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L L Parks

Publications and source records attributed to L L Parks.

4 recordsLinked to original sources
PubMed1998

An ACTH-producing small cell lung cancer expresses aberrant glucocorticoid receptor transcripts from a normal gene.

ACTH production by non-pituitary tumors is generally not suppressible by exogenous glucocorticoid administration. We had postulated that defects in the glucocorticoid receptor (GR) signaling system might be responsible for this apparent glucocorticoid resistance and had previously demonstrated that DMS-79 cells, derived from an ectopic ACTH-producing tumor, express an abnormal GR mRNA. In this DMS-79 cell GR the sequence normally derived from exons 8 and 9 is replaced by sequence unmatched in the DNA databases. The protein encoded by this mRNA lacks the steroid-binding domain and does not function as a ligand-activated transcription factor. In the present work, we sought to identify the origin of the novel GR mRNA sequence. Southern blot analysis of DMS-79 genomic DNA showed no major structural alteration of the GR gene. Southern blotting of cosmid clones of the normal GR gene revealed that the novel DMS-79 GR mRNA sequence is derived from intron G, between exons 7 and 8. No splice site mutations were found in PCR-amplified DMS-79 DNA fragments surrounding the downstream splice junctions. Further sequencing indicated that the aberrant GR transcript appears to be generated by use of a consensus cleavage/polyadenylation signal found 3650 base pairs into the normal intron G. We conclude that abnormal GR pre-mRNA processing rather than a GR gene mutation confers glucocorticoid resistance on DMS-79 cells.

Adrenocorticotropic Hormone↗
PubMed1998

Expression of 11beta-hydroxysteroid dehydrogenase type 2 in an ACTH-producing small cell lung cancer.

Non-pituitary tumors that produce adrenocorticotropic hormone (ACTH) exhibit resistance to the normal feedback effects of glucocorticoids on proopiomelanocortin (POMC) gene expression. This glucocorticoid resistance is typically complete, although some tumors show only relative glucocorticoid resistance in the clinical setting. The molecular mechanisms responsible for these clinical pathophysiologic observations are unknown, but might include glucocorticoid receptor defects or aberrant expression of enzymes or transporters that exclude glucocorticoids from access to their intracellular receptors. We examined whether ACTH-producing non-pituitary tumor cells might express 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the principal 'gatekeeper' enzyme known to metabolize glucocorticoids. 11Beta-HSD mRNA and enzyme activity were assessed in DMS-79 cells, a line derived from an ACTH-producing small cell lung cancer. RT-PCR studies showed expression of mRNA encoding 11beta-HSD2 but not 11beta-HSD1 in DMS-79 cells. Control human fibroblasts expressed predominantly 11beta-HSD1 but also had detectable 11beta-HSD2 mRNA, while HepG2 hepatoma cells also expressed only 11beta-HSD2 mRNA. Whole cell assays in DMS-79 cells revealed 11beta-HSD activity with a Km for cortisol of 26.1 +/- 9.0 nM and Vmax of 57.0 +/- 5.9 pmol/h/mg protein. HepG2 cells expressed a similar high affinity enzyme activity, while control fibroblasts expressed 11beta-HSD activity with a Km for cortisol of 652 nM. Conversion of cortisol to cortisone in DMS-79 cells was inhibited to 7% of baseline by addition of 10 microM glycyrrhetinic acid. Dexamethasone (20 nM) was converted to a single product in DMS-79 cells at a rate of 17.2 pmol/h/mg protein; this activity was also inhibited by glycyrrhetinic acid. We conclude that DMS-79 cells express 11beta-HSD2. While DMS-79 cells harbor additional defects in glucocorticoid signaling, these data suggest that expression of 11beta-HSD2 might contribute to the development of the glucocorticoid-resistant phenotype of some ACTH-producing tumors.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Effects of patient-controlled analgesia on postoperative anxiety in elderly men.

OBJECTIVE: To determine whether the use of patient-controlled analgesia vs intramuscular injections improves postoperative psychological parameters, particularly anxiety. DESIGN: Randomized, controlled trial of patient-controlled analgesia vs as-needed intramuscular morphine with pre- and postoperative assessments of pain, mental status, narcotic use, anxiety and mood states. SETTING: General surgical wards and surgical intensive care unit at a Veterans Administration hospital. PATIENTS: Eighty-three elderly, chronically ill males undergoing major elective surgery. INTERVENTION: Subjects randomized to receive postoperative patient-controlled analgesia vs as-needed intramuscular morphine. Pre- and postoperative assessments of State-Trait Anxiety Inventory, McGill-Dartmouth Part IV and Short Portable Mental Status Questionnaire. Pain (using linear analog scale), sedation score and narcotic use assessed every 4 hours for 72 hours. RESULTS: No differences were found in state anxiety or self-perceived mood states. Postoperative state anxiety was found to relate most closely to preoperative anxiety and postoperative complications, rather than method of analgesia or severity of pain. However, patient-controlled analgesia subjects had significantly improved analgesia and increased satisfaction. CONCLUSION: The use of patient-controlled analgesia does not significantly alter the measured psychological parameters, compared with intramuscular injections. Improved analgesia is the result of pharmacologic effects, independent of psychological factors.

Affect↗