The Read clinical classification.
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Disease↗
Biomedical subjects
J Chisholm
Publications and source records attributed to J Chisholm.
cis-acting negative regulatory element of prolactin gene.
The prolactin (PRL) gene in clonal strains of rat pituitary tumor cells in culture (GH cells) exhibit several regulatory responses, similar to the ones observed in rat pituitary gland. A comparative analysis of regulation of PRL gene expression in PRL-producing (PRL+) and PRL-nonproducing (PRL-) GH cells was conducted by monitoring the PRL promoter driven transient expression of chloramphenicol acetyltransferase (CAT) gene in GH4C1 (PRL+) and GH12C1 (PRL-) cells. The PRL promoter activity was drastically inhibited only in PRL-nonproducing cells (PRL-) and not in PRL producing cells (PRL+) when a 80-base pair (bp) DNA sequence from 5'-flanking region of PRL gene (located between -330 and -250 bp) was included in the PRL-CAT fusion gene constructs. Furthermore, a DNA/protein interaction involving this 80-bp DNA sequence and a 60-kDa nuclear protein was detected only in PRL- cells but not in PRL+ GH cells. These results suggested that the strain-specific suppression of PRL gene in PRL-, GH12C1 cells was mediated via interaction of a cis-acting negative regulatory element with a negative regulatory trans-acting factor in these cells. The negative regulatory element within the AT-rich 80-bp DNA sequence was mapped immediately adjacent to the site of interaction of trans-activators of PRL gene.
Animals↗
Suppression of prolactin gene expression in GH cells correlates with site-specific DNA methylation.
Prolactin- (PRL) producing and nonproducing subclones of the GH line of (rat) pituitary tumor cells have been compared to elucidate the regulatory mechanisms of PRL gene expression. Particular emphasis was placed on delineating the molecular basis of the suppressed state of the PRL gene in the prolactin-nonproducing (PRL-) GH subclone (GH(1)2C1). We examined six methylatable cytosine residues (5, -CCGG- and 1, -GCGC-) within the 30-kb region of the PRL gene in these subclones. This analysis revealed that -CCGG-sequences of the transcribed region, and specifically, one in the fourth exon of the PRL gene, were heavily methylated in the PRL-, GH(1)2C1 cells. Furthermore, the inhibition of PRL gene expression in GH(1)2C1 was reversed by short-term treatment of the cells with a sublethal concentration of azacytidine (AzaC), an inhibitor of DNA methylation. The reversion of PRL gene expression by AzaC was correlated with the concurrent demethylation of the same -CCGG- sequences in the transcribed region of PRL gene. An inverse correlation between PRL gene expression and the level of methylation of the internal -C- residues in the specific -CCGG-sequence of the transcribed region of the PRL gene was demonstrated. The DNase I sensitivity of these regions of the PRL gene in PRL+, PRL-, and AzaC-treated cells was also consistent with an inverse relationship between methylation state, a higher order of structural modification, and gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neplanocin A. Actions on S-adenosylhomocysteine hydrolase and on hormone synthesis by GH4C1 cells.
We have investigated the biochemical actions of Neplanocin A (Nepl A), a carbocyclic adenosine analog, on purified calf liver S-adenosylhomocysteine hydrolase and in the GH4C1 strain of functional rat pituitary cells. Addition of 1 mol of Nepl A/2 mol of S-adenosylhomocysteine hydrolase subunit led to rapid and complete inactivation. Concomitant with inactivation, half of the enzyme-bound NAD was reduced and adenine was released stoichiometrically from Nepl A. In GH4C1 cells Nepl A caused a dose-dependent rapid (within 5 min) and irreversible inactivation of S-adenosylhomocysteine hydrolase and concomitant increase in intracellular S-adenosylhomocysteine. In cells treated with Nepl A for 4-5 days, methylation of DNA cytosine was depressed approximately 50%, and the level of cytoplasmic prolactin mRNA was elevated 2-fold. While acute (30 min) release of prolactin from intracellular stores was unaffected, Nepl A acted in a dose- and time-dependent manner to increase the production of both prolactin and growth hormone, the two hormones synthesized and secreted by GH4C1 cells. The lowest effective dose was 0.12 microM, the concentration required to decrease S-adenosylhomocysteine hydrolase activity by 50%. By 4-7 days the production of both hormones in Nepl A-treated cells was increased 2-3 times above control. The action on hormone production persisted for at least 7 days after removal of Nepl A from the culture medium. We conclude that Nepl A inhibits S-adenosylhomocysteine hydrolase, raises cellular S-adenosylhomocysteine, decreases bulk DNA methylation, and increases hormone synthesis in GH4C1 cells.
Adenosine↗
Development of benzodiazepine binding subtypes in three regions of rat brain.
An examination of the development of benzodiazepine binding of the high and low affinity triazolopyridizine (TPZ) type was undertaken in rat cortex, hippocampus and cerebellum. Various concentrations of a typical triazolopyridizine, CL-218-872, were used to displace [3H]flunitrazepam from synaptosomal fractions from rats of postnatal ages day 0, 7, 14, 21, 35 and 70. In contrast to the cortex and cerebellum, hippocampus displays high affinity TPZ binding at birth, prior to the periods of dendritic elaboration and synaptogenesis, suggesting that adult proportions of high and low affinity sites are maintained throughout postnatal development. Delayed postnatal development of high affinity TPZ sites is observed in the cerebellum, similar to the postnatal development previously observed in the cortex.
Aging↗
Neural and behavioral consequences of prenatal exposure to diazepam.
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Animals↗
Synergistic effects of the combination of cis-platinum diamminodichloride and 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine in transplanted mouse leukemias.
cis-Platinum diamminodichloride has been studied in combination with 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine on an every-4-day schedule in various lines of mouse leukemia. This combination is synergistic in leukemias L1210 and P388 and sublines made resistant to 5-fluorouracil or methotrexate. There is no cross-resistance between cis-platinum diamminodichloride and 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine, but the combination is no more effective against lines of leukemia made resistant to cis-platinum diamminodichloride or to 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine than either single active compound alone. Since these compounds have no cross-resistance, act by quite different mechanisms of action, and have different limiting toxicity, the combination is now being evaluated clinically.
Ancitabine↗
Lack of cross-resistance between certain platinum coordination compounds in mouse leukemia.
Two congeners of cis-platinum diamminodichloride, 1,2-diamminocyclohexylplatinum malonate (NSC 224964) and 1,2-cyclohexyldiamminoplatinum sulfate (NSC 250427), show approximately equal inhibitory activity in vitro against leukemia L1210 and a line of L1210 (L1210/PDD) that has developed resistance to cis-platinum diamminodichloride. These compounds are also active against L1210/PDD in vivo. These observations suggest that they be tried clinically in patients whose disease has become resistant to cis-platinum diamminodichloride.
Animals↗
Melanotic neuroectodermal tumor of infancy: clinical, radiological, and pathological features.
We present a case of a 4-month-old female infant with a maxillary melanotic neuroectodermal tumor of infancy (MNTI) and review the pooled data from previous publications on this entity. The literature to date comprises 378 reported cases from 1918 to the present, from which data on the presence or absence of metastatic disease was available in 311, and on the presence or absence of local recurrence in 165. These pooled data suggest a local recurrence rate of 36% with metastasis occurring in 7% of cases. At present, the optimal management includes complete surgical excision with clear margins, but there are no reliable histopathological or molecular features to predict the biological behavior in individual cases.
Antigens, Neoplasm↗
Primary thoracic myxoid variant of extrarenal rhabdoid tumor in childhood.
Primary extrarenal rhabdoid tumors (RT) are now recognized as a specific entity in pediatric oncological pathology practice. We present an unusual case of a small cell myxoid variant of a thoracic RT in an infant and highlight the importance of recent molecular developments in the diagnosis of these tumors. An 8-month-old child presented with a short history of cough and shortness of breath. Imaging demonstrated a large mass occupying the majority of the thoracic cavity on the right side. A percutaneous needle biopsy of the mass showed fragments of tissue composed of malignant tumor with a predominant "small ovoid cell" phenotype and extensive myxoid change, with small nests and islands of tumor cells; occasional cells demonstrated open vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasmic inclusions. Immunohistochemical staining revealed focal strong cytoplasmic positivity for cytokeratin, focal strong paranuclear cytoplasmic vimentin positivity, and INI1 staining showed normal nuclear positivity in control tissues but was negative in tumor cell nuclei. Electron microscopy demonstrated characteristic paranuclear whorls of intermediate filaments confirming the diagnosis of extrarenal malignant RT. The diagnosis of malignant rhabdoid tumor may be difficult, particularly in cases, such as the present, with a predominant small-cell myxoid phenotype. The characteristic expression patterns of cytokeratin and vimentin provide strong clues to the diagnosis, and the use of INI1 antibody now makes definitive diagnosis possible even on needle core biopsies.
Cell Nucleolus↗
Developmental hyperthermic seizures alter adult hippocampal benzodiazepine binding and morphology.
Experimental hyperthermic seizures in 15-day-old rats resulted in both an alteration in the benzodiazepine (BDZ) binding site in the hippocampal region and morphologic changes in hippocampal neurons. These alterations were not apparent until adulthood. Experimental adult animals also showed a reduced anticonvulsant response to a selective BDZ ligand when challenged with pentylenetetrazol. Developmental hyperthermic seizures may initiate dynamic changes in the hippocampus that contribute to adult functional impairment.
Animals↗