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A marker of neuroendocrine differentiation, neuron-specific enolase (NSE) is assessed in the diagnosis of small cell lung cancer (SCLC). The market was found to be highly sensitive and extremely specific in high risk groups (smokers and chronic bronchitics).
Neuron-specific enolase (NSE) is the best described serum tumor marker for small cell lung cancer (SCLC). Almost all clinical studies carried out so far used assays involving polyclonal antibodies against NSE; the majority of the studies analyzed the samples by a RIA NSE kit. We evaluated a new monoclonal kit and compared it to the polyclonal kit. We analyzed 392 serum samples, 265 from patients with SCLC, 88 from non-small cell lung cancers (NSCLC) and 39 from children with neuroblastomas. We found a good correlation between the results of the two assays. When correlating NSE in SCLC as measured with the two assays with clinical data, we found the same sensitivity, prognostic impact and value in treatment monitoring. We conclude that the "new" monoclonal assay is a fully acceptable alternative to the "old" polyclonal assay.
The onset and development of neuron-specific enolase (NSE) and calbindin immunoreactivities were studied in the inner ear of human fetuses aged from 6-7 to 14 weeks of gestation. NSE occurred very early in ganglion neurons. Its appearance in vestibular sensory cells at 8 weeks coincided with the formation of the first afferent synapses, and showed an apex/base gradient in the cristae. Calbindin was found in vestibular ganglion neurons at 6-7 weeks and in the cochlear ganglion neurons at 8-9 weeks. Vestibular sensory cells and the whole ventral wall of the cochlear duct were stained from 8-9 weeks. At 14 weeks, calbindin staining occurred only in the sensory cells of the cochlear neuroepithelium. Non-neuronal secretory structures, i.e. Kölliker's organ and some cells of the transitional zone of the utricle, were also reactive. Staining appeared in Kölliker's organ with a base to apex gradient and disappeared from it with an internal to external gradient. Calbindin appeared in vestibular sensory cells later than NSE staining, synapse formation and sensory hair bundle differentiation. By contrast in the cochlea, calbindin staining appeared in the neuroepithelium before sensory cell differentiation, but remained only in the hair cells after they had differentiated and been contacted by the afferent fibers.
One source of diversity in the inositol (1,4,5)-trisphosphate receptors (IP3Rs) is generated at the level of alternative splicing. Our previous studies of splice isoforms of the receptor in various tissues suggested that some tissues, specifically those containing neurons, selectively express a 40 amino acid insert located between 2 sites for phosphorylation by cyclic AMP-dependent protein kinase (PKA), and that the presence of this insert changes the preferred site of phosphorylation of the receptor. Studies of the mouse receptor have also suggested the existence of intermediately spliced forms containing partial versions of the splice and exhibiting different brain distributions. In this study, we have investigated the alternative splicing of the rat receptor in greater detail using RNase protection and PCR analysis. We find little evidence for the existence of intermediately spliced forms in rat, raising the possibility that the degree of alternative splicing at this site differs in the brains of two very similar species. Our screen of tissue distribution supports the selectively neuronal expression of the long spliced form, and suggests that regulation of this receptor in neurons may be different than in other tissues.
In the present work, I describe an antiserum that specifically stains all neurons in C. elegans. This probe should facilitate developmental studies in this organism in the same way as anti-horseradish peroxidase has in Drosophila. The antiserum was raised against an 8 amino acid peptide representing part of an insect neuropeptide precursor, but there are no indications that this cross-reactivity reflects evolutionary homology. The antiserum allows the whole nervous system of C. elegans, including all cell bodies and processes, to be brightly stained. The subcellular staining pattern suggests that a cytoskeletal component is recognized. I have also isolated a mutation (e2481) that abolishes staining in all but 7 neurons, the 6 microtubule cells and 1 cell in the tail. Finally, I show that the pattern of staining in the nematode P. redivivus is similar to that seen in animals carrying the e2481 mutation.
Differentiation of CNS glia is regulated by Notch signaling through neuron-glia interaction. Here, we identified Delta/Notch-like EGF-related receptor (DNER), a neuron-specific transmembrane protein, as a previously unknown ligand of Notch during cellular morphogenesis of Bergmann glia in the mouse cerebellum. DNER binds to Notch1 at cell-cell contacts and activates Notch signaling in vitro. In the developing cerebellum, DNER is highly expressed in Purkinje cell dendrites, which are tightly associated with radial fibers of Bergmann glia expressing Notch. DNER specifically binds to Bergmann glia in culture and induces process extension by activating gamma-secretase- and Deltex-dependent Notch signaling. Inhibition of Deltex-dependent, but not RBP-J-dependent, Notch signaling in Bergmann glia suppresses formation and maturation of radial fibers in organotypic slice cultures. Additionally, deficiency of DNER retards the formation of radial fibers and results in abnormal arrangement of Bergmann glia. Thus, DNER mediates neuron-glia interaction and promotes morphological differentiation of Bergmann glia through Deltex-dependent Notch signaling.
Changes of monoamines, monoamine metabolites, neuron specific enolase (NSE) and myelin basic protein (MBP) levels in cerebrospinal fluid were measured in 8 patients for up to 7 days after cardiopulmonary resuscitation. The outcomes were assessed by the Glasgow Outcome Scale. One showed good recovery 3 developed a persistent vegetate state (PVS) and 4 became brain dead (BD). The concentration of NSE increased to a peak about 3 days after resuscitation, then gradually decreased. MBP also showed an increase with time up to 7 days. The time course suggests that neuronal and/or axonal damage progresses for several days after hypoxic or anoxic brain insult. NSE and MBP in the BD group were higher than those in the PVS group, thus CSF levels may be prognostic with regard to hypoxic brain injury. Tyrosine, dopamine, 3-methoxytyramine (3-MT), 3-dihydroxy-4-phenylacetic acid (DOPAC), homovanillic acid (HVA), vanillylmanderic acid (VMA), normetanephrine (NMN), metanephrine (MN), 3-methoxy-4-hydroxyphenylglycol (MHPG), vanillic acid (VA), tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were analyzed by HPLC with an electrochemical detector. Concentrations changed within 2 or 3 days after resuscitation, so concentrations at that period may indicate neuronal damage. However, there are some cases with abnormal NSE and MBP levels without abnormal monoamine levels, suggesting that differences in concentrations are not the consequence of the amount of affected neurons, but of the sites of regions.
In order to better define the use of neuron-specific enolase (NSE) as a marker for neuroendocrine neoplasms, we studied 11 thymic carcinoid tumors, three bronchial small-cell carcinomas (all with cutaneous metastases), and 10 trabecular carcinomas of the skin for its presence, using the peroxidase-antiperoxidase (PAP) technic with an antiserum directed at NSE. All 11 carcinoid tumors stained positively, as did two of the bronchial small-cell carcinomas and seven of the trabecular carcinomas. We conclude that PAP staining for NSE content may be a useful adjunct to morphologic analysis in diagnostically identifying the tumors we studied and that our results support the concept of a functionally unified APUD system, as reflected in the tumors originating from it. Nevertheless, because of the vagaries of the PAP method, exemplified by the results in our small series, it cannot be relied upon as a sole indicator that a tumor contains NSE and is therefore neuroendocrine. Also, since it is hypothesized that NSE is present in all tumors of this type, staining for its presence would seem to be of little benefit in distinguishing primary from secondary neuroendocrine tumors or in identifying the origin of metastatic lesions that have a neuroendocrine histologic appearance.
The gamma-subunit of 2-phospho-D-glycerate hydrolyase, E.C. 4.2.1.11 (enolase), neuron-specific enolase (NSE), is present at high concentrations in neurons and neuroendocrine cells and has therefore recently been introduced as a marker for neuroendocrine tumors. By the indirect methods, immunocytochemistry and radioimmunoassay, NSE has been detected also in some nonneuroendocrine tumors, a finding that could reflect technical artifacts or the capacity for NSE expression in nonneuroendocrine tumor cells. This paper reports on the expression of NSE in human neuroendocrine and nonneuroendocrine tumor specimens and in a panel of permanent human cell lines, by using a direct (enzymatic) and an indirect (radioimmunoassay) method for determination of NSE. We detected NSE in all tested tumor specimens and neuroendocrine tumor cell lines and in a majority (21 of 24) of the nonneuroendocrine tumor cell lines. In general, neuroendocrine tumor specimens and derived tumor cell lines contained more NSE than the nonneuroendocrine tumor specimens and cell lines. However, some of the cultured hematopoietic cell lines (T leukemia and Epstein-Barr virus immortalized B lymphoblastoid cell lines) had NSE levels comparable to those found in some neuroblastoma and small-cell lung carcinoma cell lines. We conclude that NSE is not exclusively expressed in neuroendocrine tumor cells.
The expression of the synapsin I gene is neuron-specific and developmentally regulated. As a step toward characterizing the molecular mechanisms that are responsible for its transcriptional regulation in vivo, we have generated transgenic mice that carry the chloramphenicol acetyltransferase (CAT) receptor gene under the control of approximately 4,300 nucleotides of 5'-flanking sequence of the rat synapsin I gene. In four independent transgenic mouse lines, high level CAT expression is observed specifically in the brain and other neural tissues. Two of these lines also exhibit notable CAT expression in testis. The transgene is expressed at similar levels in many different regions of the central nervous system. Immunohistochemical staining detects the CAT marker protein in various cell populations of neuronal morphology within the brain and the spinal cord. Transgene expression is developmentally regulated in a way that correlates well with the expression of the endogenous synapsin I gene. Both follow a characteristic, biphasic postnatal time course with a maximum around day 20. We conclude that the DNA region investigated contains cis-regulatory elements sufficient to drive the expression of a reporter gene in a spatial and temporal pattern that resembles the expression of the endogenous synapsin I gene.
We investigated whether neuron-specific enolase (NSE) in serum or cerebrospinal fluid (CSF) reflects subtle or manifest brain injury in children undergoing cardiac surgery using cardiopulmonary bypass (CPB). NSE was measured in serum (s-NSE) before, and up to, 102 h after surgery in 27 children undergoing cardiac surgery with CPB. In 11 children, CSF-NSE was also measured 48 or 66 h post-surgery. As erythrocytes contain NSE, hemoglobin concentration in the samples was determined spectrophotometrically at 550 nm (cut-off limit: absorbance 0.4 = 560 mg/l) in 14 children and in a further 13 children by spectroscopic multicomponent analysis (cut-off limit 5 micromol/l = 80 mg/l). One hundred and one of 214 post-operative serum samples (47%) had to be discarded because of hemolysis (18% spectrophotometrically at 550 nm and 88% with spectroscopic multicomponent analysis). On the first and second post-operative day, the median s-NSE values were significantly higher when compared with samples taken after 54 h or longer (P = 0.008 and P = 0.002). All CSF-NSE levels were within the normal range and below the s-NSE measured in the same patient. Although in our study elevated s-NSE seems to indicate brain injury in CPB-surgery, the low concentration of NSE in the post-operative CSF of 11 children puts the neuronal origin of s-NSE in question. NSE from other non-neuronal tissues probably contributes to the elevated s-NSE. Additionally, normal post-operative CSF-NSE values in two children with post-operative neurological sequelae might question the predictive value of CSF-NSE with regard to brain injury.
Neuron-specific enolase (NSE) is one of the glycolytic enzymes distributed exclusively in neurons. It was measured serially in the cerebrospinal fluid (CSF) of 10 children with bacterial meningitis during the illness using radio-immunoassay. The relationship between CSF-NSE levels and neurological complications or outcome was examined. CSF-NSE levels were significantly higher in the patients with bacterial meningitis than in the patients with the other central nervous system (CNS) infectious diseases, suggesting that CNS damage in those patients with bacterial meningitis was exacerbated. As CSF-NSE levels increased to above 25 ng/mL in the acute phase, all patients except one had subdural effusion. In those patients whose CSF-NSE level rose again during the illness, CNS complications or sequelae occurred. CSF-NSE may be a useful prognostic factor for predicting CNS damage in childhood bacterial meningitis.
The activation of cyclin-dependent kinase 5 (Cdk5) depends on the binding of its neuronal specific activator Nck5a. The minimal activation domain of Nck5a is located in the region of amino acid residues 150 to 291 (Tang, D., Chun, A. C. S., Zhang, M., and Wang, J. H. (1997) J. Biol. Chem. 272, 12318-12327). In this work we show that a 29-residue peptide, denoted as the alphaN peptide, encompassing amino acid residues Gln145 to Asp173 of Nck5a is capable of binding Cdk5 to result in kinase inhibition. This peptide also inhibits an active phospho-Cdk2-cyclin A complex, with a similar potency. Direct competition experiments have shown that this inhibitory peptide does not compete with Nck5a or cyclin A for Cdk5 or Cdk2, respectively. Steady state kinetic analysis has indicated that the alphaN peptide acts as a non-competitive inhibitor of Cdk5. Nck5a complex with respect to the peptide substrate. To understand the molecular basis of kinase inhibition by the peptide, we determined the structure of the peptide in solution by circular dichroism and two-dimensional 1H NMR spectroscopy. The peptide adopts an amphipathic alpha-helical structure from residues Ser149 to Arg162 which can be further stabilized by the helix-stabilizing solvent trifluoroethanol. The hydrophobic face of the helix is likely to be the kinase binding surface.
A new ganglioside antigen, termed Chol-1 alpha-b, recognized by cholinergic neuron-specific antibody, Chol-1 alpha, was isolated from bovine brain ganglioside mixture using Q-Sepharose. The yield was approximately 1.3 mg from 5 g of the total ganglioside. The chemical structure was characterized as a novel ganglioside by means of gas-liquid chromatography, a permethylation study, mild acid hydrolysis, thin layer chromatography-enzyme immunostaining, fast atom bombardment mass spectrometry, and proton nuclear magnetic resonance spectroscopy. The ganglioside has the following unique structure. [formula: see text] When examined by thin layer chromatography immunostaining and enzyme-linked immunosorbant assays, this ganglioside has the most intense immunoreactivity with Chol-1 alpha antibody among bovine brain gangliosides. As combined with our previous results (Hirabayashi, Y., Hyogo, A., Nakao, T., Tsuchiya, K., Suzuki, Y., Matsumoto, M., Kon, K., and Ando, S. (1990) J. Biol. Chem. 265, 8144-8151; Ando, S., Hirabayashi, Y., Kon, K., Inagaki, F., Tate, S., and Whittaker, X. (1992) J. Biochem. (Tokyo), 111, 287-290), the present study indicates the occurrence of a new series of gangliosides containing N-acetylneuraminic acid residue attaching to N-acetylgalactosamine as cholinergic specific antigens.
BACKGROUND: Chromogranin A (CgA), neuron specific enolase (NSE), carcinoembryonic antigen (CEA), and urinary 5-hydroxyindole-3-acetic acid (5-HIAA) are the markers currently used in the diagnosis, prognosis, and follow-up of patients with neuroendocrine tumors (NETs). The authors examined the role of such biomarkers in a large series of patients with NETs. METHODS: One hundred and twenty-seven patients entered the study. Multiple blood and 24-hour urine specimens were assayed for biomarker quantitation. RESULTS: The accuracy of each marker was assessed in patients with (n = 106) and without (n = 21) disease. CgA proved to be the best marker (specificity of 85.7% and sensitivity of 67.9%). Patients with disease had significantly higher CgA and NSE levels compared with disease free patients (P = 0.00003 and P = 0.00240, respectively). NSE and 5-HIAA determination showed a very high specificity (100%) but a rather low sensitivity (32.9% and 35.1%, respectively). CEA was found to have little diagnostic value (sensitivity of 15.4%). CgA was the most sensitive marker for detecting patients with disseminated disease and 5-HIAA displayed the highest sensitivity in identifying syndromic patients. Tumor marker modifications were studied during follow-up. In particular, rises in CgA were associated with progressive disease in 83.3% of cases and stable CgA was associated with stable disease in 53.8% of cases. The relation between CgA modifications and liver lesions during follow-up also was studied; increases in CgA levels were associated with local progression in 100% of cases and stable marker levels were found in 68.7% of the patients with unchanged lesions. CONCLUSIONS: The results of the current study demonstrate that CgA has the highest accuracy and is the most reliable biomarker reflecting the clinical evolution of NETs.
A new method for the rapid determination of neuron-specific gamma-enolase (NSE), gamma-subunit of alpha gamma- and gamma gamma-enolase in human serum was developed by employing monoclonal antibodies for the separation method. The assay system consists of 0.1 ml Sepharose 4B column with immobilized rabbit anti-mouse IgG antibodies for the separation of bound label, Fab' fragments of rabbit anti-bovine gamma gamma-enolase IgG labeled with beta-D-galactosidase from Escherichia coli, and F(ab')2 fragments of two mouse monoclonal antibodies to gamma gamma-enolase. Serum samples or standard NSE solutions were incubated at 30 degrees C with the monoclonal antibody fragments. 10 min later, the galactosidase-labeled antibody fragments were added to the mixture, and incubated at 30 degrees C for 30 min. Then the reaction mixture was applied to a micro-column of Sepharose 4B with immobilized anti-mouse IgG antibodies. From the galactosidase activity bound in the column, NSE concentration in the samples could be estimated within 2 h. The minimum detection limit of the assay system was 30 pg/tube, being sufficiently sensitive for the assay of serum NSE with a satisfactory precision. Serum concentrations of NSE determined by the present method correlated well with that by the colorimetric solid-phase immunoassay method.
Serum concentrations of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and CA-50 antigen were determined in 168 consecutive patients with lung cancer. All three markers were significantly elevated compared with levels in 102 patients with non-malignant chest diseases. NSE and CEA varied significantly across histological lung cancer types, with most highly elevated serum levels in small cell lung cancer and adenocarcinomas, respectively. The overall diagnostic accuracy was 0.66 for NSE, 0.74 for CEA, and 0.62 for CA-50, implying that CEA best discriminated between lung cancer and benign chest diseases, while CA-50 was less efficient as a diagnostic marker. In multivariate analysis of the three markers combined, a positive predictive value of 95% for lung cancer could be achieved with a diagnostic sensitivity of 57%, with a cut-off level defined as 0.037.NSE + 0.052.CEA + 0.011.CA-50 > 1. In 22% of the cancer patients, the time from admission to histological or cytological lung cancer diagnosis exceeded 1 month. In 52% of these patients, the initial weighted tumour marker index was > 1, strongly implying the cancer diagnosis. The study lends support to the potential use of combined analysis of NSE, CEA and CA-50 as a complementary tool in the diagnosis of lung cancer.
Pretreatment serum levels of neurone specific enolase (NSE) were measured in patients with small cell lung cancer (SCLC). Median values were significantly higher in patients with extensive compared with limited stage disease (48 ng ml-1 v. 17 ng ml-1: P less than 0.001). Serial NSE levels paralleled the clinical response to treatment. In 37 patients with limited SCLC, receiving identical chemotherapy, the pretreatment NSE level was of prognostic significance: with an approximate reduction in median survival of 10% for each 5 ng ml-1 incremental rise in NSE (P = 0.004).