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Biomedical subjects

M Dekker

Publications and source records attributed to M Dekker.

At least 19 recordsLinked to original sources
PubMed2006

Effective oligonucleotide-mediated gene disruption in ES cells lacking the mismatch repair protein MSH3.

We have previously demonstrated that site-specific insertion, deletion or substitution of one or two nucleotides in mouse embryonic stem cells (ES cells) by single-stranded deoxyribo-oligonucleotides is several hundred-fold suppressed by DNA mismatch repair (MMR) activity. Here, we have investigated whether compound mismatches and larger insertions escape detection by the MMR machinery and can be effectively introduced in MMR-proficient cells. We identified several compound mismatches that escaped detection by the MMR machinery to some extent, but could not define general rules predicting the efficacy of complex base-pair substitutions. In contrast, we found that four-nucleotide insertions were largely subject to suppression by the MSH2/MSH3 branch of MMR and could be effectively introduced in Msh3-deficient cells. As these cells have no overt mutator phenotype and Msh3-deficient mice do not develop cancer, Msh3-deficient ES cells can be used for oligonucleotide-mediated gene disruption. As an example, we present disruption of the Fanconi anemia gene Fancf.

Animals↗
PubMed2005

Feasibility study for the development of certified reference materials for specific migration testing. Part 2: estimation of diffusion parameters and comparison of experimental and predicted data.

This paper describes the second part of a project whose main objective was to develop the know-how to produce certified reference materials (CRMs) for specific migration testing. Certification parameters discussed are the diffusion coefficient, D(P), the respective polymer-specific coefficient, A(P), of the migrant polymer combinations and the partitioning coefficient, K(P,F), describing the partitioning of the migrant between the polymer and a food simulant. The parameters were determined for 16 preliminary candidate CRMs. Each parameter was determined by one laboratory. The six materials most suitable as reference materials were selected and the parameters then determined by four laboratories. The coefficients resulting from this small-scale interlaboratory comparison study can be regarded as the most reliable values available to date. These coefficients were applied for a comparison of experimental and predicted migration data. The experimental migration data arose from the same project and were determined by one laboratory for the first 16 materials and subsequently by four laboratories for the six materials selected in the second phase. Overall, experimental and predicted migration data fit together quite well. Roughly half of the predicted data were within +/-10%; almost all predicted data were within +/-40% compared with the experimental data.

Benzophenones↗
PubMed2003

Modelling the effect of oil/fat content in food systems on flavour absorption by LLDPE.

One of the phenomena in food-packaging interactions is flavour absorption. Absorption of flavour compounds from food products into food-packaging materials can result in loss of flavour compounds or an unbalance in the flavour profile changing a product's quality. The food matrix influences the amounts of absorbed flavour compounds; the presence of oil or fat especially determines the ability to absorb flavour compounds from the food to the package. On the other hand, the polarity of the flavour compound itself is a characteristic that also influences the level of absorption into synthetic polymers. A model based on the effect of the polarity (logP) of flavour compounds and on their partitioning coefficients between the food (matrix) and the packaging material is described. The model can be used for predicting absorption of flavour compounds from foods into LLDPE. However, an attempt to apply the proposed model on real foods shows serious limitations of the model for (very) low fat products. Predictive values deviate from the measured values, probably due to other interaction phenomena, e.g. with proteins. Predictive and measured values from a product with a substantial amount of fat match much better, suggesting that the model is valid for products having a substantial amount of (free) fat.

Absorption↗
PubMed2003

Alternative fatty food simulants and diffusion kinetics of nylon 12 food packaging.

The migration of laurolactam and cyclic di- and trimer of nylon 12 was assessed using three different films and five food simulants (olive oil, isooctane, 95% ethanol, 50% ethanol, water). Substitute test conditions for migration into olive oil according to European Union Directive EC/97/48 were applied using 95% ethanol and isooctane. Results showed that 95% ethanol overestimated while isooctane underestimated the respective migration into olive oil. Water was the best olive oil substitute, as migration of laurolactam into water and olive oil using the same temperature gave similar results. Additionally, diffusion kinetics of laurolactam were investigated by migration kinetic studies using isooctane and olive oil. Diffusion coefficients determined with isooctane were significantly higher than those found using olive oil. It was proved that isooctane had an interaction and olive oil was inert to the polymer. The diffusion conductance parameter, A(p), for nylon 12 determined using olive oil ranged from 0.3 to 0.6.

Dietary Fats↗
PubMed2002

Influence of solvent absorption on the migration of Irganox 1076 from LDPE.

The effect of solvent absorption on additive migration was studied by relating the diffusion coefficient (D) of Irganox 1076 to the maximum solvent absorption of different solvents in low-density polyethylene (LDPE) film. Solvents tested were ethanol, isopropanol, isooctane, ethylacetate, cyclohexane, tributyrin, tricaprylin and olive oil. Diffusion and partition coefficients were determined by fitting the migration curves, i.e. the concentration of Irganox 1076 in solvent as a function of time, with Fick 's diffusion equation. The results for the low molecular weight solvents show that with increasing maximum solvent absorption, D of Irganox 1076 is increasing as well. This trend is not observedfor the two triglycerides and olive oil. In spite of absorption, no increase in D was observed. The obtained result is the basis of an extended predictive migration model that, besides migrant and polymer properties, is also based on the maximum solvent absorption in the polymer.

Absorption↗
PubMed2001

Activity and concentration of polyphenolic antioxidants in apple: effect of cultivar, harvest year, and storage conditions.

Consumers' increasing interest in the relationship between diet and health is a sign for food producers to pay more attention to potential health-protecting compounds in new product development and food processing. From a production chain perspective the choice of the raw material that is used is important for the health-protecting potential of the end product. Four apple cultivars (Jonagold, Golden Delicious, Cox's Orange, and Elstar), which can be used as fresh apples or in processed apple products, were compared with regard to flavonol, catechins, phloridzin, and chlorogenic acid concentrations and antioxidant activity. Jonagold apples possessed the highest flavonoid concentration and the highest antioxidant activity. To study seasonal differences, apples from three different harvest years were analyzed, but in three cultivars no effect on flavonoid concentration and antioxidant activity was observed. Long-term storage, both at refrigerator temperature and under controlled atmosphere conditions, was found not to influence flavonoid concentration or antioxidant activity.

Antioxidants↗
PubMed2000

Acceleration of lymphomagenesis in mismatch-repair deficient mice by exposure to genotoxic agents.

Hemizygosity for genes that are essential for DNA mismatch repair (MMR) was found to underlie cancer predisposition in hereditary nonpolypsis colorectal cancer (HNPCC). Loss of the wild-type allele generates a MMR-deficient cell compartment with a high propensity to oncogenic transformation. MMR deficiency not only accelerates spontaneous mutagenesis resulting from DNA replication errors, but also affects the cellular response to genotoxic agents. To study the consequences of MMR deficiency in vitro and to provide experimental access to HNPCC we have generated MMR-deficient cell lines and mice. The combination of MMR deficiency and exposure to genotoxic agents strongly accelerated lymphomagenesis.

Animals↗
PubMed2000

An improved, rapid in vitro method to measure antioxidant activity. Application On selected flavonoids and apple juice.

A rapid in vitro method for measuring antioxidant activity is presented, which enables the evaluation of health claims and the optimization of product development with respect to health protecting compounds. Antioxidant activity is assessed in a system in which lipid peroxidation is induced in male rat liver microsomes by ascorbic acid and FeSO(4). This method has been significantly improved by enabling the use of microtiter plates and an ELISA reader. Large numbers of samples can be analyzed with good reproducibility, which is necessary when dealing with microsomes possessing biological variability. An objective mathematical procedure has been developed to translate data obtained from the lipid peroxidation assay into a value describing the antioxidant activity. As an illustration the method has been applied to measure antioxidant activity of individual flavonoids and apple juice.

Animals↗
PubMed1999

Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine.

Deficiency in genes involved in DNA mismatch repair increases susceptibility to cancer, particularly of the colorectal epithelium. Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide. Experiments using Msh2-deficient cells in vitro suggest that an element of this effect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N'-nitro-N-nitrosoguanidine, and cisplatin. This was not influenced by the in vivo depletion of O6-alkylguanine-DNA-alkyltransferase after administration of O6-benzylguanine. By analyzing mice mutant for both Msh2 and p53, we found that the Msh2-dependent apoptotic response was primarily mediated through a p53-dependent pathway. Msh2 also was required to signal delayed p53-independent death. Taken together, these studies characterize an in vivo Msh2-dependent apoptotic response to methylating agents and raise the possibility that Msh2 deficiency may predispose to malignancy not only through failed repair of mismatch DNA lesions but also through the failure to engage apoptosis.

Animals↗
PubMed1999

Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis.

Members of the mammalian mismatch repair protein family of MutS and MutL homologs have been implicated in postreplicative mismatch correction and chromosome interactions during meiotic recombination. Here we demonstrate that mice carrying a disruption in MutS homolog Msh5 show a meiotic defect, leading to male and female sterility. Histological and cytological examination of prophase I stages in both sexes revealed an extended zygotene stage, characterized by impaired and aberrant chromosome synapsis, that was followed by apoptotic cell death. Thus, murine Msh5 promotes synapsis of homologous chromosomes in meiotic prophase I.

Animals↗
PubMed1999

HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.

Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.

Alleles↗
PubMed1998

p107 is a suppressor of retinoblastoma development in pRb-deficient mice.

Hemizygosity for the retinoblastoma gene RB in man strongly predisposes to retinoblastoma. In the mouse, however, Rb hemizygosity leaves the retina normal, whereas in Rb-/- chimeras pRb-deficient retinoblasts undergo apoptosis. To test whether concomitant inactivation of the Rb-related gene p107 is required to unleash the oncogenic potential of pRb deficiency in the mouse retina, we inactivated both Rb and p107 by homologous recombination in embryonic stem cells and generated chimeric mice. Retinoblastomas were found in five out of seven adult pRb/p107-deficient chimeras. The retinal tumors showed amacrine cell differentiation, and therefore originated from cells committed to the inner but not the outer nuclear layer. Retinal lesions were already observed at embryonic day 17.5. At this stage, the primitive nuclear layer exhibited severe dysplasia, including rosette-like arrangements, and apoptosis. These findings provide formal proof for the role of loss of Rb in retinoblastoma development in the mouse and the first in vivo evidence that p107 can exert a tumor suppressor function.

Animals↗
PubMed1998

Mouse models for hereditary nonpolyposis colorectal cancer.

Hemizygous germ-line defects in mismatch repair (MMR) genes underlie hereditary nonpolyposis colorectal cancer (HNPCC). Loss of the wild-type allele results in a mutator phenotype, accelerating tumorigenesis. Tumorigenesis specifically occurs in the gastrointestinal and genitourinary tracts; the cause of this tissue specificity is elusive. To understand the etiology and tissue distribution of tumors in HNPCC, we have developed mouse models carrying a deficiency in the MMR gene Msh2. Most of the completely Msh2-deficient mice succumbed to lymphomas at an early age; lymphomagenesis was synergistically enhanced by exposure to ethylnitrosourea. Lymphomas were absent in immunocompromised Tap1-/-;Msh2-/- mice; these mice generally succumbed to HNPCC-like tumors. Together, these data suggest that the HNPCC tumor spectrum is determined by exposure of MMR-deficient cells to exogenous mutagens, rather than by tissue-specific loss of the wild-type MMR allele or by immune surveillance. Msh2 hemizygous mice had an elevated tumor incidence that, surprisingly, was rarely correlated with loss of the Msh2+ allele. To develop a model for intestinal tumorigenesis in HNPCC, we introduced the Min allele of the Apc tumor suppressor gene. We observed loss of the wild-type Msh2 allele in a significant fraction of intestinal tumors in Apc+/Min;Msh2+/- mice. In some of the latter tumors, one area of the tumor displayed loss of the Msh2+ allele, but not of the Apc+ allele, whereas another area displayed the inverse genotype. This apparent biclonality might indicate a requirement for collaboration between independent tumor clones during intestinal tumorigenesis.

Adenomatous Polyposis Coli Protein↗
PubMed1998

The use of microsomal in vitro assay to study phase I biotransformation of chlorobornanes (Toxaphene) in marine mammals and birds. Possible consequences of biotransformation for bioaccumulation and genotoxicity.

The factors determining the bioaccumulation of lipophilic compounds in wildlife are often poorly understood, partly because it is difficult to do in vivo experiments with animals such as marine mammals and birds. To evaluate the role of phase I biotransformation in the bioaccumulation process of chlorobornanes (toxaphene), this was studied in in vitro assays with hepatic microsomes of animals that could be sampled shortly after death. The capacity of microsomes to metabolise a technical toxaphene mixture decreased in the order Phoca vitulina (harbour seal) >> Lagenorhynchus albirostris (whitebeaked dolphin) approximately equal to Diomedea immutabilis (Laysan albatross) > Physeter macrocephalus (sperm whale). Harbour seal microsomes metabolised the chlorobornane (CHB) congeners CHB-32 and CHB-62; whitebeaked dolphin and Laysan albatross microsomes only metabolised CHB-32. Metabolism of CHB-26 and CHB-50 was never observed. The negative chemical ionisation (NCI-) mass spectra of some of the hydroxylated metabolites were obtained. The number of peaks in the toxaphene residues of wildlife extracts decreased in the order of increasing in-vitro biotransformation capacity. Thus, the results of the in vitro assays and residue analysis were in accordance, although assays with microsomes of more individuals of the same species are required for a more general conclusion at the species level. Finally, the effect of in vitro biotransformation was evaluated in terms of the genotoxic potential using the Mutatox assay. Only technical toxaphene and CHB-32 were genotoxic in the direct assay, whereas the addition of rat S9 fraction or microsomes of harbour seal and albatross decreased the genotoxic response. Thus, organisms with a low ability to metabolise chlorobornanes, such as whales, may be most affected by the carcinogenic properties of toxaphene. A hypothetical reaction which fits the experimental results is discussed. Based on these results it is concluded that in vitro assays with microsomes of wildlife animals which died a natural cause can act as a valuable tool to assess the occurrence and effects of phase I metabolism. Some precautions are discussed, that should be taken to reduce the chance of false negative results.

Animals↗
PubMed1998

Subtyping stereotypic behavior in children: the association between stereotypic behavior, mood, and heart rate.

The stereotypic behavior of children (N = 26) while in a playroom session with their parent was studied. The sample included children with a pervasive developmental disorder, an attention-deficit/hyperactivity disorder, a developmental expressive language disorder, or a developmental receptive language disorder and normally developing children. Stereotypic behaviors associated with distress, elation, and composure were compared on mean duration and form of the stereotypies and heart rate changes around the onset of the stereotypies. Results showed that stereotypies associated with different moods differed in all variables studied. Results confirm that a valid classification scheme for stereotypic behaviors is needed as they indicate different functions of individual stereotypies.

Affect↗
PubMed1998

Protection of UV-induced suppression of skin contact hypersensitivity: a common feature of flavonoids after oral administration?

In this study we investigated the effect of the dietary ingredients fruit and vegetable, green tea phenol extract (GTP) and the specific flavonoid components quercetin and chrysin on the UV-induced suppression of the contact hypersensitivity (CHS) response to picryl chloride (PCl). The SKH-1 mice were fed with test diet from 2 or 4 weeks before and during the UV irradiation (daily, 95 mJ/cm2) and tested for the CHS ear-swelling response 10 weeks after the onset of the irradiation. For the CHS, mice were immunized with PCl by epicutaneous application on nonirradiated sites. Four days after sensitization all mice were challenged on both sides of each ear by topical application of one drop PCl. In addition, from mice fed with the fruit and vegetable mixture the number of Langerhans cells (LC) were scored in the skin and from mice fed with quercetin, quercetin levels in plasma were measured at week 11 after the start of UV irradiation. It was found that fruit and vegetable (19% in the diet), GTP (0.1% and 0.01% in the drinking water), quercetin (1% in the diet) and chrysin (1% and 0.1% in the diet), prevented statistically significantly the UV-induced suppression of CHS to PCl. In the skin of mice fed with fruit and vegetables combined with UV irradiation the number of LC were comparable to the control mice, whereas the number of LC were significantly diminished in mice treated with UV only. This protective effect on the presence of LC in the epidermis after UV irradiation, which was also observed in a previous study with quercetin, may play a role in the prevention of UV-induced immunosuppression by the flavonoids tested. In conclusion, we found protection of flavonoids against UV-induced effects on CHS, which may be a common feature of most flavonoids.

Animal Feed↗