression. In contrast, elevated NAA and myo-inositol concentrations in the left medial temporal lobe could be associated with neuronal and glial cell changes in the amygdala.
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13 MeSH Terms
Human deafness mutation E385D disrupts the mechanochemical coupling and subcellular targeting of myosin-1a.
Yengo CM, Ananthanarayanan SK, Brosey CA, Mao S, Tyska MJ
(2008) Biophys J 94: L5-7
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Aspartic Acid, Deafness, Dictyostelium, Glutamic Acid, Green Fluorescent Proteins, Humans, Mechanotransduction, Cellular, Mutation, Myosin Heavy Chains, Myosin Type I, Myosin Type II, Protein Transport, Recombinant Fusion Proteins, Subcellular Fractions
Show Abstract · Added May 19, 2014
Missense mutations in the membrane-binding actin-based motor protein, myosin-1a (Myo1a), have recently been linked to sensorineural deafness in humans. One of these mutations, E385D, impacts a residue in the switch II region of the motor domain that is present in virtually all members of the myosin superfamily. We sought to examine the impact of E385D on the function of Myo1a, both in terms of mechanochemical activity and ability to target to actin-rich microvilli in polarized epithelial cells. While E385D-Myo1a demonstrated actin-activated ATPase activity, the V(MAX) was reduced threefold relative to wild-type. Despite maintaining an active mechanochemical cycle, E385D-Myo1a was unable to move actin in the sliding filament assay. Intriguingly, when an enhanced-green-fluorescent-protein-tagged form of E385D-Myo1a was stably expressed in polarized epithelial cells, this mutation abolished the microvillar targeting normally demonstrated by wild-type Myo1a. Notably, these data are the first to suggest that mechanical activity is essential for proper localization of Myo1a in microvilli. These studies also provide a unique example of how even the most mild substitution of invariant switch II residues can effectively uncouple enzymatic and mechanical activity of the myosin motor domain.
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17 MeSH Terms
The reovirus sigma1 aspartic acid sandwich: a trimerization motif poised for conformational change.
Schelling P, Guglielmi KM, Kirchner E, Paetzold B, Dermody TS, Stehle T
(2007) J Biol Chem 282: 11582-9
MeSH Terms: Amino Acid Motifs, Aspartic Acid, Capsid Proteins, Cell Adhesion Molecules, Crystallography, X-Ray, Models, Molecular, Mutation, Orthoreovirus, Mammalian, Protein Binding, Protein Structure, Quaternary, Protein Structure, Tertiary, Protein Subunits, Structural Homology, Protein
Show Abstract · Added December 10, 2013
Reovirus attachment protein sigma1 mediates engagement of receptors on the surface of target cells and undergoes dramatic conformational rearrangements during viral disassembly in the endocytic pathway. The sigma1 protein is a filamentous, trimeric molecule with a globular beta-barrel head domain. An unusual cluster of aspartic acid residues sandwiched between hydrophobic tyrosines is located at the sigma1 subunit interface. A 1.75-A structure of the sigma1 head domain now reveals two water molecules at the subunit interface that are held strictly in position and interact with neighboring residues. Structural and biochemical analyses of mutants affecting the aspartic acid sandwich indicate that these residues and the corresponding chelated water molecules act as a plug to block the free flow of solvent and stabilize the trimer. This arrangement of residues at the sigma1 head trimer interface illustrates a new protein design motif that may confer conformational mobility during cell entry.
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13 MeSH Terms
A cross-reactive material positive variant of coagulation factor XI (FXIP520L) with a catalytic defect.
Gailani D, Schmidt A, Sun MF, Bolton-Maggs PH, Bajaj SP
(2007) J Thromb Haemost 5: 781-7
MeSH Terms: Aspartic Acid, Binding Sites, Blood Coagulation, Catalysis, Chymotrypsin, Factor XI, Humans, Kinetics, Leucine, Models, Molecular, Proline, Protein Binding, Recombinant Proteins, Serine Endopeptidases
Show Abstract · Added May 19, 2014
Inherited deficiency of the trypsin-like protease factor (F) XI is associated with a mild to moderate bleeding diathesis. In most cases, FXI protein is reduced in plasma, and examples of dysfunctional circulating FXI variants are rare. We characterized the defect in one such variant with a proline to leucine substitution at residue 520. FXI Pro520 corresponds to chymotrypsin Pro161, and is conserved in most members of the chymotrypsin protease family. Recombinant FXI containing this substitution will be referred to as FXI(P161L). k(cat) for cleavage of chromogenic substrates and for activation of the natural FXIa substrate FIX is approximately 3-fold lower for activated FXI(P161L) (FXIa(P161L)) than for wild-type FXIa (FXIa(WT)), consistent with an abnormal protease active site. Inhibition of FXIa(P161L) by diisopropyl fluorophosphate is 2.4-fold slower than for FXIa(WT), suggesting distortion of the protease oxyanion hole. Binding to p-aminobenzamidine, a probe for the integrity of the S1 substrate-binding site, was similar for FXIa(WT) and FXIa(P161L). Rates of carbamylation of Ile16 were also similar for FXIa(WT) and FXIa(P161L), indicating that the critical salt bridge between Ile16 and Asp194 forms normally during protease activation. Cumulatively, the data demonstrate that Pro161 is required for normal active site oxyanion hole conformation in FXIa. Examination of the FXIa crystal structure and modeling studies indicate that Pro161 forms several hydrophobic contacts with adjacent amino acids that stabilize active site conformation. Leucine can be incorporated at position 161 in FXIa, but would not form the extensive stabilizing network of hydrophobic interactions formed by Pro161.
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14 MeSH Terms