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:1.14.16.2 (tyrosine hydroxylase)
14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of angiogenesis has been shown to reduce tumor growth, metastasis, and tumor microvascular density in experimental models. To these effects we would now like to add induction of differentiation, based on biological analysis of xenografted human neuroblastoma (SH-SY5Y, WAG rnu/rnu) treated with the angiogenesis inhibitor TNP-470. Treatment with TNP-470 (10 mg/kg s.c., n = 15) reduced the tumor growth by 66% and stereological vascular parameters (Lv, Vv, Sv) by 36-45%. The tumor cell apoptotic fraction increased more than threefold, resulting in a decrease in viable tumor cells by 33%. In contrast, the mean vascular diameter (29 microm) and the mean tumor cell proliferative index (49%) were unaffected. TNP-470-treated tumors exhibited striking chromaffin differentiation of neuroblastoma cells, observed as increased expression of insulin-like growth factor II gene (+88%), tyrosine hydroxylase (+96%), chromogranin A, and cellular processes. Statistical analysis revealed an inverse correlation between differentiation and angiogenesis. It is suggested that by inhibiting angiogenesis, TNP-470 induces metabolic stress, resulting in chromaffin differentiation and apoptosis in neuroblastoma. Such agonal differentiation may be the link between angiostatic therapy and tumor cell apoptosis.
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PMID:Inhibition of angiogenesis induces chromaffin differentiation and apoptosis in neuroblastoma. 1002 98

The chromogranin family comprises chromogranin A and B, and secretogranin II. The present study has focused on the axonal transport of chromogranins/secretogranin II and their detailed distribution in peripheral nerves and the spinal cord. With radioimmunoassay (RIA) and column chromatography, we first studied the processing of chromogranin B and secretogranin II during axonal transport. No larger precursors of these peptides were detected in the sciatic nerves, indicating that they are already processed to a high degree early during axonal transport. We also analysed nerve segments above and below a crush, using RIA, in order to compare these accumulation data with those obtained by the cytofluorimetric-scanning (CFS) technique. For the latter technique, the amounts of accumulation distal to the crush (presumably representing recycling and retrogradely transported peptides) were 30-40% of the amounts in the proximal accumulation for chromogranin A and secretoneurin, in contrast to chromogranin B, which showed 15% recycling. With the RIA, the corresponding values for secretoneurin and PE-11 (antibody against chromogranin B) were 42% and 14%, respectively. Therefore, the data obtained by CFS were in excellent agreement with those obtained by RIA. In crushed sciatic nerves, chromogranin A was present in large axons as well as in small- and medium-sized axons. Chromogranin B was mainly restricted to large axons, while secretoneurin was localized to bundles of small axons. This differential distribution was also found in the spinal roots and in the peripheral terminals. Chromogranin A was present in both ventral and dorsal roots, and chromogranin B was detected in ventral roots and in large sensory axons in the dorsal roots. Secretoneurin was dominant in the dorsal root. Double-labelling studies with antibodies against choline acetyltransferase/vesicular acetylcholine transporter, or against tyrosine hydroxylase, confirmed that chromogranin A was distributed in cholinergic, sensory, as well as adrenergic neurons. Chromogranin B was mainly present in cholinergic motor neurons and large sensory neurons, and secretoneurin was restricted to adrenergic and sensory neurons. The present study demonstrates that chromogranins A and B, and secretoneurin are transported with fast axonal transport in the peripheral nerves, with different amounts of recycling, and that they are differentially distributed in different types of neurons in the peripheral nervous system and the spinal cord, suggesting that each of them may play a special role in subsets of neurons.
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PMID:Proteolytic processing, axonal transport and differential distribution of chromogranins A and B, and secretogranin II (secretoneurin) in rat sciatic nerve and spinal cord. 1005 53

Carney complex (CNC) is characterized by lentiginosis and myxomatosis together with a variety of endocrine, neural crest-derived, and other tumors, including primary pigmented nodular adrenocortical disease (PPNAD). PPNAD is characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors, including the myxomas and PPNAD, are unclear. In this study, seven paraffin-embedded PPNAD tumors, one skin myxoma, and two cell lines (one myxoma and one PPNAD) established from patients with CNC were stained with antisera for synaptophysin (SYN), neuron-specific enolase, chromogranin A, tyrosine hydroxylase, and the neural cell adhesion molecule (NCAM). In addition, one PPNAD specimen and one myxoma were analyzed by electron microscopy. The results showed that chromogranin A and tyrosine hydroxylase stained adrenomedullary tissue, but not the PPNAD nodules or the extranodular adrenal cortex. SYN, neuron-specific enolase, and NCAM also stained the medulla. PPNAD nodules and the PPNAD cell line, but not the extranodular adrenal cortex, stained intensely for SYN. The myxoma cell line, but not normal fibroblasts, stained for SYN and NCAM. Ultrastructural analysis of a PPNAD tumor and a skin myxoma revealed a well developed rough endoplasmic reticulum, prominent mitochondria, and vesicle-like structures dispersed throughout the cytoplasm. We conclude that immunostaining for SYN, a marker protein for neuroendocrine cells, clearly distinguishes PPNAD nodules from surrounding adrenocortical tissue and can be helpful in the detection of small nodules in apparently unaffected cortex. The cells of a cutaneous myxoma were also stained positive by two of the three neuroendocrine markers. Finally, both PPNAD and myxoma cells demonstrated ultrastructural features suggestive of neuroendocrine properties. These results support the previously suggested hypothesis that the genetic mechanism leading to CNC involves genes with a neuroendocrine role.
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PMID:Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex. 1008 5

Neuroblastoma is a malignant solid tumor of childhood with a poor prognosis. The growth of solid tumors has been shown to be dependent on new blood vessel formation, i.e. angiogenesis. Several steps in the metastatic process have also been found to be angiogenesis-dependent. Neuroblastomas grow quickly, are highly vascularized, and metastasize early, and hence inhibition of angiogenesis--angiostatic therapy--may be indicated in this disease. In order to investigate the effects of angiostatic agents in this disease, a new animal experimental model for human neuroblastoma was developed. Three angiostatic agents were tested in the model: TNP-470, the synthetic analogue of fumagillin, given subcutaneously, and the endogenous steroid 2-methoxyestradiol and its derivative 2-propynylestradiol, given orally. TNP-470 administration resulted in a significant reduction of the tumor growth rate and microvascular counts, and of the fraction of viable tumor cells, compared to controls. The fraction of apoptotic tumor cells increased threefold, while that of proliferative cells remained unaltered. This can explain the reduced net growth. Treatment with the angiostatic and chemotherapeutic steroids 2-methoxyestradiol and 2-propynylestradiol yielded similar results. However, the mechanism of action of these steroids was bimodal; the effect occurring both through inhibition of tumor angiogenesis and through induction of tumor cell apoptosis. It was shown for the first time that inhibition of angiogenesis regardless of agent induces striking chromaffin differentiation, observed as increased expression of insulin-like growth factor II gene, tyrosine hydroxylase, and chromogranin A, and increased formation of cellular processes. It is suggested that inhibition of angiogenesis induces metabolic stress, resulting in chromaffin differentiation and apoptosis. Such agonal differentiation may be the link between angiostatic therapy and tumor cell apoptosis. Angiostatic agents administered as single therapy have an objective tumoristatic effect in our neuroblastoma model. Angiostatic treatment of neuroblastoma is a new and promising treatment modality that merits clinical investigation.
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PMID:Angiostatic treatment of neuroblastoma. 1037 67

Because few previous studies have shown the immunohistochemical localization of tryptophan 5-hydroxylase (TPH) in the gastrointestinal tract, we developed a specific antibody against TPH purified from mouse mastocytoma P-815 and stained human and rat gastrointestinal tracts. The specificity of the antibody was examined by Western blotting and by immunohistochemistry in brain sections. Human ileum and colon specimens, rat stomach, duodenum, jejunum, ileum and colon specimens, with and without colchicine treatment were prepared for immunohistochemistry. Immunoelectron microscopic double staining of TPH and serotonin/chromogranin A and immunofluorescence double staining of TPH and serotonin were performed to identify the cell types. Epithelial enterochromaffin (EC) cells, mast cells in the lamina propria and submucosa, and varicose fibers in the submucosa and muscle layer showed positive immunoreactivity in all segments examined from human and normal rat specimens. In colchicine-treated rat specimens, nerve cell bodies in the myenteric plexus were stained. Because the antibody does not cross react with tyrosine hydroxylase as defined in Western blotting or brain sections, these positive structures may contain TPH. The present results show evidence that EC cells, mast cells, and nerve cell bodies and fibers in the gastrointestinal tracts of both the human and the rat contain TPH and therefore may have the ability to synthesize serotonin from tryptophan.
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PMID:Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts. 1042 74

A case of an unusual spinal neuronal tumor is described in a 36-year-old woman presenting with a buttock pain. The spinal tumor was fully characterized by neuroradiological means, and in particular MRI was of significant value in delineating the extension of the tumor within the spinal canal and its exophitic growth pattern. Pathologically, a well circumscribed tumor originating from the intradural filum terminale characteristically comprised both large and small cells, resembling mature and immature neuronal cells, respectively. In addition, two neuronal markers, i.e., chromogranin A (CGA) and neuron-specific enolase (NSE), and other markers such as glial fibrilary acidic protein (GFAP), S-100 protein, HNK-1, tyrosine hydroxylase and beta 2-microgloblin were investigated immunohistochemically. We found that both neuronal cells expressed immunoreactivity for CGA and NSE, and small neuronal cells showed more intense CGA immunoreactivity, indicating an earlier stage of neuronal differentiation. Weakly positive immunoreactivity for HNK-1 was also demonstrated in small neuronal cells, consistent with evidence of maturation along a neuronal differentiation. From these findings a pathological diagnosis of ganglioneuroma was made. This unique group of ganglion-cell spinal tumors is reviewed in the literature and differential diagnosis and immunohistochemical features are discussed.
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PMID:Ganglion-cell tumor of the filum terminale: immunohistochemical characterization. 1058 16

Synaptosomal-associated protein of 25 kDa (SNAP-25) is one of a limited number of soluble N-ethylmaleimide-sensitive fusion attachment protein receptors (SNAREs) that play a major role in membrane docking of synaptic vesicles and secretory granules during regulated exocytosis. We have previously shown that SNAP-25 levels differ between noradrenergic and adrenergic chromaffin cell populations of the adult adrenal gland. We examine SNAP-25 expression by immunofluoresence in cells of the sympathoadrenal lineage in the rat during late embryonic and postnatal development. In parallel, tyrosine hydroxylase was used to identify sympathoadrenal cells, phenylethanolamine N-methyltransferase to distinguish adrenergic from noradrenergic chromaffin cells, and chromogranin A to define the presence of secretory granules. In addition, SNAP-25 protein and mRNA levels were followed in adrenal gland extracts by immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR). Protein levels were compared with those of other molecules also implicated in organelle trafficking, including syntaxin 1 and vesicle-associated membrane protein (VAMP-2) and the nonneuronal analogues SNAP-23 and cellubrevin. This study provides evidence that SNAP-25 is expressed early during development in sympathoadrenal neurons and migrating cells. It is detected in intra-adrenal chromoblasts as soon as they enter the adrenal primordium. Its differential expression between catecholamine chromaffin cell phenotypes is already evident from the 17th embryonic day, future noradrenergic cells appearing to express higher levels than adrenergic cells. The granule maturation marker chromogranin A is expressed in chromaffin cells later than SNAP-25. Both SNAP-25 protein and mRNA increased rapidly in the adrenal gland in the perinatal period to peak during the first postnatal week, after which levels dropped dramatically to adult values. In contrast, levels of both syntaxin and SNAP-23 appeared to remain fairly constant throughout adrenal gland development. VAMP-2 expression increased gradually around birth to reach maximal levels during the first two postnatal weeks, and then decreased slightly. Cellubrevin levels also appeared to increase gradually until adult values were attained by the end of the second postnatal week. The threefold increase of SNAP-25 mRNA shortly after birth compared to the low adult levels suggests that during this period SNAP-25 is implicated in additional functions than regulated secretion, possibly associated with cellular growth or maturation.
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PMID:SNAP-25 regulation during adrenal gland development: comparison with differentiation markers and other SNAREs. 1084 12

Solid-pseudopapillary tumor of the pancreas (SPT) has distinctive morphologic and biologic features but an unclear origin. It is classified among the pancreatic epithelial tumors, though many are reported to be negative for cytokeratin. Also unclear are its neuroendocrine differentiation, its capability to express alpha-1-antitrypsin (AAT) and, in view of the tumor's striking prevalence in women, its relationship with the female genital tract. To clarify these issues, the immunoprofiles of 59 SPTs were defined by applying a battery of antibodies against cytokeratin, vimentin, neuron-specific enolase (NSE), synaptophysin, chromogranin A, tyrosine hydroxylase (TH), AAT, LeuM1, Ki-M1P, smooth-muscle actin, CD34, alpha-inhibin, calretinin, placental alkaline phosphatase (PLAP), and progesterone and estrogen receptors. The most consistent markers with the strongest immunoreactivity were vimentin, AAT, NSE, and the progesterone receptor, which were each found in more than 90% of the tumors. Using immunocytochemical methods involving antigen retrieval, cytokeratin was demonstrated in almost 70% of the cases. Synaptophysin was found in 22% of the tumors, while chromogranin was absent and tyrosine hydroxylase was only present in a few tumors. None of the other markers tested were expressed by SPTs. This staining pattern fails to reveal a clear phenotypic relationship with any of the defined cell lineages of the pancreas. In view of the striking female preponderance of SPTs and the known close approximation of the genital ridges to the pancreatic anlage during embryogenesis, it is, however, hypothesized that SPTs might derive from genital ridge/ovarian anlage-related cells, which were attached to the pancreatic tissue during early embryogenesis.
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PMID:Solid-pseudopapillary tumor of the pancreas: its origin revisited. 1088 41

With the aid of IGF2 and VEGF in situ hybridization; tyrosine hydroxylase, chromogranin A, and Ki67 immunohistochemistry; and TUNEL staining applied to a large series of clinical neuroblastomas and to an animal model, we show here that stroma-poor neuroblastomas show evidence of chromaffin differentiation similar to that of type 1 small intensely fluorescent (SIF) cells and that this occurs in a vascular-dependent fashion, indicating a role for local tumor hypoxia in the differentiation process.
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PMID:Evidence of chromaffin oxygen sensing in neuroblastoma. 1146 71

Specific and sensitive tumor cell detection is becoming increasingly important for diagnosing and staging as well as for the therapeutic management of neuroblastoma patients. We propose a chromogranin A heminested reverse transcription polymerase chain reaction (CgA hn RT-PCR) procedure for the detection of neuroblastoma minimal residual disease in peripheral blood and bone marrow samples. The results were checked in comparison with the presently available procedures (i.e., with the tyrosine hydroxylase nested RT-PCR [TH n RT-PCR] and with the immunocytochemical approach using anti-GD2 antibodies). Controls from healthy patients or from people with unrelated disease (12 samples of bone marrow and 23 samples of peripheral blood) and serial dilution experiments using neuroblastoma cell lines (SKNLP, SKNFI, STA6, STA8) showed CgA hn RT-PCR full specificity and sensitivity ranging from 10(3) to 10(6) (depending on the cell line). The results compared favorably with those obtained using TH n RT-PCR. Preliminary data obtained analyzing bone marrow and peripheral blood specimens from stage IV neuroblastomas showed substantially overlapping results between CgA and TH n RT-PCR procedures. Our data support the potential usefulness of CgA heminested RT-PCR as a specific and sensitive procedure for minimal disease detection in neuroblastoma. A prospective evaluation of this tool in clinical studies might be warranted.
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PMID:Detection procedures for neuroblastoma cells metastatic to blood and bone marrow: blinded comparison of chromogranin A heminested reverse transcription polymerase chain reaction to tyrosine hydroxylase nested reverse transcription polymerase chain reaction and to anti-GD2 immunocytology. 1204 13


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