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Biomedical subjects

C M Hansen

Publications and source records attributed to C M Hansen.

At least 19 recordsLinked to original sources
PubMed1998

Down-regulation of laminin-binding integrins by 1 alpha,25-dihydroxyvitamin D3 in human melanoma cells in vitro.

In the present investigation the effect of 1 alpha,25(OH)2D3 on the expression of the integrin laminin receptor on the melanoma cell line SK-MEL-28 has been examined. The SK-MEL-28 cells were shown to contain high-affinity receptors for 1 alpha,25(OH)2D3 and cell proliferation was found to be inhibited in a dose-dependent manner in response to the hormone. Using monoclonal antibodies against the alpha 6-sub-unit of the integrin laminin receptor, immunocytochemistry demonstrated that exposure of cells to 1 alpha,25(OH)2D3 for 5 days caused a reduced staining intensity. This observation was further confirmed by dot blot analysis, where a dose-dependent decline of alpha 6 expression was obtained after treatment of the cells with 1 alpha,25(OH)2D3 for 6 days. FACS-analysis was performed in order to quantify this decline, and it was found that the level of alpha 6-subunits on the cell surface was reduced by more than 40%. Additional investigations including Northern blot analyses of poly(A)+RNA extracts also showed a dose-dependent reduction of alpha 6 mRNA. Interestingly, the decrease of alpha 6 expression on the surface of SK-MEL-28 melanoma cells was accompanied by a reduced ability of the cells to adhere to an artificial basement membrane. In conclusion, the present investigation shows that besides having an antiproliferative effect on the SK-MEL-28 melanoma cells, 1 alpha,25(OH)2D3 is also able to inhibit the surface expression of the alpha 6-subunit of the integrin laminin receptor. Moreover, the results strongly indicate that 1 alpha,25(OH)2D3 exerts its regulatory effect on the alpha 6-subunit at the transcriptional level rather than at the protein level.

Antigens, CD↗
PubMed1997

EB 1089, a novel vitamin D analog with strong antiproliferative and differentiation-inducing effects on target cells.

The physiologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3, plays an important role not only in the establishment and maintenance of calcium metabolism, but also in regulating cell growth and differentiation. As the clinical usefulness of 1alpha,25-dihydroxyvitamin D3 is limited by its tendency to cause hypercalcemia, new analogs with a better therapeutic profile have been synthesized. One of these new synthetic vitamin D analogs is EB 1089, which is characterized by an altered side chain structure featuring 26,27-dimethyl groups and two double bonds. This analog has been shown to be more potent than 1,25-dihydroxyvitamin D3 in inhibiting proliferation, stimulating differentiation, and inducing apoptosis in a number of different cell types, including cancer cells. Despite being more potent than 1alpha,25-dihydroxyvitamin D3 with respect to its cell regulatory effects, EB 1089 displays weaker calcemic side-effects. These characteristics make EB 1089 a potentially useful compound for the treatment of a diversity of clinical disorders, including cancer and metabolic bone diseases. A promising phase I study with EB 1089 in patients with advanced breast and colon cancer has already been carried out, and more clinical trials evaluating the clinical effectiveness of EB 1089 in other types of cancer are in progress.

Animals↗
PubMed1997

Sensitive induction of apoptosis in breast cancer cells by a novel 1,25-dihydroxyvitamin D3 analogue shows relation to promoter selectivity.

The biologically active form of vitamin D3, the nuclear hormone 1 alpha,25-dihydroxyvitamin D3 (VD), is an important regulator of cellular growth, differentiation, and death. The hormone mediates its action through the activation of the transcription factor VDR, which is a member of the superfamily of nuclear receptors. In most cases the ligand-activated VDR is found in complex with the retinoid X receptor (RXR) and stimulates gene transcription mainly from VD response elements (VDREs) that are formed by two hexameric core binding motifs and are arranged either as a direct repeat spaced by three nucleotides (DR3) or as an inverted palindrome spaced by nine nucleotides (1P9). The two VD analogues CB1093 and EB1089 are both very potent inhibitors of the proliferation of MCF-7 cultured breast cancer cells displaying approximately 100-fold lower IC50 values (0.1 nM) than the natural hormone. In addition, CB1093 is even more potent in vivo than EB1089 in producing regression of experimental mammary tumors. Moreover, both VD analogues induce apoptosis in MCF-7 cells, but CB1093 is effective at concentrations approximately 10-fold lower than EB1089. In accordance, the reduction of Bcl-2 protein expression showed CB1093 to be more potent than EB1089. This suggests that the antiproliferative effect of CB1093 may be related mainly to its apoptosis inducing effect, whereas EB1089 may preferentially have effects on growth arrest. EB1089 is known to result in a selectivity for the activation of IP9-type VDREs, whereas CB1093 shows a preference for the activation of DR3-type VDREs. This promoter selectivity suggests that the effects of VD and its analogues on growth arrest and the induction of apoptosis may be mediated by different primary VD responding genes. In conclusion, CB1093 was found to be a potent inhibitor of rat mammary tumor growth in vivo. CB1093 also displayed a high potency in vitro in the induction of apoptosis, a process that may be linked to a promoter selectivity for DR3-type VDREs.

Animals↗
PubMed1997

Changes in vitamin B-6 status indicators of women fed a constant protein diet with varying levels of vitamin B-6.

Changes in vitamin B-6 status indicators were evaluated in vitamin B-6-replete subjects. Ten young women consumed diets providing 85 g protein/d and 1.03, 1.33, 1.73, and 2.39 mg vitamin B-6/d for 12 or 15 d during four successive diet periods; in a second study, six women were fed diets providing 85 g protein/d and 0.84, 1.14, and 2.34 mg vitamin B-6/d for 10 or 12 d during three successive diet periods. Vitamin B-6 status indicators showing significant differences among intakes included urinary excretion of 4-pyridoxic acid and total vitamin B-6, pyridoxal 5'-phosphate and total vitamin B-6 in plasma, and xanthurenic acid excretion after a 2-g L-tryptophan load. Significant correlations were found between vitamin B-6 intake and 4-pyridoxic acid, total vitamin B-6, plasma pyridoxal 5'-phosphate, plasma total vitamin B-6, erythrocyte alanine aminotransferase percentage stimulation and postload excretion of xanthurenic acid and volatile amines (kynurenine plus acetylkynurenine). Depending on the indicator, between 20% and 70% of the subjects had inadequate values for 4-pyridoxic acid, total vitamin B-6, plasma pyridoxal 5'-phosphate, and erythrocyte alanine aminotransferase percentage stimulation at a vitamin B-6 intake of 1.33 mg/d (0.016 mg vitamin B-6/g protein). A ratio of dietary vitamin B-6 to protein > 0.016 mg/g is required for adequate vitamin B-6 status in women.

Adult↗
PubMed1996

Vitamin B-6 status indicators decrease in women consuming a diet high in pyridoxine glucoside.

Previous research has shown that the pyridoxine glucoside (PNG) form of vitamin B-6 has a reduced bioavailability compared with pyridoxine, but its effect on vitamin B-6 status has not been assessed. Following an 8-d adjustment period, nine women consumed diets containing a high or low amount of PNG for 18 d each, in a crossover design. The high and low PNG diets provided 1.52 mg/d (8.98 micromol/d) and 1.44 mg/d (8.57 micromol/d) of vitamin B-6, of which 27% and 9% was PNG, respectively. The dietary vitamin B-6 to protein ratio of both diets was 0.017 mg/g. Urinary excretions of 4-pyridoxic acid and total vitamin B-6 were significantly lower (P < 0.05) during the high PNG diet period than when the low PNG diet was consumed. Urinary PNG excretion was equal to about 9% of the total PNG intake during both periods. Plasma total vitamin B-6 (P < 0.01) and red blood cell pyridoxal 5'-phosphate (PLP) (P < 0.05) were significantly lower when the high PNG diet was consumed than during the low PNG diet period. Fecal total vitamin B-6 excretion was significantly higher (P < 0.001) when the high PNG diet was consumed. Women consuming a diet containing a higher percentage of the total vitamin B-6 intake as PNG exhibited a decrease in vitamin B-6 status indicators, consistent with the reduced bioavailability of PNG demonstrated in other studies, equal to a loss of 15-18% of the total vitamin B-6 intake. During the determination of Recommended Dietary Allowances, the reduced bioavailability of PNG and its presence in higher amounts in some diets should be considered.

Adult↗
PubMed1996

Vitamin B-6 status of women with a constant intake of vitamin B-6 changes with three levels of dietary protein.

To determine the effect of varying levels of dietary protein with a constant intake of vitamin B-6 (B-6) on B-6 status, nine women were fed diets providing daily intakes of 1.25 mg B-6 and 0.5, 1.0 and 2.0 g protein/kg body weight. After an 8-d adjustment period, the women consumed each level of dietary protein for 14 d in a Latin-square design. Several direct and indirect B-6 status indicators were measured in blood and urine. Significant differences among protein levels were found for urinary 4-pyridoxic acid (4-PA) excretion (P < 0.01), plasma pyridoxal 5'-phosphate (PLP) concentration (P < 0.05), and urinary excretion of volatile amines (VA, kynurenine plus acetylkynurenine) after a 2-g L-tryptophan load (P < 0.05). Nitrogen intake was significantly negatively correlated with urinary 4-PA excretion (r = -0.619, P < 0.001) and plasma PLP concentration (r = -0.549, P < 0.01), and positively correlated with erythrocyte alanine aminotransferase percentage stimulation (r = 0.418, P < 0.05) and urinary post-tryptophan load excretion of xanthurenic acid (r = 0.535, P < 0.05), kynurenic acid (r = 0.563, P < 0.05) and VA (r = 0.626, P < 0.01). Compared with men consuming diets with similar B-6 to protein ratios In a previous study, the women excreted a greater percentage of the B-6 intake as 4-PA, had lower plasma PLP concentrations and excreted greater amounts of postload urinary tryptophan metabolites at all three protein levels. If the Recommended Dietary Allowance (RDA) of vitamin B-6 is to be based on the dietary B-6 to protein ratio, gender differences in response to varying protein intakes should be considered. For the levels of protein intake used in this study and a B-6 intake of 1.25 mg/d, a B-6 to protein ratio of greater than 0.020 mg/g is required for adequate vitamin B-6 status in women.

Adult↗
PubMed1996

The anti-proliferative and differentiation-inducing effects of vitamin D analogs are not determined by the binding affinity for the vitamin D receptor alone.

Calcipotriol, a synthetic analog of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25[OH]2D3), is used in the treatment of psoriasis. In this investigation, the biological profile of calcipotriol and of two new vitamin D analogs, EB 1213 and GS 1500, has been studied and compared with the profile of 1 alpha,25(OH)2D3. Despite the fact that the affinity for the intracellular vitamin D receptor of the three analogs is comparable (EB 1213) or lower (GS 1500, calcipotriol) than that of 1 alpha,25(OH)2D3, they were all found to be more potent in inhibiting human skin cell proliferation in vitro. The anti-proliferative effect was accompanied by a change in the cytokeratin pattern of the skin cells, indicating a differentiation-inducing effect of the compounds similar to that of 1 alpha,25(OH)2D3. Further investigations including ligand-induced vitamin D receptor transcription studies in chloramphenicol acetyl transferase assays showed that EB 1213 and GS 1500 were more efficient than 1 alpha,25(OH)2D3 in inducing vitamin D receptor transcription. This strongly indicates that not only the binding affinity for the receptor, but more importantly, the ability of the compounds to induce vitamin D receptor transcription, is a determinant of the biological activity of the compounds.

Binding Sites↗
PubMed1995

Permeability of commercial solvents through living human skin.

A procedure has been developed for measuring the steady state rate of permeation of commercial solvents through living human skin. To get the most consistent results, it was necessary with some solvents to normalize the solvent permeation rate of a given skin sample with its [3H]water permeation rate. For other solvents this was not necessary, so the un-normalized data were used. High [3H]water permeation rate also was used as a criterion for "defective" skin samples that gave erroneous permeability rates, especially for solvents having slow permeability. The linearity of the steady state data was characterized by calculation of the "percent error of the slope." The following permeability rates (g/m2h) of single solvents were measured: dimethyl sulfoxide (DMSO), 176; N-methyl-2-pyrrolidone, 171; dimethyl acetamide, 107; methyl ethyl ketone, 53; methylene chloride, 24; [3H]water, 14.8; ethanol, 11.3; butyl acetate, 1.6; gamma-butyrolactone, 1.1; toluene, 0.8; propylene carbonate, 0.7; and sulfolane, 0.2. The effect of [3H]water saturation on the shape of the presteady state portion of the permeation curve was determined and found to be very dependent on the solvent. The permeability of mixtures of DMSO and octyl acetate were measured. No octyl acetate was detected and the permeability of DMSO was proportional to its mole fraction in the mixture. The effect of two hours of solvent exposure on the viability of skin (based on DNA synthesis) was measured and found to be very dependent on the solvent.

Acetates↗
PubMed1994

1 alpha,25-Dihydroxyvitamin D3 inhibits the invasive potential of human breast cancer cells in vitro.

Using the Boyden chamber invasion assay, the effect of 1 alpha,25-dihydroxyvitamin D3 [1 apha,25(OH)2D3] on the invasiveness of the highly invasive, oestrogen receptor-negative human breast cancer cell line MDA-MB-231 was examined. The MDA-MB-231 cells were shown to contain high-affinity receptors for 1 alpha,25(OH)2D3 with a Kd of 1.5 x 10(-11) M. When the cells were treated with 1 alpha,25(OH)2D3 for 4 days before the assay was performed, a dose-dependent inhibition of their invasive potential was demonstrated. Fifty per cent inhibition of invasion was obtained with a concentration of 13 pM of 1 alpha,25(OH)2D3. However, when the cells were treated for only 6 h during the assay, no inhibitory effect was seen. The process of migration was also affected by treatment with 1 alpha,25(OH)2D3 for 4 days, although the inhibition was not of the same magnitude as seen for the invasion. Fifty per cent inhibition of migration occurred at a concentration of 3.2 nM of 1 alpha,25(OH)2D3 (250 times higher than in the invasion assay). Inhibition of invasion and migration was not due to the known anti-proliferative effect of 1 alpha,25(OH)2D3, as no growth reduction could be demonstrated with treatment up to 5 days. Based on the present investigation it can therefore be concluded that 1 alpha,25(OH)2D3 is able to inhibit tumour cell invasiveness by a mechanism which is not exclusively based on its anti-proliferative and anti-migrative effects.

Adenocarcinoma↗
PubMed1994

Child abuse presenting as a thoracolumbar spinal fracture dislocation: a case report.

A child sustained a traumatic thoracolumbar spinal fracture--dislocation with cord compression. A court confirmed the diagnosis of child abuse. There was no history of trauma, and the diagnosis of child abuse was missed by the physicians who first saw the child. Spinal injuries in child abuse are uncommon. They may be symptomatic or asymptomatic, stable or unstable, or occur with or without bony changes on the x-rays. Injuries without a history of trauma may be overlooked if asymptomatic. Radiologic skeletal surveys in suspected abuse should include a minimum of two views of the spine even if the child has no symptoms referrable to the spine. Conversely, a traumatic cause should be considered whenever there is spinal cord injury without vertebral injury. Having a high index of suspicion for abuse while remembering that pediatric spinal injuries may occur in the context of normal x-rays will decrease the likelihood of missed diagnosis, repeated abuse, or complications from delayed immobilization of unstable injuries.

Child Abuse↗
PubMed1988

The affinities of organic solvents in biological systems.

The affinities of organic solvents in biological systems are described using solubility parameter techniques. Materials studied include lard, water, blood serum, sucrose, urea, keratin and lignin. The tendency for organic solvents to collect in fatty material, swell (penetrate) the skin, absorb into wood, or preferentially transfer to aqueous media, for example, can be estimated rapidly for any of the solvents for which solubility parameters are available.

Blood↗