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Biomedical subjects

S de Jong

Publications and source records attributed to S de Jong.

At least 37 records · Page 2Linked to original sources
PubMed2002

Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1.

Anthranoid laxatives, belonging to the anthraquinones as do anthracyclines, possibly increase colorectal cancer risk. Anthracyclines interfere with topoisomerase II, intercalate DNA and are substrates for P-glycoprotein and multidrug resistance-associated protein 1. P-glycoprotein and multidrug resistance-associated protein 1 protect colonic epithelial cells against xenobiotics. The aim of this study was to analyse the interference of anthranoids with these natural defence mechanisms and the direct cytotoxicity of anthranoids in cancer cell lines expressing these mechanisms in varying combinations. A cytotoxicity profile of rhein, aloe emodin and danthron was established in related cell lines exhibiting different levels of topoisomerases, multidrug resistance-associated protein 1 and P-glycoprotein. Interaction of rhein with multidrug resistance-associated protein 1 was studied by carboxy fluorescein efflux and direct cytotoxicity by apoptosis induction. Rhein was less cytotoxic in the multidrug resistance-associated protein 1 overexpressing GLC4/ADR cell line compared to GLC4. Multidrug resistance-associated protein 1 inhibition with MK571 increased rhein cytotoxicity. Carboxy fluorescein efflux was blocked by rhein. No P-glycoprotein dependent rhein efflux was observed, nor was topoisomerase II responsible for reduced toxicity. Rhein induced apoptosis but did not intercalate DNA. Aloe emodin and danthron were no substrates for MDR mechanisms. Rhein is a substrate for multidrug resistance-associated protein 1 and induces apoptosis. It could therefore render the colonic epithelium sensitive to cytotoxic agents, apart from being toxic in itself.

Anthraquinones↗
PubMed2002

Alzheimer's disease is not associated with altered concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine in cerebrospinal fluid.

Nitric oxide (NO) may play a role in the pathophysiology of Alzheimer's disease (AD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is involved in regulation of NO production. Recently it has been reported that dimethylarginine dimethylaminohydrolase, an enzyme that hydrolyses ADMA into citrulline and dimethylamine, is specifically elevated in neurons displaying cytoskeletal abnormalities and oxidative stress in AD. We hypothesized that this could lead to altered CSF concentrations of ADMA in AD. Measurement of ADMA and dimethylamine in CSF revealed no significant differences between AD patients (n = 20) and age-matched control subjects (n = 20). Our results suggest that in early stages of AD overall regulation of NO production by ADMA is not aberrant.

Aged↗
PubMed2002

The potential role of thrombopoietin in idiopathic thrombocytopenic purpura.

Thrombopoietin (TPO) plays a central role in the pathogenesis of idiopathic thrombocytopenic purpura (ITP), as it does in other immune-mediated thrombocytopenias. Because TPO is bound and internalized by platelets, it is destroyed together with platelets at an accelerated rate in the macrophage system. Because the spleen acts as a TPO sink, compensation of the decreased platelet count by an increased production in the bone marrow is insufficient. This aspect of ITP, as well as the use of TPO in the treatment of ITP, will be the focus of this article.

Blood Platelets↗
PubMed2001

Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation.

High-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) may accelerate telomere length loss in haematopoietic stem cells. As data including pre-and post-treatment samples are lacking, we studied leukocyte telomere length and telomerase activity before and after treatment in breast cancer patients randomized to receive 5 adjuvant courses FEC (5-FU, epirubicin and cyclophosphamide) (n = 17), or 4 x FEC followed by high-dose cyclophosphamide, thiotepa, carboplatin and autologous PBSCT (n = 16). Haemoglobin, MCV, leukocyte-and platelet numbers were assessed prior to (t(0)), 5 months after (t(1)) and 9 months after chemotherapy (t(2)); these parameters were decreased at t(1)and t(2)compared to t(0)(high-dose: all parameters; standard-dose: leukocytes and platelets), and all parameters were lower after high-dose than standard-dose treatment at t(1). Paired individual leukocyte samples of t(0)and t(1)showed telomere length change (determined by telomere restricted fragment (TRF) assay) ranging from +0.8 to -2.2 kb, with a decreased TRF length in 9 patients of both groups. Telomerase activity (determined by TRAP assay) was below detection limit in leukocyte samples of t(0)and t(1). Thus, standard-and high-dose chemotherapy negatively affect haematological reconstitution in this setting. In individual patients, telomere length can be remarkably changed following haematological proliferative stress after treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Telomerase in relation to clinicopathologic prognostic factors and survival in cervical cancer.

We investigated, in cervical cancer, the relation between telomerase activity, telomerase RNA (hTR) and mRNA of the catalytic subunit of telomerase, hTERT, with "classic" clinicopathological factors as well as survival. Frozen specimens were obtained from 107 consecutive patients with cervical cancer, treated with surgery or radiotherapy with or without chemotherapy. Telomerase activity was determined with fluorescence-based TRAP and hTR and hTERT with semi-quantitative RT-PCR. Eight normal cervical specimens served as controls. Analysis of prognostic factors and survival was limited to early-stage patients, treated primarily with radical hysterectomy. Telomerase activity was not detected in normal cervices and was present in 85 of 107 (79%) cervical cancers (p < 0.001). hTR was detected in all normal cervices and cervical cancers, while hTERT mRNA was detected in 1 of 8 (13%) normal cervices and in 83 of 104 (80%) cervical cancers (p < 0.001). In contrast to semi-quantitative hTR expression levels, semi-quantitative hTERT mRNA levels were related to telomerase activity levels (p < 0.01). In all patients, telomerase activity levels were related to differentiation grade (p < 0.05) but not to stage and histotype. In early-stage patients, telomerase activity, hTR and hTERT were not related to tumor volume, vascular invasion or presence of metastatic lymph nodes. Tumor volume, vascular invasion and presence of metastatic lymph nodes were related to (progression-free) survival, while telomerase activity and its subunits were not. Frequent up-regulation of telomerase activity and hTERT mRNA is especially observed in cervical cancers, while hTR is also detected in normal cervices. Telomerase is not applicable as a prognostic factor in early-stage cervical cancer patients.

Cervix Uteri↗
PubMed2001

Death receptor ligands, in particular TRAIL, to overcome drug resistance.

The efficacy of chemotherapeutic drugs is hampered by the occurrence of intrinsic and acquired drug resistance. A variety of mechanisms cause drug-resistance. A final common factor, however, is the reduced capacity of drug resistant cells to go into apoptosis following treatment with DNA damaging agents. This is due to defects in apoptotic pathways, for example, changes in p53. The presence of a common factor makes it of interest to search for ways that facilitate the cell to go into apoptosis following exposure to chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands are capable to potentiate the effect of chemotherapeutic drugs in vitro and in vivo in the animal model. Based on preclinical toxicity and activity profiling, especially TRAIL is considered to be of interest for clinical use. Systemic treatment of non-human primates with TRAIL did not result in acute toxicity. Animal studies demonstrated antitumor activity of TRAIL and potentiation of the chemotherapy efficacy by TRAIL. Phase 1 studies with TRAIL will therefore be initiated. As TRAIL is supposed to be non-toxic, it will be a major challenge to design surrogate end points to find the optimal dose in the clinic. In analogy to the herceptin therapy, it may be helpful to characterize the tumor of the patient. In addition, ex vivo exposure of the tumor may also be useful to select the proper ligand therapy for the individual patient. For optimal effect it is most likely that ligand therapy will be combined with chemotherapy, but even a combination of ligands for patient treatments can be envisioned. It is to be expected that smart, small molecules targeting these death receptors will be designed in order to lower toxicity and increase antitumor activity.

Animals↗
PubMed2001

Hyperhomocysteinaemia in patients with peripheral arterial occlusive disease.

In the Western world, cardiovascular disease is still the most common cause of death. Over the past decade it has become clear that apart from common risk factors, high concentrations of total homocysteine are relavant to the process of atherosclerosis, especially in the development of premature vascular disease. Hyperhomocysteinaemia (HHC) can be found in 25-32% of the patients with premature peripheral arterial occlusive disease (PAD). Retrospective and prospective studies, evaluating the clinical course of patients with PAD, showed significant associations between high concentrations of total homocysteine and the severity of atherosclerosis and with a more rapid disease progression and mortality rates. HHC can be treated with vitamin B6 and folic acid. Although there may be indications that there is a protective effect of treatment, prospective randomized clinical trials are urgently needed to unravel the role of HHC and its treatment in patients with premature PAD.

Arterial Occlusive Diseases↗
PubMed2000

Sequential projection pursuit using genetic algorithms for data mining of analytical data.

Sequential projection pursuit (SPP) is proposed to detect inhomogeneities (clusters) in high-dimensional analytical data. Such inhomogeneities indicate that there are groups of objects (samples) with different chemical characteristics. The method is compared with principal component analysis (PCA). PCA is generally applied to visually explore structure in high-dimensional data, but is not specifically used to find clustering tendency. Projection pursuit (PP) is specifically designed to find inhomogeneities, but the original method is computationally very intensive. SPP combines the advantages of both methods and overcomes most of their weak points. In this method, latent variables are obtained sequentially according to their importance measured by the entropy index. This involves an optimization step, which is achieved by using a genetic algorithm. The performance of the method is demonstrated and evaluated, first on simulated data sets, and then on near-infrared and gas chromatography data sets. It is shown that SPP indeed reveals more easily information about inhomogeneities than PCA.

Algorithms↗
PubMed2000

Mathematical modelling of insect neuropeptide potencies. Are quantitatively predictive models possible?

The potencies of natural adipokinetic hormones and synthetic variants have been determined in Locusta migratoria using the lipid mobilisation assay in vivo, and/or the acetate uptake assay in vitro. These data are combinations of previously published and unpublished data (a total of sixty-nine analogues), and form data sets for the construction of mathematical models of the hormone potencies. The sequence variations of amino acids in both natural and artificial adipokinetic hormone analogues were described using continuous descriptor scales z(1)', z(2)', and z(3)', each previously published scale being derived from various properties of the amino acids. By means of these z'-scales and partial least squares regression we attempted to model the potencies in Locusta migratoria of adipokinetic hormones in the two assays. Correlations (r(2) values) between predicted and actual potencies of the different peptides were up to 0.73. We discuss the potential of the partial least squares method for formulating quantitative relationships between different hormone structures and their potencies, and describe how the procedure might be used in structure-activity prediction with the construction of an optimised peptide data set.

Amino Acid Sequence↗
PubMed1999

Changes in fat cell size and in vitro lipolytic activity of abdominal and gluteal adipocytes after a one-year cross-sex hormone administration in transsexuals.

We prospectively studied the effects of cross-sex hormone administration on fat cell size and in vitro lipolytic activity in subcutaneous abdominal and gluteal fat biopsies obtained from 19 male-to-female (M-F) transsexuals and 17 female-to-male (F-M) transsexuals. The amount of subcutaneous fat at the abdominal and gluteal levels was quantified with the use of magnetic resonance imaging (MRI). Before cross-sex hormone administration, M-F transsexuals had less subcutaneous fat with smaller fat cells compared with F-M transsexuals, with a higher baseline in vitro lipolytic activity expressed as glycerol release per milligram of triglyceride (TG) in the abdominal region (P < .05). Before cross-sex hormone treatment, no differences in lipolytic activity stimulated with arterenol (ART), isoproterenol (ISO), or ISO + insulin (INS) were observed between groups or regions. After a 1-year treatment with estrogens and antiandrogens in M-F transsexuals, subcutaneous fat areas on MRI and fat cell size were increased (P < .001) and reductions were observed in the basal lipolytic activity of gluteal and abdominal fat biopsies (P < .05). Following administration of testosterone to F-M transsexuals, subcutaneous fat and fat cell size at the gluteal and abdominal depots were decreased (P < .01) and basal lipolysis was increased significantly at the abdominal level (P < .05) but not at the gluteal level. In both M-F and F-M transsexuals, no effect of sex hormone administration was observed on stimulated lipolytic activities. In conclusion, regional sex differences in the amount of subcutaneous fat, adipocyte size, and in vitro basal lipolytic activity were demonstrated that could be largely reversed by cross-sex hormone treatment in adult subjects, providing evidence for their dependence on the sex steroid milieu.

Abdomen↗
PubMed1999

DNA topoisomerase IIalpha and -beta expression in human ovarian cancer.

To study DNA topoisomerase IIalpha (Topo-IIalpha) and -beta expression and regulation in human ovarian cancer, 15 ovarian tumour samples were investigated. To compare different levels of expression, the samples were screened for topo IIalpha and -beta mRNA with Northern blotting and a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay for Topo-IIalpha mRNA. Additionally, protein levels were determined with Western blotting and topoisomerase II activity levels with the decatenation assay. The results obtained were compared with each other and with the tumour volume index of the samples. In tumours with a tumour volume index > or = 50%, the mRNA levels (as determined by Northern blotting) and protein levels for each isozyme were in accordance. Additionally, correlations were found between Topo-IIalpha RT-PCR data and Topo-IIalpha Northern blot results, and between Topo-IIalpha RT-PCR data and Topo-IIalpha protein levels. Interestingly, Topo-IIbeta protein levels correlated better with Topo-II activity than Topo-IIalpha protein levels. In eight ovarian cystadenoma samples, no Topo-IIalpha protein could be found. In only three out of eight of these cystadenomas, Topo-IIbeta protein could be detected. These findings suggest that Topo-IIalpha and Topo-IIbeta protein levels are up-regulated in ovarian cancer and may indicate that Topo-IIbeta is an interesting target for chemotherapy in ovarian tumours.

Adenocarcinoma↗
PubMed1999

Combined cytotoxic effects of tumor necrosis factor-alpha with various cytotoxic agents in tumor cell lines that are drug resistant due to mutated p53.

Several studies suggest that tumor necrosis factor-alpha (TNF) is able to overcome drug resistance in tumors. Whether TNF is able to do so in tumor cell lines that are drug resistant due to a mutation in the tumor suppressor gene p53 is unclear. Therefore, we studied the in vitro cytotoxic effects of TNF combined with various cytotoxic agents in a model consisting of a human ovarian cancer cell line containing endogenous wild-type p53 (wtp53) and sublines that were made drug resistant against various cytotoxic agents by transfection of several forms of mutated p53 (mtp53). Using the microculture tetrazolium assay, the cytotoxic effects of TNF alone, the cytotoxic agents VM-26, melphalan, cisplatin, vinblastine, paclitaxel, and mitoxantrone, plus the combined effects of 10 ng/ml TNF added 30 min before various concentrations of the cytotoxic agents were established. Compared with the control cell line (A2780/cmv), two cell lines transfected with mtp53 (A2780/m248 and A2780/m273) showed increased resistance against several cytotoxic agents but also an enhanced sensitivity to TNF. Interaction of TNF with the cytotoxic drugs was additive in the drug-sensitive control cell line as well as in the drug-resistant sublines. However, because of the increased sensitivity of A2780/m248 to TNF at the dose used for the combinations, the combination of TNF with several cytotoxic drugs reduced the level of resistance in A2780/m248 compared with the control cell line A2780/cmv. In conclusion, this study shows that addition of TNF can ameliorate resistance to cytotoxic agents in a subline that is drug-resistant because of mutated p53. This reduction in resistance by TNF is not due to synergistic interaction, but to collateral sensitivity to TNF.

Antineoplastic Agents↗
PubMed1998

Sequence specificity of illegitimate plasmid recombination in Bacillus subtilis: possible recognition sites for DNA topoisomerase I.

Previous work in our group indicated that structural plasmid instability in Bacillus subtilis is often caused by illegitimate recombination between non-repeated sequences, characterized by a relatively high AT content. Recently we developed a positive selection vector for analysis of plasmid recombination events in B. subtilis which enables measurement of recombination frequencies without interference of selective growth differences of cells carrying wild-type or deleted plasmids. Here we have used this system to further analyse the sequence specificity of illegitimate plasmid recombination events and to assess the role of the host-encoded DNA topoisomerase I enzyme in this process. Several lines of evidence suggest that single-strand DNA nicks introduced by DNA topoisomerase I are a major source of plasmid deletions in pGP100. First, strains overproducing DNA topoisomerase I showed increased levels of plasmid deletion. Second, these deletions occurred predominantly (>90% of the recombinants) between non-repeated DNA sequences, the majority of which resemble potential DNA topoisomerase I target sites. Sequence alignment of 66 deletion end-points confirmed the previously reported high AT content and, most importantly, revealed a highly conserved C residue at position -4 relative to the site of cleavage at both deletion termini. Based on these genetic data we propose the following putative consensus cleavage site for DNA topoisomerase I of B.subtilis: 5'-A/TCATA/TTAA/TA/TA-3'.

Bacillus subtilis↗
PubMed1998

Effects of dietary coconut oil, butter and safflower oil on plasma lipids, lipoproteins and lathosterol levels.

OBJECTIVE: The aim of this present study was to determine plasma levels of lathosterol, lipids, lipoproteins and apolipoproteins during diets rich in butter, coconut fat and safflower oil. DESIGN: The study consisted of sequential six week periods of diets rich in butter, coconut fat then safflower oil and measurements were made at baseline and at week 4 in each diet period. SUBJECTS: Forty-one healthy Pacific island polynesians living in New Zealand participated in the trial. INTERVENTIONS: Subjects were supplied with some foods rich in the test fats and were given detailed dietary advice which was reinforced regularly. RESULTS: Plasma lathosterol concentration (P < 0.001), the ratio plasma lathosterol/cholesterol (P=0.04), low density lipoprotein (LDL) cholesterol (P<0.001) and apoB (P<0.001) levels were significantly different among the diets and were significantly lower during coconut and safflower oil diets compared with butter diets. Plasma total cholesterol, HDL cholesterol and apoA-levels were also significantly (P< or =0.001) different among the diets and were not significantly different between buffer and coconut diets. CONCLUSIONS: These data suggest that cholesterol synthesis is lower during diets rich in coconut fat and safflower oil compared with diets rich in butter and might be associated with lower production rates of apoB-containing lipoproteins.

Adult↗
PubMed1998

Telomerase activity as a biomarker for (pre)neoplastic cervical disease in scrapings and frozen sections from patients with abnormal cervical smear.

PURPOSE: To evaluate the diagnostic value of semi-quantitative telomerase activity assessment in cervical scrapings together with human papillomavirus (HPV) typing for detection of (pre)neoplastic cervical lesions and to compare telomerase activity in cervical scrapings and frozen specimens from the same patients. PATIENTS AND METHODS: A cross-sectional study was performed in 161 patients referred for an abnormal cervical cytology report. In cervical scrapings, telomerase activity was determined by modified telomere repeat amplification protocol (TRAP) assay and HPV typing by polymerase chain reaction (PCR) with general and type-specific primers. Final diagnosis was made by pathologic examination of biopsy and/or loop excision specimens. RESULTS: Telomerase activity was detectable in assessable scrapings from one of nine (11%) patients without cervical intraepitheleal neoplasia (CIN), in three of 26 (12%) with CIN I, eight of 35 (22%) with CIN II, 18 of 62 (29%) with CIN III, and four of 13 (31%) with cancer. Sensitivity and negative predictive value of the TRAP assay for CIN II/III and cancer lesions were 25% and 28%, respectively, while specificity for no CIN or CIN I was 89%. In representative frozen sections, frequency of detectable telomerase activity was related to grade of CIN/cancer; none of 21 normal cervices, none of two CIN I, two of 12 (17%) CIN II, 10 of 31 (32%) CIN III, and 18 of 21 (86%) cervical cancer lesions were telomerase-positive (P < .0005). Telomerase activity levels in paired scrapings and frozen sections appeared to be only weakly related; telomerase-positive sections with negative scrapings and vice versa (only in CIN III) were observed. In oncogenic HPV-negative scrapings (n = 14), no telomerase activity was detected, but in frozen sections, telomerase activity levels appeared to be unrelated to presence of specific HPV types. CONCLUSION: Telomerase activity is more frequent in higher grade CIN/cervical cancer lesions. Telomerase activity assessment in cervical scrapings has a low sensitivity for CIN II/III and/or cervical cancer and does not appear to be useful in primary screening for cervical cancer. However, increased telomerase activity in frozen CIN sections may be a possible marker of progressive disease.

Biomarkers, Tumor↗
PubMed1997

[Arson usually is not pyromania].

Three patients, two males of 37 and 38 years and one female of 23 years, committed arson inspired by complicated psychiatric problems. They did not meet the specific diagnostic criteria of pyromania. Arson as a rule is not the same thing as pyromania.

Adult↗
PubMed1997

Addition of granulocyte colony-stimulating factor to chemotherapy in patients with AIDS-related lymphoma: effects on neutrophil Fc gamma receptor expression and soluble Fc gammaRIII plasma levels.

AIDS-related neutropenia and neutrophil dysfunction can (partly) be reversed by granulocyte-colony stimulating factor (G-CSF). We studied the effect of G-CSF on neutrophil increment and levels of soluble Fc gamma receptor type III in 15 patients with AIDS-related lymphoma (ARL) undergoing chemotherapy. In six of these patients we performed a detailed kinetic analysis of the membrane expression of the functionally important Fc gamma-receptors type I, II and III. In all these patients G-CSF induced Fc gammaRI positive neutrophils with a decreased expression of the Fc gammaRIII receptor. These changes were similar to those seen both in healthy volunteers and in non-HIV-infected individuals treated with chemotherapy. Interestingly, the mean neutrophil and sFc gammaRIII increment were significantly lower and more patients had a nadir granulocyte count < 0.5 x 10(9)/l after the first cycle than after the second cycle of chemotherapy. This may be related to a therapy-associated decrease in HIV-1 viral load. The conclusion is that patients treated with chemotherapy for ARL have a qualitatively normal response to G-CSF.

AIDS-Related Opportunistic Infections↗