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A Smits

Publications and source records attributed to A Smits.

At least 19 recordsLinked to original sources
PubMed2005

A PDGFRA promoter polymorphism, which disrupts the binding of ZNF148, is associated with primitive neuroectodermal tumours and ependymomas.

BACKGROUND: Platelet derived growth factor receptor alpha (PDGFRalpha) expression is typical for a variety of brain tumours, while in normal adult brain PDGFRalpha expression is limited to a small number of neural progenitor cells. The molecular mechanisms responsible for the PDGFRalpha expression in tumours are not known, but in the absence of amplification, changes in transcriptional regulation might be an important factor in this process. METHODS AND RESULTS: We have investigated the link between single nucleotide polymorphisms (SNPs) within the PDGFRalpha gene promoter and the occurrence of brain tumours (medulloblastomas, supratentorial primitive neuroectodermal tumours (PNETs), ependymal tumours, astrocytomas, oligodendrogliomas, and mixed gliomas). These SNPs give rise to five different promoter haplotypes named H1 and H2alpha-delta. It is apparent from the haplotype frequency distribution that both PNET (10-fold) and ependymoma (6.5-fold) patient groups display a significant over-representation of the H2delta haplotype. The precise functional role in PDGFRalpha gene transcription for the H2delta haplotype is not known yet, but we can show that the H2delta haplotype specifically disrupts binding of the transcription factor ZNF148 as compared to the other promoter haplotypes. CONCLUSIONS: The specific over-representation of the H2delta haplotype in both patients with PNETs and ependymomas suggests a functional role for the ZNF148/PDGFRalpha pathway in the pathogenesis of these tumours.

Base Sequence↗
PubMed2004

[Hydrops fetalis as an indication for a systematic investigation into the presence of lysosomal storage diseases].

As a result of the decreased incidence of immunological hydrops fetalis and increased insight, the role of inborn errors of metabolism (IEM) as a cause of hydrops fetalis has acquired increased significance. This growing awareness of the manifestation of IEM in pregnancy has revealed that some 20 of these disorders may cause hydrops fetalis, accounting for a few percent of all cases. These IEM are, for the most part, lysosomal storage diseases. We recommend that standard metabolites and enzymes reflecting lysosomal storage diseases be measured in the amniotic fluid and the amniocytes already withdrawn for karyotyping. The value of the diagnosis of lysosomal storage diseases lies in the opportunity for risk evaluation, genetic counselling and targeted prenatal diagnostics in case of subsequent pregnancies. Obtaining insight into the possible therapestic interventions during the pregnancy in which the hydrops is observed is not a goal of this protocol since the necessary investigations are too time-consuming.

Diagnosis, Differential↗
PubMed2003

Growth factor analysis of low-grade glioma CSF: PDGF and VEGF are not detectable.

Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) are involved in the development of grade 2 gliomas. The aim of the present study was to determine the presence of these growth factors in the cerebrospinal fluid (CSF) and to assess their usefulness as biological markers. CSF was collected from 7 adult patients with newly diagnosed supratentorial low-grade gliomas by lumbar puncture and was analysed together with matched serum samples using radioreceptor and enzyme-linked immunosorbant assays. Neither PDGF nor VEGF were detected in the CSF, and FGF-2 was measurable at extremely low concentrations in only 2 of 7 patients. Serum levels were within normal limits. We conclude that these growth factors are not released into the CSF in any significant amounts and are therefore not suitable as biological markers in grade 2 gliomas.

Adolescent↗
PubMed2002

Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas.

OBJECTIVE: To determine whether the expression of platelet derived growth factor alpha receptor (PDGFRalpha) in low grade astrocytomas and oligoastrocytomas is associated with survival. METHODS: Formalin fixed and paraffin embedded tumour samples of 40 consecutive patients with supratentorial diffuse astrocytomas and oligoastrocytomas of WHO grade 2, resected between 1986 and 1993, were used for immunohistochemical staining. The fraction of tumour cells expressing PDGFRalpha protein was quantified and entered into univariate and multivariate survival analyses. Changes in PDGFalpha expression over time were analysed in seven patients in whom reoperations had been performed. RESULTS: Patients with a relatively high fraction of PDGFRalpha expressing cells had a more favourable outcome in both univariate (p = 0.04) and multivariate analyses (p = 0.02). Expression of PDGFRalpha was greater in oligoastrocytomas than in astrocytomas (p = 0.05). In four reoperated patients with histologically confirmed malignant transformation, there was a marked decrease in the number of cells expressing the receptor. CONCLUSIONS: There is an association between high PDGFRalpha expression and long survival time in patients with grade 2 astrocytomas and oligoastrocytomas. The findings suggest that expression of the receptor may be a useful prognostic marker in such patients.

Adult↗
PubMed2002

Low-grade gliomas: clinical and pathobiological aspects.

The optimal management of patients with low-grade gliomas remains a challenge for the treating physician. The natural history of the disease shows a large variety, and there is a substantial controversy about many of everyday treatment recommendations. However, new developments in clinical and basic research in neuro-oncology have occurred during the last years. In this review some of these new insights into clinical and biological aspects of low-grade gliomas are discussed, with focus on the translation of new knowledge from basic research into clinical practice. For example, molecular genetic profiling of tumour material has started to guide treatment recommendations and clinical management of some patients with oligodendrogliomas. Experimental studies of the different molecular pathways in tumour cells and in their normal counterparts involved in cell-cycle check-point control have elucidated some of the underlying mechanisms of resistance of gliomas to radiotherapy and chemotherapy. Finally, improved classification of the different subtypes of low-grade gliomas may be achieved in the near future by characterization of the genetic heterogeneity within the tumour and by identification of a putative stem cell as the origin of the tumour cells.

Animals↗
PubMed2001

Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas.

BACKGROUND: Considerable numbers of patients with low-grade gliomas experience an early malignant course and may benefit from aggressive treatment. These patients are difficult to identify using established prognostic factors. A retrospective study was performed to determine whether the (11)C-methionine uptake in tumor is a survival factor in adult patients with supratentorial gliomas classified as World Health Organization Grade 2. METHODS: The authors identified 89 patients with histologically confirmed low-grade gliomas in whom an (11)C-methionine positron emission tomography (PET) scan had been performed as part of the diagnostic tumor investigation from 1983 to 1998. Clinical data were collected, and the PET scans were re-evaluated according to a fixed protocol. The (11)C-methionine uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analyses. RESULTS: At the end of the study, 49 patients (55.1%) had died. The median overall survival was 5.7 years. Low methionine uptake was significantly favorable in the multivariate survival analysis (P = 0.04) along with oligodendroglioma (P = 0.003). In the histologic subgroups, (11)C-methionine uptake was an important survival factor among patients with astrocytomas (P = 0.05) and oligodendrogliomas (P = 0.03). Tumor resection was a favorable prognostic factor in patients with high methionine uptake (P = 0.01) but not in patients with low uptake. CONCLUSIONS: Baseline (11)C-methionine PET is a prognostic indicator in patients with low-grade gliomas. The results imply that PET is a valuable tool in the clinical management of these patients and may assist in the selection of patients for therapy.

Adult↗
PubMed2001

Molecular analysis of a familial case of renal cell cancer and a t(3;6)(q12;q15).

We identified a novel familial case of clear-cell renal cancer and a t(3;6)(q12;q15). Subsequent cytogenetic and molecular analyses showed the presence of several abnormalities within tumour samples obtained from different patients. Loss of the der(3) chromosome was noted in some, but not all, of the samples. A concomitant VHL gene mutation was found in one of the samples. In addition, cytogenetic and molecular evidence for heterogeneity was obtained through analysis of several biopsy samples from one of the tumours. Based on these results and those reported in the literature, we conclude that loss of der(3) and subsequent VHL gene mutation may represent critical steps in the development of renal cell cancers in persons carrying the chromosome 3 translocation. Moreover, preliminary data suggest that other (epi)genetic changes may be related to tumour initiation.

Adult↗
PubMed2000

[Low malignancy grade glioma in the Uppsala++/Orebro region. Prognostic factors and survival among 119 patients].

The benefit of surgery and radiotherapy for patients with low-grade gliomas is controversial. We studied case records of 119 patients diagnosed with low-grade glioma during 1987-1993 at our hospital. Statistical analysis was made on overall survival and on survival related to histological diagnosis and treatment modality. A large variation in survival of patients with similar histological diagnosis was seen. No correlation was found between survival and treatment modality. This clinical diversity probably reflects variations in tumor biological characteristics of low-grade gliomas. Greater understanding of the biology of these tumors will thus be needed for more effective therapies.

Adolescent↗
PubMed2000

[Risk of increased malignancy a reason for follow-up of low malignancy grade glioma. Early identification of high-risk patients is the key to good care].

Management of patients with low-grade gliomas remains a challenge. Controversies exist regarding the value of surgery and radiotherapy as well as the right timing of these treatments with respect to disease course. Several factors have been shown to have a positive correlation with better outcome, involving tumor size and localization, age and clinical condition of the patient on presentation, and epileptic seizures as a single symptom. The absence of contrast enhancement on CT-scans is also a favorable prognostic factor. Taking into account the results of these studies as well as our own experience, we suggest some strategies for the management of patients with low-grade gliomas. The importance of identifying "high-risk" patients by systematic clinical and radiological follow-up is discussed.

Brain Neoplasms↗
PubMed2000

Introduction of an N-glycosylation site increases secretion of heterologous proteins in yeasts.

Saccharomyces cerevisiae is often used to produce heterologous proteins that are preferentially secreted to increase economic feasibility. We used N-glycosylation as a tool to enhance protein secretion. Secretion of cutinase, a lipase, and llama V(HH) antibody fragments by S. cerevisiae or Pichia pastoris improved following the introduction of an N-glycosylation site. When we introduced an N-glycosylation consensus sequence in the N-terminal region of a hydrophobic cutinase, secretion increased fivefold. If an N-glycosylation site was introduced in the C-terminal region, however, secretion increased only 1.8-fold. These results indicate that the use of N glycosylation can significantly enhance heterologous protein secretion.

Animals↗
PubMed1999

Noninvasive test for fragile X syndrome, using hair root analysis.

Identification of the FMR1 gene and the repeat-amplification mechanism causing fragile X syndrome led to development of reliable DNA-based diagnostic methods, including Southern blot hybridization and PCR. Both methods are performed on DNA isolated from peripheral blood cells and measure the repeat size in FMR1. Using an immunocytochemical technique on blood smears, we recently developed a novel test for identification of patients with fragile X syndrome. This method, also called "antibody test," uses monoclonal antibodies against the FMR1 gene product (FMRP) and is based on absence of FMRP in patients' cells. Here we describe a new diagnostic test to identify male patients with fragile X syndrome, on the basis of lack of FMRP in their hair roots. Expression of FMRP in hair roots was studied by use of an FMRP-specific antibody test, and the percentage of FMRP-expressing hair roots in controls and in male fragile X patients was determined. Control individuals showed clear expression of FMRP in nearly every hair root, whereas male fragile X patients lacked expression of FMRP in almost all their hair roots. Mentally retarded female patients with a full mutation showed FMRP expression in only some of their hair roots (<55%), and no overlap with normal female controls was observed. The advantages of this test are (1) plucking of hair follicles does no appreciable harm to the mentally retarded patient, (2) hairs can be sent in a simple envelope to a diagnostic center, and (3) the result of the test is available within 5 h of plucking. In addition, this test enabled us to identify two fragile X patients who did not show the full mutation by analysis of DNA isolated from blood cells.

Alkaline Phosphatase↗
PubMed1998

A familial case of renal cell carcinoma and a t(2;3) chromosome translocation.

Cytogenetic analysis was performed on peripheral blood lymphocytes of members of a family with inherited renal cell cancer. Four family members in three generations developed multiple/bilateral renal cell carcinomas of the clear cell type. In one additional case a bladder carcinoma was diagnosed. In two of the renal cell carcinoma patients a constitutional t(2;3)(q35;q21) was encountered, whereas in the two other (deceased) patients the presence of this translocation could be deduced. Also, the bladder cancer patient was found to be positive for t(2;3)(q35;q21). This is the third familial renal cell carcinoma-associated chromosomal translocation ever described. The previously reported cases also involved chromosome 3, thereby supporting the notion that this chromosome may play a crucial role in the development of renal cell carcinomas. Interestingly, the translocation breakpoints in these three families map at different locations, suggesting that multiple genes on chromosome 3 may be involved.

Aged↗
PubMed1998

Platelet-derived growth factor (PDGF) in primary brain tumours of neuroglial origin.

It has become clear that disruptions in the genome of somatic cells play a causative role in tumour development. We know that the ultimate formation of a malignancy is the result of a multistep process in which the functional loss and/or the altered or increased expression of genes play important roles. One such family of genes are the oncogenes, encoding protein products with mainly growth stimulating effects. Platelet-derived growth factor (PDGF) belongs to the family of oncogenes. It is likely that PDGF plays an essential role in the development of at least a subgroup of malignant astrocytic tumours that do not contain amplification of the EGF-receptor. The expression of PDGF alpha-receptors is related to tumour progression in these tumours, and some of the most malignant tumours were shown to contain amplification of the PDGF alpha-receptor. It is also clear now from several experimental studies that PDGF can drive the transformed phenotype, and that PDGF antagonists, by blocking the PDGF autocrine pathway revert the transformed phenotype of certain tumour cells. Because of the findings that receptor protein tyrosine kinases such as the EGF- and the PDGF-receptor play a crucial role in the development of gliomas, it is possible that inhibitors of the phosphorylation of the protein tyrosine kinases will be future candidates for glioma therapy. They might be able to at least delay the development of a fully malignant glioma. The role of PDGF in other tumours of neuroglial origin in the central nervous system has not been studied as extensively as its role in gliomas. Recent data suggest that also for the primitive neuroectodermal tumours overexpression of the PDGF alpha-receptor is related to malignancy of the tumours. For other tumours, such as neuroblastomas, PDGF exerts a differentiating rather than a mitogenic function and is an important survival factor. Further studies are needed to elucidate the role of PDGF in these non-glial primary brain tumours. Moreover, for a complete understanding of the role of PDGF in malignancies of the CNS, it is important to explore its function in the development of the normal CNS further.

Animals↗
PubMed1998

Intraspecific isozyme polymorphism of Anopheles gambiae in relation to environment, behavior, and malaria transmission in southwestern Burkina Faso.

A cellulose acetate electrophoresis system was used to study the isozyme polymorphism of the Anopheles gambiae complex in a rural village and a city in southwestern Burkina Faso. In both areas A. gambiae Giles was the dominant species (95%) whereas A. arabiensis Patton represented only 5%. Both species were separated readily by octanol dehydrogenase Odh and mannose phosphate isomerase (Mpi) even if they shared some alleles at these two loci. Polymorphism analysis (13 loci) at the intraspecific level of A. gambiae showed a significant difference between the specimens collected in the city from those collected in the village in their allelic and genotypic frequencies of isocitrate dehydrogenase-1 and malate dehydrogenase-1 and in their allelic frequencies for Mpi. No genetic difference was observed between the human biting A. gambiae collected inside or outside the houses in either the village or the city. The Plasmodium falciparum-infected A. gambiae differed from the noninfected ones in their allelic and genotypic frequencies at Mpi and acid phosphatase (Acp). A two-fold difference in infection rate was found for the genotype Mpi130/130 and Acp110/100 compared with other genotypes. However, infected anophelines were found in all genotypes that belonged to these two enzyme systems. Consequently, no refractory mechanism occurs in these natural populations.

Alcohol Oxidoreductases↗