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Biomedical subjects

J Wesseling

Publications and source records attributed to J Wesseling.

13 recordsLinked to original sources
PubMed2000

Behavioural outcome of school-age children after prenatal exposure to coumarins.

In utero exposure to coumarin derivatives may affect the development of the central nervous system of the child, irrespective of the period of exposure in pregnancy. Little is known about effects on development in the long term. The aim of the present study was to determine whether prenatal exposure to coumarins affects behavioural outcome in children at school age. Behavioural outcome was assessed in a cohort of 305 exposed children, aged 7-15 years. Findings were compared with those in a cohort of 263 non-exposed controls, matched for sex, age, and demographic region. Behaviour was rated by parents and teachers using standardized questionnaires: the Groningen Behaviour Checklist Family situation (GBF) and the Groningen Behaviour Checklist School situation (GBS), respectively. The findings of the GBF were supported by the results of the GBS, filled in by teachers who were blind for the exposure status of the child. In comparison to the non-exposed children, the coumarin-exposed children scored lower on the cluster 'positive task orientation' (GBF P<0.05, GBS P<0.01), they scored higher on 'emotional instability' (GBF P<0.001, GBS P<0.05), and they had more problems on the social clusters (P<0.01). Based on the results of both questionnaires, we conclude that behavioural development may be negatively influenced in school-age children after in utero exposure to coumarins, leading to less favourable task-oriented and social-emotional behaviour. However, the frequency of clinically relevant 'problem behaviour' (GBF) was not increased in relation to coumarin exposure, the odds ratio was 1.2 (CI(95) 0.7-1.8).

Adolescent↗
PubMed1996

Immunoscintigraphy of small-cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: improvement of tumour uptake by internalisation.

The efficacy of three murine monoclonal antibodies (MAbs) for immunoscintigraphy of small-cell lung cancer (SCLS) xenografts was studied in a Balb/c nu/nu mouse model. These Mabs, 123C3, 123A8 and MOC191, belong to cluster 1 of anti-SCLC MAbs and bind to the neural cell adhesion molecule (NCAM) with similar affinity. After intraperitoneal injection of these MAbs, labelled with 125I, the highest uptake in tumour tissue was obtained with MAb 123C3. Seven days after the administration of this MAb 13.9% of the injected dose per gram of tumour tissue was retained in the tumour. The corresponding tumour tissue ratios ranged from 3.97 for blood to 31.03 for colon. The imaging results and the tumour uptake were less favourable for the two other MAbs, 123A8 and MOC191 (fractions of injected dose respectively 6.7% and 9.2%), although affinity, biological activity after labelling and uptake in non-tumour tissues were very similar for all three MAbs. These results may be explained by the differences in the interaction between the MAbs and the tumour cells. Mab 123C3 is internalised into tumour cells, whereas both other anti-NCAM Mabs are not. Internalisation into NCI H69 cells was demonstrated in vitro by radioimmunoassay, confocal laser scanning microscopy and electron microscopy. The internalised fraction of MAb 123C3 was 22.3% after 24h, whereas this fraction was only 7.5% for MAb 123A8. Although the internalised radiolabeled Mabs are usually degraded and dehalogenated intracellularly, the retained radioactivity is high. Apparently, intracellular degradation of radiolabelled MAb 123C3 and subsequent secretion of radioactive iodine did not prevent the accumulation of intracellular radioactivity. In conclusion, accumulation and retention of radioactivity in the tumour tissue, due to internalisation of radiolabelled MAbs, may improve the results immunoscintigraphy.

Animals↗
PubMed1996

A mechanism for inhibition of E-cadherin-mediated cell-cell adhesion by the membrane-associated mucin episialin/MUC1.

Episialin (MUC1, PEM, EMA, CA15-3 antigen) is a sialylated, membrane-associated glycoprotein with an extended mucin-like ectodomain. This domain mainly consists of 30-90 homologous 20-amino acid repeats that are rich in O-glycosylation sites (serines and threonines). It is likely that this part forms a polyproline beta-turn helix. As a result, the ectodomain can protrude more than 200 nm above the cell surface, whereas most cell surface molecules do not exceed a length of 35 nm. Normally, episialin is present at the apical side of glandular epithelial cells. On carcinoma cells, however, it can be strongly overexpressed and it is often present over the entire cell surface. We have previously shown that episialin, if it is interspersed between adhesion molecules, nonspecifically reduces cell-cell and cell-extracellular matrix interactions in vitro and in vivo, presumably by steric hindrance caused by the extreme length and high density of the episialin molecules at the cell surface. To analyze the molecular mechanism for this anti-adhesion effect in more detail, we have now deleted an increasing number of repeats in the episialin cDNA and transfected the resulting mutants into murine L929 cells expressing the homophilic adhesion molecule E-cadherin. Here we show that the length of episialin is the dominant factor that determines the inhibition of E-cadherin-mediated cell-cell interactions. For the anti-adhesive effect mediated by the full length episialin, charge repulsion by negatively charged sialylated O-linked glycans is far less important.

Animals↗
PubMed1995

Nucleus-associated phosphorylation of Ins(1,4,5)P3 to InsP6 in Dictyostelium.

Although many cells contain large amounts of InsP6, its metabolism and function is still largely unknown. In Dictyostelium lysates, the formation of InsP6 by sequential phosphorylation of inositol via Ins(3,4,6)P3 has been described [Stevens and Irvine (1990) Nature (London) 346, 580-583]; the second messenger Ins(1,4,5)P3 was excluded as a potential substrate or intermediate for InsP6 formation. However, we observed that mutant cells labelled in vivo with [3H]inositol showed altered labelling of both [3H]Ins(1,4,5)P3 and [3H]InsP6. In this report we demonstrate that Ins(1,4,5)P3 is converted into InsP6 in vitro by nucleus-associated enzymes, in addition to the previously described stepwise phosphorylation of inositol to InsP6 that occurs in the cytosol. HPLC analysis indicates that Ins(1,4,5)P3 is converted into InsP6 via sequential phosphorylation at the 3-, 6- and 2-positions. Ins[32P]P6, isolated from cells briefly labelled with [32P]Pi, was analysed using Paramecium phytase, which removes the phosphates of InsP6 in a specific sequence. The 6-position contained significantly more 32P radioactivity than the 4- or 5-positions, indicating that the 6-position is phosphorylated after the other two positions. The results from these in vivo and in vitro experiments demonstrate a metabolic route involving the phosphorylation of Ins(1,4,5)P3 via Ins(1,3,4,5)P4 and Ins(1,3,4,5,6)P5 to InsP6 in a nucleus-associated fraction of Dictyostelium cells.

Adenosine Triphosphate↗
PubMed1995

Is episialin/MUC1 involved in breast cancer progression?

Episialin, also designated MUC1, CA 15-3 antigen and PEM, is an established serum marker for breast cancer. Its function and possible involvement in tumor progression has not yet been completely established. The molecule is an extended rod-like molecule protruding high above the cell surface. It is often highly overexpressed in breast cancer relative to normal breast epithelium cells. Overexpression of episialin on cells in vitro reduces cell-cell and cell-extracellular matrix adhesion, because the rod-like molecule masks the adhesion receptors. Episialin also exerts its anti-adhesion effect in vivo. In certain human tumors, where episialin was present at the basal side of the cell, abnormal contacts between the plasma membrane and the stroma were observed. As a consequence of its anti-adhesion properties, episialin overexpression reduces the sensitivity of the cells for cytotoxic lymphocytes. This might be one of the reasons why episialin transfected cells are more potent to form experimental metastases after i.v. injection into nude mice.

Animals↗
PubMed1995

Episialin (MUC1) overexpression inhibits integrin-mediated cell adhesion to extracellular matrix components.

Episialin (MUC1) is a transmembrane molecule with a large mucin-like extracellular domain protruding high above the cell surface. The molecule is located at the apical side of most glandular epithelial cells, whereas in carcinoma cells it is often present at the entire surface and it is frequently expressed in abnormally large quantities. We have previously shown that overexpression of episialin reduces cell-cell interactions. Here we show that the integrin-mediated adhesion to extracellular matrix of transfectants of a melanoma cell line (A375), a transformed epithelial cell line (MDCK-ras-e) and a human breast epithelial cell line (HBL-100) is reduced by high levels of episialin. This reduction can be reversed by inducing high avidity of the beta 1 integrins by mAb TS2/16 (at least for beta 1-mediated adhesion). The adhesion can also be restored by redistribution of episialin on the cell surface by monoclonal antibodies into patches or caps. Similarly, capping of episialin on ZR-75-1 breast carcinoma cells, growing in suspension, caused adherence and spreading of these cells. We propose that there is a delicate balance between adhesion and anti-adhesion forces in episialin expressing cells, which can be shifted towards adhesion by strengthening the integrin-mediated adhesion, or towards anti-adhesion by increasing the level of expression of episialin.

Animals↗
PubMed1994

The mucin epiglycanin on TA3/Ha carcinoma cells prevents alpha 6 beta 4-mediated adhesion to laminin and kalinin and E-cadherin-mediated cell-cell interaction.

TA3/Ha murine mammary carcinoma cells grow in suspension, do not adhere to extracellular matrix molecules, but do adhere to hepatocytes and form liver metastases upon intraportal injection. Recently we showed that the integrin alpha 6 beta 4 on the TA3/Ha cells is involved in adhesion to hepatocytes. However, despite high cell surface levels of alpha 6 beta 4, TA3/Ha cells do not adhere to the alpha 6 beta 4 ligands laminin and kalinin. Here we show that this is due to the mucin epiglycanin that is highly expressed on TA3/Ha cells. Some monoclonal antibodies generated against epiglycanin induced capping of most of the epiglycanin molecules. TA3/Ha cells treated with these mAb did adhere to laminin and kalinin, and an epithelial monolayer was formed on kalinin, with alpha 6 beta 4 localized in HD1-containing hemidesmosome-like structures and E-cadherin at the cell-cell contact sites. Similar results were obtained after treatment of TA3/Ha cells with O-sialoglycoprotein endopeptidase which removes all epiglycanin. In addition, the enzyme induced E-cadherin-mediated cell-cell aggregation. Both treatments also enhanced the adhesion to hepatocytes, but given the potent antiadhesive effect of epiglycanin it is remarkable that nontreated TA3/Ha cells adhere to hepatocytes at all. We found that during this interaction, epiglycanin was redistributed. We conclude that epiglycanin can completely prevent both intercellular and matrix adhesion, but that this effect can be overcome in certain intercellular interactions because of the induced redistribution of the mucin.

Animals↗
PubMed1993

Genomic organization and expression of the 3' end of the canine and feline enteric coronaviruses.

The genomic organization at the 3' end of canine coronavirus (CCV) and feline enteric coronavirus (FECV) was determined by sequence analysis and compared to that of feline infectious peritonitis virus (FIPV) and transmissible gastroenteritis virus (TGEV) of swine. Comparison of the latter two has previously revealed an extra open reading frame (ORF) at the 3' end of the FIPV genome, lacking in TGEV, now designated ORF 6b. Both CCV and FECV possess 6b-related ORFs. The CCV ORF 6b is colinear with that of FIPV, but the predicted amino acid sequences are only 58% identical. The FECV ORF 6b contains a large deletion compared to that of FIPV, reducing the colinear part to 60%. The sequence homologies were highest between CCV and TGEV on the one hand and between FECV and FIPV on the other. The expression product of the CCV and the FECV ORF 6b can be detected in infected cells by immunoprecipitation.

Animals↗
PubMed1992

Genomic organization and expression of the 3' end of the canine and feline enteric coronaviruses.

The genomic organization at the 3' end of canine coronavirus (CCV) and feline enteric coronavirus (FECV) was determined by sequence analysis and compared to that of feline infectious peritonitis virus (FIPV) and transmissible gastroenteritis virus (TGEV) of swine. Comparison of the latter two has previously revealed an extra open reading frame (ORF) at the 3' end of the FIPV genome, lacking in TGEV, which is currently designated ORF 6b. Both CCV and FECV possess 6b-related ORFs at the 3' ends of their genomes. The presence of ORF 6b in three of four viruses in this antigenic cluster strongly suggests that TGEV has lost this ORF by deletion. The CCV ORF 6b is collinear with that of FIPV, but the predicted amino acid sequences are only 58% identical. The FECV ORF 6b contains a large deletion compared to that of FIPV, reducing the collinear part to 60%. The sequence homologies were highest between CCV and TGEV on the one hand and between FECV and FIPV on the other. Previously, we showed that the expression product of the FIPV ORF 6b can be detected in infected cells by immunoprecipitation (Vennema et al., 1992). In the present study we have performed similar experiments with CCV and FECV. In infected cells both viruses produced proteins related to but different from the FIPV 6b protein.

Amino Acid Sequence↗