Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plexiform layer synaptic and photoreceptor cell components were investigated in retinas of Royal College of Surgeons (RCS) dystrophic rats transplanted with normal retinal pigment epithelial (RPE) cells by immunocytochemistry using previously characterized monoclonal antibodies. In retinas of normal adult rats and RPE-cell transplanted retinas of 4 month-old RCS rats, HNK-1, a marker for a carbohydrate of the neural cell adhesion molecule (N-CAM), was detected immunocytochemically in the inner and outer plexiform layers and ganglion cell bodies and their axons. HNK-1 was also detected in the inner plexiform layer of nontreated retinas of 4 month-old RCS rats, but was reduced to scattered patches in the outer plexiform layer. In addition, immunoreactivity for the SVP-38 antibody recognizing synaptophysin was found in both plexiform layers of normal adult rat retinas and RPE-transplanted retinas of 4 month-old RCS rats. Furthermore, photoreceptor cell bodies and their inner and outer segments were immunostained for the opsin monoclonal antibody RET-P1 in retinas of normal adult rats and RPE-cell transplanted retinas of 4 month-old RCS rats. However, in nontreated retinas of 4-month-old RCS rats, only immunostained debris material was detected. These results strongly suggest that normal RPE transplants not only rescue photoreceptor cells in RCS rats, but also maintain an essential functional capacity, in this case, synaptic components in the plexiform layers.
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PMID:Synaptic and photoreceptor components in retinal pigment epithelial cell transplanted retinas of Royal College of Surgeons dystrophic rats. 750 40

Synaptophysin and synaptobrevin, two integral proteins of synaptic vesicles, have been used as immunocytochemical markers of the synaptic vesicle membrane during Cd(2+)- or K(+)-induced ACH release at the frog neuromuscular junction. ACh release was stimulated in cutaneous pectoris nerve-muscle preparations by: (1) 1 mM Cd2+ in Ca(2+)-free medium for a period of 3 h, (2) 25 or 40 mM K+ in normal Ringer's solution. Synaptophysin and synaptobrevin were immunolabelled in single fibres teased from fixed muscles using rabbit antisera raised against synaptophysin and synaptobrevin revealed with fluorescein-conjugated IgG. The postsynaptic ACh receptors were simultaneously labelled with rhodaminated alpha-bungarotoxin. Unstimulated and K(+)-stimulated preparations showed synaptophysin and synaptobrevin immunolabelling only after membrane permeabilization with 0.1% Triton X-100. In preparations stimulated with Cd2+ in Ca(2+)-free medium, the immunofluorescence was also observed in non Triton X-100 treated muscle fibres. Confocal laser scanning microscopy analysis revealed that in unstimulated and K(+)-stimulated preparations, synaptophysin and synaptobrevin immunofluorescence appears as bands regularly spaced along the permeabilized nerve terminals and that their distribution corresponds to clusters of synaptic vesicles. After Cd2+ stimulation in Ca(2+)-free medium, labelling for both proteins is irregularly distributed, being more intense at the lateral margins of swollen nerve terminals, suggesting a translocation of synaptic vesicle proteins to the axolemma. At the electron microscopic level, Cd2+ stimulation in Ca(2+)-free medium produces nerve terminal swelling and synaptic vesicle depletion. The results show that when ACh release is stimulated under an impairment of synaptic vesicle recycling, which leads to synaptic vesicle depletion, synaptophysin and synaptobrevin translocation occurs. These findings are in favour of a permanent incorporation of synaptic vesicle membrane into the axolemma. In contrast, after K+ stimulation, the immunofluorescence and the normal synaptic vesicle population observed, suggest that a double process of synaptic vesicle exo-endocytosis rapidly occurs, without incorporation of synaptic vesicle components into the axolemma.
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PMID:Cd(2+)-and K(+)-evoked ACh release induce different synaptophysin and synaptobrevin immunolabelling at the frog neuromuscular junction. 759 64

Several studies have suggested that biochemical or molecular markers examined in non-small cell lung cancer carry prognostic or treatment response information. Non-small cell lung cancer patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of HER2 (c-erbB-2), a membrane-bound receptor with tyrosine kinase activity, has been associated with shortened survival. The Cancer and Leukemia Group B (CALGB) performed a study of patients with stage IIIA (N2 nodes positive) non-small cell lung cancer in which patients received initial chemotherapy followed by surgery, then post-operative therapy consisting of sequential chemotherapy and radiation therapy. Since all patients underwent mediastinoscopy, this provided an opportunity to compare pre- and post-chemotherapy tumor specimens to test the hypothesis that these proteins would predict treatment response. In particular, we hypothesized that the post-chemotherapy specimens would be enriched for NE marker negative cells because of the increased sensitivity of NE positive cells to chemotherapy. We performed immunohistochemical analysis for a panel of NE markers [neuron-specific enolase (NSE), Leu-7, chromogranin A (ChrA), synaptophysin (Syn)], HER2 and CEA to determine if there was an effect of therapy on the percentage of cells expressing these markers. Secondary endpoints were a correlation with chemotherapy response and survival. Slides were scored for intensity (0-4) and percentage of cells positive (0-4). Of 61 eligible patients, there were 38 with both pre- and post-chemotherapy specimens. When both intensity of staining and percentage of positive cells were considered, post-chemotherapy specimens had a higher percentage of positive NE markers compared with pre-chemotherapy. In addition, there was no correlation between NE marker, HER2 or CEA expression (prior to or post treatment) and response to chemotherapy or survival. These data do not support the hypothesis that NE positive tumor cells are preferentially killed by chemotherapy in patients with stage IIIA non-small cell lung cancer.
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PMID:Analysis of neuroendocrine markers, HER2 and CEA before and after chemotherapy in patients with stage IIIA non-small cell lung cancer: a Cancer and Leukemia Group B study. 985 98

Norepinephrine (NE) transporters (NETs) constitute the primary mechanism for inactivation of synaptically released NE, are targets for multiple antidepressants and psychostimulants, and have been reported to be deficient in affective and autonomic disorders. Although the regional distribution of NETs has been defined through synaptosomal transport and autoradiographic approaches, NET protein expression has yet to be characterized fully in the central nervous system (CNS). We identified a cytoplasmic NET epitope (amino acids 585-602) and corresponding antibody (43411) that permits cellular localization of endogenous NET expression in the CNS and periphery. In the adult rat brain, NET labeling was confined to noradrenergic neuronal somata, axons, and dendrites, including extensive arborizations within the hippocampus and cortex, but was absent from epinephrine- and dopamine-containing neurons. Intracerebroventricular anti-dopamine beta-hydroxylase/saporin, a treatment that destroys a majority of noradrenergic neurons and their projections, validated the specificity of the 43411 antibody. At the level of light microscopy, 43411 labeling colocalized with the axonal markers syntaxin, synaptophysin, and SNAP-25. Indirect immunofluorescence revealed a nonuniform pattern of NET expression along axons, particularly evident within sympathetic fibers of the vas deferens, reflecting a high degree of spatial organization of NE clearance. NET labeling in somata was intracellular and absent from plasma membranes. Among nonneuronal cells, glial cells lacked NET immunoreactivity, whereas CNS ependymal cells were an unexpected site of labeling. NET immunoreactivity was also evident in a subset of adrenal chromaffin cells where labeling appeared to be predominantly associated with intracellular vesicles. Initial ultrastructural evaluation via preembedding immunogold techniques also revealed substantial cytoplasmic NET immunoreactivity in axon terminals within the prelimbic prefrontal cortex, consistent with postulates of regulated trafficking controlling neurotransmitter clearance. NET visualization should be of significant benefit in evaluating neuronal injury resulting from chronic drug exposure and in disease states.
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PMID:Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter. 1075 8

Small cell carcinoma of the breast is an uncommon neoplasm that has been reported rarely in the literature. The aim of this study was to characterize better the pathologic and immunohistochemical features of this neoplasm. Nine examples of mammary small cell carcinoma were retrieved from the authors' consultation files and reviewed. The patients ranged in age from 43 to 70 years. Two patients had a previous history of cutaneous malignant melanoma and one had prior lobular carcinoma in situ and atypical duct hyperplasia in the same breast as the small cell carcinoma. Eight patients presented with a mass in the breast; one patient had an axillary tumor. Tumor size ranged from 1.3 to 5.0 cm (mean, 2.6 cm). Histologically, the nine tumors had characteristics of small cell carcinoma with high mitotic activity and necrosis. A dimorphic histologic appearance was observed in four tumors. In one instance, this consisted of small cell carcinoma merging with invasive lobular carcinoma. In three cases, small cell carcinoma was present together with invasive, poorly differentiated duct carcinoma; invasive carcinoma with "lobular and gland-forming elements"; and focal squamous differentiation, respectively. Lymphatic tumor emboli were identified in four instances. An in situ component was seen in seven tumors; five were of the small cell type in ducts and two were of the ductal type with high nuclear grade. Immunohistochemical analysis showed consistent staining for cytokeratin markers but variable staining with neuroendocrine markers. Sixty-six percent of the tumors (six of nine) were reactive for chromogranin, synaptophysin, or peptide hormones, including four positive for chromogranin and synaptophysin, one positive for synaptophysin and calcitonin, and one positive for calcitonin alone. One tumor that was reactive for chromogranin and synaptophysin also contained calcitonin immunoreactive cells, whereas gastrin-releasing peptide was present in two other tumors that were also positive for chromogranin. Leu 7 was positive in three cases that were reactive for either chromogranin or synaptophysin. Five tumors were estrogen and progesterone receptor-positive. All tumors were positive for bcl-2 and negative for HER2/neu. Patients were treated by mastectomy (n = 3) or lumpectomy (n = 6). Eight underwent an axillary dissection that revealed metastatic carcinoma in four patients. Seven patients received adjuvant chemotherapy and four patients received radiation. Two patients also received tamoxifen treatment. Metastases developed in two patients (22%) with a follow-up period of 11 and 32 months. All patients were alive at last follow up 3 to 35 months after treatment. When compared with published reports of mammary small cell carcinoma, our results show that the prognosis in these patients may not be as poor as previously suggested.
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PMID:Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. 1139 67

Several studies have suggested that non-small cell lung cancer (NSCLC) patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of p53 and HER2 may confer relative chemotherapy resistance and shortened survival. The Cancer and Leukemia Group B performed a series of studies involving sequential chemotherapy followed by radiation for patients with unresectable stage III NSCLC. The objectives of this study were to analyze pathological specimens using immunohistochemistry for NE markers, p53 and HER2 to determine if there was a correlation between marker expression and response or survival. Of 160 eligible patients, 28 (18%) were not evaluable because of inadequate material. The percentage of specimens positive for markers was as follows: neuron-specific enolase 38%, Leu-7 2%, chromogranin A 0%, synaptophysin 5%, > or =2+NE markers 3%, p53 61%, and HER2 65%. There was no statistically significant correlation between any individual marker and response to induction chemotherapy or response to combined chemotherapy/radiation except for synaptophysin. Six of 6 (100%) synaptophysin positive tumors responded by the completion of all therapy compared with 69/125 (55%) synaptophysin negative tumors (P=0.04). None of the individual markers had a significant effect on survival in univariate analysis. Neuron-specific enolase was marginally significant in multivariate analysis (P=0.08). In conclusion, this study did not demonstrate that expression of NE markers, p53 and HER2 were predictive of response to chemotherapy, combined chemotherapy/radiation or for survival in this group of patients with stage III NSCLC. Future studies must employ either different markers or be performed on more adequate surgical specimens.
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PMID:Use of neuroendocrine markers, p53, and HER2 to predict response to chemotherapy in patients with stage III non-small cell lung cancer: a Cancer and Leukemia Group B study. 1155 6

Glomus tumors usually occur in the peripheral soft tissues, but similar tumors have also been reported in the stomach and occasionally in the intestines. However, the relationship of these tumors to peripheral glomus tumors and gastrointestinal stromal tumors has not been fully clarified because previous series of gastrointestinal glomus tumors predate availability of immunohistochemistry. This clinicopathologic study examined 32 gastrointestinal glomus tumors. All but one of the tumors were located in the stomach and the remaining tumor was from the cecum. The tumors occurred with a strong female predominance (23 females and 9 males) and a median age of 55 years (range 19-90 years). The gastric tumors typically presented with gastrointestinal bleeding or ulcer-like symptoms, and 14 tumors had mucosal ulceration. Five tumors were incidental findings. The tumor sizes varied from 1.1 to 7 cm (median 2 cm), and most were located in the antrum. Histologically, the tumors typically had a solid pattern of sharply demarcated, round glomus cells with prominent, mildly dilated pericytoma-like vessels. Vascular invasion and focal atypia were relatively common (seen in 11 and 13 cases, respectively), and low mitotic activity (1-4 per 50 high power fields), was seen in 10 cases. Immunohistochemically, all tumors were positive for alpha-smooth muscle actin and calponin, and nearly all had a net-like pericellular laminin and collagen type IV positivity. All tumors were negative for desmin and S-100 protein. Three tumors had focal synaptophysin positivity, but none was positive for chromogranin. All tumors lacked KIT expression and the GIST-specific mutations in the c-kit gene. Follow-up revealed one patient death of metastatic disease to liver at 50 months; this tumor had 1 mitosis per 50 high power fields, but had spindle cell foci, mild atypia, and vascular invasion. Thirteen patients were well and alive after long-term follow-up. Gastrointestinal glomus tumors occur almost exclusively in the stomach, and they have a good overall prognosis, but a small, unpredictable potential for malignant behavior exists. These tumors are phenotypically similar to peripheral glomus tumors and differ from epithelioid GISTs.
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PMID:Gastrointestinal glomus tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 32 cases. 1185 1

Metastasized neuroendocrine tumors of the gastrointestinal tract and of unknown origin show a highly variable clinical course. Within this group, low-grade and high-grade malignant tumors can be recognized based on the revised classification of neuroendocrine tumors of the lung, pancreas, and gut published by Capella et al in 1995. The present study investigated whether fine-tuning the prediction of prognosis was possible by dividing the group of low-grade malignant tumors of the midgut and of unknown origin into typical and atypical carcinoids by grading them according to the World Health Organization (WHO) classification criteria for neuroendocrine tumors of the lung. Moreover, the prognostic value of immunohistochemical stainings and clinical parameters was evaluated. The study group comprised patients diagnosed between 1983 and 1999 with liver metastases of a neuroendocrine tumor of the midgut n = 40) or of unknown origin (n = 16). As a control for the consistency of grading, 10 patients with metastasized neuroendocrine tumors of the lung also were evaluated. Immunohistochemical stainings for chromogranin A, synaptophysin, Leu 7/CD57, neural cell adhesion molecule/CD56, cytokeratin 8, bcl-2, p53, ki67, and HER2/neu were performed. The clinical parameters age, gender, urinary 5-HIAA level, and presence or absence of the carcinoid syndrome were evaluated. Tumors of the midgut and of unknown origin were evaluated together, because they were clinically similar. In this group of 56 patients, both the Capella and the WHO classification systems recognized the high-grade malignant tumors with a bad prognosis. When the low-grade malignant tumors (Capella) were divided into typical and atypical carcinoids (WHO), no difference in survival was observed, but when the dichotomy into typical and atypical was based on mitotic count alone, the difference became borderline significant (P =.072). Of the immunohistochemical stainings used, synaptophysin, cytokeratin 8, and ki67 had limited prognostic value. Age above 60 was the only clinical parameter of unfavorable prognostic significance. We conclude that high-grade malignant neuroendocrine tumors of the midgut and of unknown origin are recognized by both the Capella classification and the WHO classification of neuroendocrine tumors of the lung. Further subdividing low-grade malignant tumors at this location appears to be of less value than in the lung, but assessing the mitotic activity of these tumors might be of prognostic value.
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PMID:Classification of low-grade neuroendocrine tumors of midgut and unknown origin. 1245 18

B5 clearing is a step used before immunoperoxidase staining to remove the precipitated mercuric chloride deposits caused by B5 fixation of tissue. In the B5 clearing procedure, the slides are treated with Lugol's iodine and 5% sodium thiosulfate before antigen retrieval and the application of the primary antibody. The goal of this project was to study the effect of the B5 clearing protocol on immunoperoxidase staining on paraffin-embedded tissue, which has not been previously reported in a series of antibodies. We evaluated 75 antibodies using the 2-step clearing protocol and performed paired immunoperoxidase staining on the Ventana ES instrument, with and without the clearing protocol. We found that among 75 antibodies studied, 3 (CD5, CD30, and synaptophysin) showed total obliteration of reactivity, and 3 (ALK, Ulex, and GFAP) showed partial reduction of the staining compared with the controls. Pathologists must be aware of the possible false-negative staining effect caused by the routinely used B5 clearing protocol. Control tissues must receive the same clearing protocol (i.e., placed on case slides) to ensure detection of this effect.
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PMID:Removal of mercuric chloride deposits from B5-fixed tissue will affect the performance of immunoperoxidase staining of selected antibodies. 1261 Mar 63

The antidepressant-sensitive L-norepinephrine (NE) transporter (NET;SLC6A2) is a critical determinant of neurotransmitter inactivation following NE release at synapses. Although regulated trafficking of NET has been documented in transfected cells, a lack of reagents suitable for reporting native NET surface exposition has limited validation of this concept in neurons. In the current report, we document the utility of a novel antibody (43408) directed at conserved sequences in the NET second extracellular loop. Using human NET (hNET) stably transfected cells, we document loss of NET surface expression following acute (30 min) phorbol ester treatments. In superior cervical ganglion (SCG) cultures, NET surface expression is prominent on varicosities defined by FM1-43 labeling of living neurons or synaptophysin labeling of fixed preparations. Moreover, NET surface density can be rapidly augmented by brief depolarization (5 min, 40 mM K(+)). Similarly, in brainstem cultures, we demonstrate an increase in NET surface labeling following either depolarization or angiotensin II stimulation. These findings provide the first evidence for regulated trafficking of NET in neurons and support the suggestion that activity-dependent NET trafficking may provide additional modulatory capacity for noradrenergic signaling.
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PMID:Cell surface trafficking of the antidepressant-sensitive norepinephrine transporter revealed with an ectodomain antibody. 1469 74


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