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Biomedical subjects

D Spinner

Publications and source records attributed to D Spinner.

6 recordsLinked to original sources
PubMed2000

Natural metabolites of 1alpha,25-dihydroxyvitamin D(3) retain biologic activity mediated through the vitamin D receptor.

1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), the active metabolite of vitamin D, mediates many of its effects through the intranuclear vitamin D receptor (VDR, NR1I1), that belongs to the large superfamily of nuclear receptors. Vitamin D receptor can directly regulate gene expression by binding to vitamin D response elements (VDREs) located in promoter or enhancer regions of various genes. Although numerous synthetic analogs of 1alpha,25(OH)(2)D(3) have been analysed for VDR binding and transactivation of VDRE-driven gene expression, the biologic activity of many naturally occurring metabolites has not yet been analyzed in detail. We therefore studied the transactivation properties of 1alpha,24R, 25-trihydroxyvitamin D(3) (1alpha,24R,25(OH)(3)D(3)), 1alpha, 25-dihydroxy-3-epi-vitamin D(3) (1alpha,25(OH)(2)-3-epi-D(3)), 1alpha,23S,25-trihydroxyvitamin D(3) (1alpha,23S,25(OH)(3)D(3)), and 1alpha-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D(3) (1alpha(OH)-24,25,26,27-tetranor-23-COOH-D(3); calcitroic acid) using the human G-361 melanoma cell line. Cells were cotransfected with a VDR expression plasmid and luciferase reporter gene constructs driven by two copies of the VDRE of either the mouse osteopontin promoter or the 1alpha,25(OH)(2)D(3) 24-hydroxylase (CYP24) promoter. Treatment with 1alpha,25(OH)(2)D(3) or the metabolites 1alpha,24R,25(OH)(3)D(3), 1alpha,25(OH)(2)-3-epi-D(3), and 1alpha,23S,25(OH)(3)D(3) resulted in transactivation of both constructs in a time- and dose-dependent manner, and a postitive regulatory effect was observed even for calcitroic acid in the presence of overexpressed VDR. The metabolites that were active in the reporter gene assay also induced expression of CYP24 mRNA in the human keratinocyte cell line HaCaT, although with less potency than the parent hormone. A ligand-binding assay based on nuclear extracts from COS-1 cells overexpressing human VDR demonstrated that the metabolites, although active in the reporter gene assay, were much less effective in displacing [(3)H]-labeled 1alpha,25(OH)(2)D(3) from VDR than the parent hormone. Thus, we report that several natural metabolites of 1alpha,25(OH)(2)D(3) retain significant biologic activity mediated through VDR despite their apparent low affinity for VDR.

Animals↗
PubMed1998

The E protein CTF4 and acetylcholine receptor expression in development and denervation supersensitivity.

Motor activity blocks the extrasynaptic expression of many genes in skeletal muscle, including those encoding ion channels, receptors, and adhesion molecules. Denervation reinduces transcription throughout the multinucleated myofiber, restoring the developmental pattern of expression, especially of the genes coding for the acetylcholine receptor. A screen for trans-acting factors binding to the enhancer region of the alpha-subunit gene of the acetylcholine receptor identified CTF4, a ubiquitously expressed and alternatively spliced chicken homologue of the human E protein transcription factor HTF4/HEB. Expression of the CTF4 locus closely parallels that of myogenin and acetylcholine receptor during development and maturation of skeletal muscle, but transcription is not similarly regulated by neuronal cues. Alternative splicing within the region encoding the transactivation domain generates two CTF4 isoforms with different tissue distributions, but similar binding affinities for the acetylcholine receptor alpha-subunit enhancer and similar transcriptional potential when complexed to myogenin. Direct injection of a myogenin, but not a MyoD, antisense expression vector into denervated skeletal muscle caused a significant decrease in the transcriptional activation of a depolarization-sensitive reporter gene. Similarly, injection of a CTF4, but less so of an E12, antisense expression vector impaired the denervation response, further implicating the involvement of a myogenin/CTF4 heterodimer in the expression of AChR genes in vivo.

3T3 Cells↗
PubMed1998

Conversion problems concerning automated mapping from ICD-10 to ICD-9.

The increasing parallel use of ICD-9 and ICD-10 complicates the comparability of coded diagnoses. This is the reason why we developed a symmetric table for interactive conversion between ICD-9 and ICD-10, based on a vector space text-retrieval method that resulted in unambiguous mapping from ICD-9 to ICD-10 in 64%, from ICD-10 to ICD-9 in 87% of all three- and four-character classes of the tabular list. Out of the remaining 13% of multi-valued relations, a table for automated mapping from ICD-10 to ICD-9 was created. In 9% of cases, the selection offered no problems. A compromise between preserving information content and maintaining the logical integrity had to be found in 2.4%; in 1.6% automated mapping was impossible because of newly defined concepts and structural differences between ICD-9 and ICD-10 that are not counterbalanced by a consistent system of residual categories. We recommend that in a future revision of the ICD, compatibility with the then existing classification system should be considered.

Diagnosis, Computer-Assisted↗
PubMed1994

Phase II study of pirarubicin combined with cisplatin in recurrent ovarian cancer.

Although 50%-80% of patients with advanced ovarian cancer demonstrate an objective response after platinum-based chemotherapy, a majority of these patients will ultimately experience a relapse of their disease. Effective second-line treatment for these patients is of the most importance. We performed a phase II study with cisplatin and pirarubicin (each drug 50 mg/m2 i.v. every 28 days) in 17 patients with relapsed or persistent ovarian carcinoma. All patients had received platinum-containing primary chemotherapy. Overall survival from the time of diagnosis was 38.3 months (45.3 months in relapsed ovarian carcinoma and 28.3 months in ovarian carcinoma persisting after primary chemotherapy). Survival from entrance into the study was 13.0 months (14.2 months in relapsed disease and 11.2 months in refractory disease). Time to progression was 10.3 months. An objective response was observed in 4 patients and another 3 patients had stable disease. Major toxicity consisted of emesis (grade III/IV in 60/64 courses) and myelosuppression WHO grade III/IV in 15 courses. Neurotoxicity occurred in 3 patients and nephrotoxicity in 1 patient. Alopecia occurred in 12 patients. Tachycardia and other low-grade heart toxicities were observed after 5 courses. Dose reduction was necessary because of severe myelosuppression in 4 courses and because of nephrotoxicity in 1 course. Delay of subsequent chemotherapy courses for more than 7 days was necessary after 13 courses and was always due to myelosuppression. The dose-limiting toxicity of combination chemotherapy with cisplatin and pirarubicin is myelosuppression. Response and survival rates are superior in patients with relapsed disease compared to patients with resistant ovarian carcinoma.

Adolescent↗