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Biomedical subjects

W Zumkeller

Publications and source records attributed to W Zumkeller.

At least 19 recordsLinked to original sources
PubMed2003

Three novel PAX6 mutations in patients with aniridia.

AIMS: To describe mutations in the PAX6 gene in five patients with aniridia from three unrelated families. METHODS: The PAX6 gene was analysed using single stranded conformational polymorphism analysis and direct sequencing. RESULTS: In one family, three individuals from two generations had aniridia, whereas in each of the other families only one member was affected. The first patient had the heterozygous Q221X (1023C --> T) nonsense mutation in exon 8. The same mutation was found in his mother and sister. Another patient had a heterozygous Q297X (1252C --> T) mutation in exon 10. The third patient carried a heterozygous IVS5+2T --> C mutation leading to aberrant splicing of mRNA. CONCLUSIONS: These findings provide further examples of haploinsufficiency of PAX6 in aniridia.

Aniridia↗
PubMed2001

The IGF/IGFBP system in CNS malignancy.

The insulin-like growth factor (IGF) system includes IGF-I and IGF-II, the type I and type II IGF receptors, and specific IGF binding proteins (IGFBP-1 to IGFBP-6). These factors regulate both normal and malignant brain growth. Enhanced expression of IGF-I and IGF-II mRNA transcripts has been demonstrated in gliomas, meniningiomas, and other tumours. Abnormal imprinting of IGF-II occurs in gliomas, medulloblastomas, and meningiomas. Both types of IGF receptor are expressed in gliomas and, in particular, the type I IGF receptor appears to be upregulated in malignant brain tissue. Antisense IGF-I receptor mRNA induces an antitumour response, resulting in complete brain tumour regression. Clinical trials for the treatment of brain tumours in humans based on a gene transfer protocol using IGF-I receptor antisense are under way. All six IGFBPs are expressed to a variable extent in brain tumours. High concentrations of IGFBP-2 are found in cerebrospinal fluid from patients with malignant central nervous system tumours; therefore, IGFBP-2 might be a useful marker for these tumours. IGFBP-4 appears to be a negative regulator of tumour proliferation. Both in vitro and in vivo experiments suggest that the IGF system represents an important target for the treatment of malignant central nervous system tumours and the ongoing trials should provide valuable information for future therapeutic approaches.

Biomarkers↗
PubMed2001

IGFs and IGFBPs: surrogate markers for diagnosis and surveillance of tumour growth?

Insulin-like growth factors (IGFs), IGF receptors, and IGF binding proteins (IGFBPs) constitute the IGF system. Comprehensive data indicate that these factors play a pivotal role in tumorigenesis. Epidemiological data indicate that cancer risk is associated with high serum IGF-I values. Because dysregulation of the IGF system is a frequent pattern in malignancy, IGFs/IGFBPs might represent novel tumour markers that could be useful both for diagnosis and surveillance.

Animals↗
PubMed2001

Clinical, endocrinological and radiography features in a child with McCune-Albright syndrome and pituitary adenoma.

McCune-Albright syndrome is a rare syndrome presenting with polyostotic dysplasia, cafe-au-lait spots and multiple endocrinopathies that is very often combined with precocious puberty. We examined the clinical, endocrinological and radiological features in a boy with McCune-Albright syndrome and pituitary adenoma. X-rays, magnetic resonance (MRI) scan, whole body scintigraphy, single photon emission computer tomography (SPECT) and 3D-reconstruction from bone SPECT was performed to evaluate clinical improvement after treatment with sandostatin and pamidronic acid. After a six-month period of treatment with sandostatin and pamidronate, bone scintigraphy revealed significantly reduced activity. Treatment with bromocriptine and methimazole led to normalization of prolactin and thyroid hormone levels. Mobility of the patient improved. A significant improvement as a result of treatment with sandostatin and pamidronic acid was found in this patient with generalized fibrous dysplasia. So far, this condition has been treated with pamidronate only in adults, but severely affected children also benefit from this treatment regimen.

Adenoma↗
PubMed2000

Retention of imprinting of the human apoptosis-related gene TSSC3 in human brain tumors.

Genomic imprinting is the result of a gamete-specific modification leading to parental origin-specific gene expression in somatic cells of the offspring. Several embryonal tumors show loss of imprinting of genes clustered in human chromosome 11p15.5, an important tumor suppressor gene region, harboring several normally imprinted genes. TSSC3, a gene homologous to mouse TDAG51, implicated in Fas-mediated apoptosis, is also located in this region between hNAP2 and p57 (KIP2). TSSC3 is the first apoptosis-related gene found to be imprinted in placenta, liver and fetal tissues where it is expressed from the maternal allele in normal human development. This study investigated the imprinting status of TSSC3 in human normal, adult brain and in human neuroblastomas, medulloblastomas and glioblastomas. A polymorphism in exon 1 at position 54 was used to analyze the allelic expression of the TSSC3 gene by a primer oligo base extension (PROBE) assay using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found that the TSSC3 gene is not imprinted in human normal, adult brain and blood. In contrast, strong allelic bias resembling imprinting could be detected in most examined tumor specimens. The results demonstrate for the first time that the tumors under investigation are associated with a retention of imprinting of a potential growth inhibitory gene.

Animals↗
PubMed2000

Genomic imprinting of IGF2 and H19 in human meningiomas.

A number of genes, including IGF2 and H19, are normally imprinted with preferential expression of the paternal or maternal allele, respectively. Loss of imprinting (LOI) of IGF2 and H19 is found in a number of tumours, suggesting that LOI of IGF2 and/or H19 may play an important role in tumorigenesis. The IGF2 gene codes for a fetal growth factor and the H19 gene is likely to act as an RNA with an antitumour effect. We investigated the imprinting status of IGF2 and H19 in human meningiomas. The normally imprinted IGF2 gene lacks imprint in the leptomeninges and choroid plexus of the brain. To examine the imprinting status of IGF2 and H19 in human meningiomas we used the ApaI polymorphism in exon 9 for the IGF2 gene and the AluI polymorphism in exon 5 for the H19 gene. In total, 24 meningiomas of WHO grade I, II and III were analysed. 15 meningiomas (63%) were informative for the ApaI polymorphism in the IGF2 gene. Monoallelic expression (MAE) for IGF2 was found in 11 out of 15 tumours (73%) which is in contrast to the lack of imprinting status of IGF2 in leptomeninges. Ten cases (42%) were heterozygous for the H19 gene and biallelic expression was found in 3 out of 10 meningiomas (30%). These results indicate that modulation of the imprinting status of IGF2 and H19 may play an important role for the development of meningiomas.

Adolescent↗
PubMed1998

Expression and synthesis of insulin-like growth factor-binding proteins in human glioma cell lines.

We previously demonstrated the presence of insulin-like growth factors (IGFs) and IGF-receptors in human glioma cell lines derived from primary glioblastomas. The biological action of IGFs is modulated by specific IGF-binding proteins (IGFBP)-1 to -7. By means of polymerase chain reaction (PCR), we detected mRNA transcripts for IGFBP-1 in 42%, IGFBP-2 in 65%, IGFBP-3 in 97%, IGFBP-4 in 3%, IGFBP-5 in 74%, IGFBP-6 in 94% and IGFBP-7 in 87% of the glioma cell lines. The specificity of the PCR reaction was verified by direct sequencing of the PCR product. In addition, the content of the most prevalent IGFBP-3 was measured in conditioned medium from glioma cells by specific radioimmunoassay with levels ranging from < 1 to 620 ng/ml. Moreover, the presence of membrane-bound IGFBPs (44, 50 and 60 kDa) as well as IGF-II receptors was demonstrated by using 125I-labelled IGF-II as a ligand. In conclusion, IGFBPs may modulate the IGF-mediated effects in these cell lines.

Aged↗
PubMed1997

The effect of insulin-like growth factors on brain myelination and their potential therapeutic application in myelination disorders.

Degenerative disorders of the cerebral white matter, leukodystrophies and demyelination diseases, are characterized by the faulty formation or excessive breakdown of myelin. Insulin-like growth factors (IGFs) promote the proliferation of oligodendrocytes as well as their myelin synthesis. IGF-I overexpressing mice show a significant increase in brain weight associated with increased myelin content. In contrast, the brains of IGF-binding protein-1 transgenic mice show a dramatic decrease in myelination. Furthermore, IGFs and IGF-binding proteins are among the factors that are induced by brain injury and have neuroprotective effects. IGFs also induce neurite growth and survival, in particular in glial cells of the peripheral nervous system. In demyelinating diseases, IGF-I may be useful for reducing myelin breakdown and promoting myelin regeneration. These observations may lead to new therapeutic applications for IGFs, for example promoting remyelination or limiting damage following brain injury.

Animals↗
PubMed1997

Immunohistochemical pattern of insulin-like growth factor (IGF) I, IGF II and IGF binding proteins 1 to 6 in carcinoma in situ of the testis.

AIM: To study the immunohistochemical localisation of insulin-like growth factor (IGF) I, IGF II, and IGF binding proteins 1-6 in intratubular germ cell neoplasia in the vicinity of solid germ cell tumours of the testis. METHODS: Testes were obtained from 13 patients (20-35 years old) who had undergone orchidectomy for treatment of a solid germ cell tumour. Tumour cells were verified histologically by their distinctive morphology and by visualisation of placental alkaline phosphatase immunoreactivity. RESULTS: The majority of carcinoma in situ (CIS) cells were immunopositive for IGF I, whereas no CIS cells stained for IGF II. Of all the IGF binding proteins investigated, CIS cells showed intense immunoreactivity for IGF binding protein 5 and lower expression of all other IGF binding proteins. CONCLUSIONS: These results suggest that the action of IGF binding protein 5 in CIS cells may modulate the activity of IGF I. This may be related to a proliferative advantage that could facilitate tumour development.

Adult↗
PubMed1996

Insulin-like growth factors and IGF binding proteins in cyst fluid from patients with craniopharyngioma prior to intracavitary irradiation with Yttrium and thereafter.

Aim-To examine a series of cyst fluid samples from patients with craniopharyngioma at various stages of treatment in order to evaluate the use of insulin-like growth factors (IGFs) and IGF binding proteins as tumour markers or indicators of successful treatment, or both.Methods-Cyst fluid samples were obtained by stereotactic puncture prior to the intracavitary application of (90)Yttrium and at subsequent occasions. Analysis was performed by gel chromatography, radio-immunoassays, binding studies, and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) with subsequent western blotting.Results-IGF-I, -II and IGF binding protein-1 concentrations were measured in three craniopharyngioma cyst fluid samples. Immunoreactive IGF-I and IGF binding protein-1 concentrations in these three samples were between 6 and 29 ng/ml, and 17 and 48 ng/ml, respectively. In contrast, the IGF-II concentrations measured in 19 cyst fluid samples from seven patients with craniopharyngioma at various stages of treatment were much higher at 25-671 ng/ml. SDS-PAGE and subsequent western blotting using [(125)I]IGF-II as the ligand gave bands with estimated molecular weights of 330, 220, 135, 96, 46, 43, 34, 29, and 13.5 kDa in one adult, and identical bands at 220, 41.5, 37.5, 32, and 19 kDa in three cyst fluid samples from three children with craniopharyngioma.Conclusions-These results suggest that IGFs and IGF binding proteins are secreted by craniopharyngiomas and that they may alter the growth characteristics of these tumours. Furthermore, the distinct pattern of IGF binding protein sizes might be used as a tool for the differential diagnosis of tumours of the central nervous system.

Journal Article↗
PubMed1996

Differential expression of novH and CTGF in human glioma cell lines.

Aims-(1) To investigate the expression in human derived glioblastoma cell lines of two structurally related genes, novH (nephroblastoma overexpressed gene) and CTGF (connective tissue growth factor), which encode putative insulin-like growth factor binding proteins of a novel type. (2) To investigate whether the same transcription factors regulate CTGF and novH expression.Methods-Expression of novH and CTGF was analysed in 24 glioblastoma derived cell lines by northern blotting. The CTGF promoter region was characterised by nucleotide sequencing, RNase protection experiments, by transient transfections, and CAT assays.Results-CTGF and novH mRNA levels differed in the glioma cell lines studied. NovH and CTGF genes were not co-expressed in all cell lines. The CTGF promoter region was highly conserved compared with the corresponding region in the mouse (FISP12) and exhibited in vitro transcriptional activity.Conclusions-Although the coding regions of novH and CTGF are highly homologous, their promoter regions are substantially different, suggesting that these two genes may be regulated by different mechanisms. Considering that novH and CTGF are likely to be, respectively, negative and positive regulators of growth and that some glioma cell lines expressing novH are not tumorigenic, expression of these two genes might represent a key element in determining the stage of differentiation or the malignant potential, or both, of some tumour cell lines.

Journal Article↗
PubMed1996

Regulation of insulin-like growth factors and IGF-binding proteins in bone tumours.

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) are important regulators of growth and development in normal bone and bone tumours. IGFs contribute to about 50% of basal bone cell proliferation. Their mitogenic actions is either enhanced or inhibited by specific IGFBPs which are also regulated by a variety of factors. This system is further complicated by the presence of specific proteases for IGFBPs. Serine proteases are secreted by malignant bone tumours and the hydrolysis of IGFBPs increases the bioavailability of IGFs. In addition, the autocrine production of IGFs may facilitate the development of bone tumours and metastatic lesions.

Animals↗
PubMed1995

Insulin-like growth factor II prevents apoptosis in a human teratoma derived cell line.

Aim-To study how insulin-like growth factor II (IGF-II) affects the behaviour of human teratoma cells.Methods-The human pluripotential teratoma cell line Tera 2 was cultured under serum-free conditions in the presence or absence of IGF-II. Effects on cell proliferation and apoptosis as well as on the expression of the proto-oncogene c-myc were studied.Results-In this study we show that Tera 2 cells deprived of serum undergo programmed cell death (apoptosis). The onset of nuclear fragmentation was observed 12 hours after serum withdrawal. The morphological changes of the Tera 2 cell nuclei were confirmed by the occurrence of a nucleosome ladder. However, the constitutive expression of the proto-oncogene c-myc was not decreased in parallel with initiation of apoptosis. The apoptotic response to serum withdrawal could be counteracted by simultaneous addition of IGF-II. In addition it was found that human testicular tumours (seminoma and embryonal carcinoma) contain raised levels of insulin-like growth factors.Conclusions-The precise roles of IGF-I and IGF-II have been unclear, and there is overwhelming evidence against these factors as primarily transforming agents. The finding that IGF-II apparently counteracts apoptosis in vitro may well explain its effects on tumours in vivo.

Journal Article↗