Biomedical subjects

K Pritchard-Jones

Publications and source records attributed to K Pritchard-Jones.

8 recordsLinked to original sources

PubMed1992

Equivalent expression of paternally and maternally inherited WT1 alleles in normal fetal tissue and Wilms' tumours.

Observations of non-random maternal 11p allele loss in Wilms' tumour (WT) have implied the possible involvement of an imprinted 11p locus in WT aetiology. A proposed 11p13 Wilms' tumour gene, WT1, has recently been isolated and encodes a zinc finger DNA-binding protein, the 3' untranslated region of which contains a polymorphic dinucleotide repeat (CA repeat) motif. We have exploited this transcribed CA repeat to examine the allelic expression pattern of WT1 and thereby determine whether transcriptional imprinting of this gene occurs. DNA and reverse-transcribed RNA from tumours and normal tissue were subjected to the polymerase chain reaction (PCR) using radiolabelled primers flanking the CA repeat. The gene was seen to be expressed from both of the constitutive alleles in 9-week human fetal kidney, all informative Wilm's tumours and neonatal kidney tissue adjacent to the tumours. In one tumour, known to be heterozygous for a point mutation in zinc finger 2, direct sequencing confirmed that both mutant and wild-type transcripts were being expressed. These results demonstrate that this gene is not subject to transcriptional imprinting in tumours or normal fetal kidney.

Alleles↗

PubMed1991

Cell types expressing the Wilms' tumour gene (WT1) in Wilms' tumours: implications for tumour histogenesis.

Wilms' tumour (nephroblastoma), a childhood embryonal kidney tumour, is believed to arise from malignant transformation of abnormally persistent metanephric blastemal cells. At a histological level, tumours show a remarkable mimicry of the normal nephrogenic pathway. There is histological and epidemiological evidence for at least two pathogenetic groupings within Wilms' tumour which may reflect different timings of the tumorigenic insult in this pathway and/or involvement of different genes. Tumorigenesis is thought to result from loss of function of a so-called tumour-suppressor gene which has an essential role in control of normal genitourinary development. Such a candidate, Wilms' tumour gene (WT1) mapping to chromosome 11p13, has been isolated and is known to be mutated in some tumours. We have examined the cell types expressing this gene in 32 Wilms' tumours and in nephroblastomatosis by in situ mRNA hybridization. Our results show that WT1 is expressed only in neoplastic structures whose normal counterparts also express the gene and that abnormally persistent high levels of expression are common in both these lesions. Thus, WT1 expression is a good marker for tumour differentiation and reveals how the normal pattern of differentiation is disrupted in Wilms' tumours. We postulate that mutation of the WT1 gene at the 11p13 locus results in Wilms' tumours associated with intralobar nephrogenic rests, which frequently show stromal-predominant histology. We have used our results and ideas to reinterpret current theories on tumour histogenesis and propose a model which explains how patterns of epithelial differentiation are disrupted in Wilms' tumour and how malignant stroma can result from mutation in WT1.

Antibodies, Monoclonal↗

PubMed1990

The candidate Wilms' tumour gene is involved in genitourinary development.

Wilms' tumour is an embryonic kidney tumour thought to arise through aberrant mesenchymal stem cell differentiation and to result from loss of function of a 'tumour suppressor' gene(s). Both sporadic and syndrome-associated Wilms' tumours are accompanied by an increased frequency of abnormalities of the urinary tract and genitalia. Deletional analysis of individuals with the WAGR syndrome (for, Wilms' tumour, aniridia, genitourinary abnormalities and mental retardation) showed that a Wilms' tumour gene lies at chromosomal position 11p13. This led to the isolation of a candidate Wilms' tumour gene, encoding a zinc-finger protein which is likely to be a transcription factor. To gain insight into the role of this candidate gene in normal development and tumorigenesis, we have now performed in situ messenger RNA hybridization on sections of human embryos and Wilms' tumours. The candidate Wilms' tumour gene is expressed specifically in the condensed mesenchyme, renal vesicle and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli and in cells approximating these structures in tumours. The other main sites of expression are the genital ridge, fetal gonad and mesothelium. These data suggest that (1) this candidate is indeed a Wilms' tumour gene, (2) the associated genital abnormalities are pleiotropic effects of mutation in the Wilms' tumour gene itself, in support of recent genetic analysis, and (3) this gene has a specific role in kidney development and a wider role in mesenchymal-epithelial transitions.

Blotting, Northern↗

PubMed1990

Wilms' tumour as a paradigm for the relationship of cancer to development.

Wilms' tumour or nephroblastoma is one of the commonest solid paediatric malignant diseases, accounting for 8% of childhood cancers. The tumour arises through aberrant differentiation of metanephric mesenchyme and thus represents a paradigm for the relationship of cancer and development. There is considerable heterogeneity in the pathology of Wilms' tumour and several genes have been implicated in its aetiology. One of these genes, located at chromosome 11p13, is categorised as a 'tumour suppressor' gene since loss of function can lead to malignancy. It has not been possible as yet to correlate the involvement of a particular locus with a subset of tumour pathology. The recently cloned Wilms' tumour gene encodes a putative transcription factor which is likely to activate or repress the expression of other genes in kidney development. We have shown by in situ hybridization that expression of this gene is restricted to specific cell types within the developing kidney. It is also expressed in a limited range of embryonic tissues, including the gonad, spleen and mesothelium. With the benefit of this new information, we speculate on the part played by this gene in normal kidney development, in tumorigenesis and in other aspects of Wilms' tumour; these include associated congenital abnormalities, genetic predisposition to second tumours and inheritance of Wilms' tumour.

Abnormalities, Multiple↗

PubMed1989

Wilms tumour: a developmental anomaly.

Wilms tumour (WT) is a developmental anomaly of the kidney which results from loss of function of at least one so called tumour suppressor gene on chromosome 11. The position of the gene at chromosome 11p13 is known through the association of WT with aniridia (lack of an iris), mental retardation and genitourinary abnormalities in the WAGR syndrome. Here we discuss the high resolution mapping studies to locate the position of the gene and conclude that the gonadal abnormalities in WAGR patients may be due to a defect in the WT gene itself. In support of this role in genitourinary development we show that a candidate WT gene is expressed in specific regions of the developing kidney and in fetal and embryonic gonads.

Abnormalities, Multiple↗

PubMed1988

The significance of an M2 bone marrow at cessation of chemotherapy in childhood acute lymphoblastic leukemia.

The decision to cease chemotherapy in childhood acute lymphoblastic leukemia (ALL) is taken when clinical examination and investigations at the end of the predetermined treatment period show no evidence of residual disease. Since 1972, 11 children treated at this institution have not fulfilled the criteria for cessation of therapy in that they all had elevated blast counts in their bone marrows at "off-treatment" studies (i.e., an M2 marrow, defined as 5-25% blasts). Initially, the significance of this finding was not appreciated and the first child in this series received a further 2 years of chemotherapy. Subsequently the relevance of such an M2 marrow to remission status was questioned and the next 10 patients were simply observed and their bone marrows were reexamined after an interval of 4-12 weeks. Nine of these 11 remain in continuous complete remission with a follow-up of 5-15 years from diagnosis. It is postulated that this finding represents an immunologic rebound phenomenon and is not related to potential for later relapse.

Bone Marrow Cells↗

PubMed1986

Insulin oedema.

A 35 year old markedly underweight woman presented with uncontrolled diabetes. Following insulin therapy she developed gross fluid retention with extensive peripheral oedema, bilateral pleural effusions and weight gain of 18.8 kg in 22 days, accompanied by a fall in plasma albumin. She responded well to treatment with diuretics and salt-poor albumin, losing 10.3 kg in 6 days without recurrence of oedema. Severe insulin oedema is an uncommon complication of insulin therapy and may be due to effects of insulin on both vascular permeability and the renal tubule.

Adult↗

PubMed1986

Continuous ECG monitoring of children with cancer receiving domperidone.

Domperidone is an effective antiemetic for children receiving cytotoxic therapy. There have been reports of cardiac arrest in older patients associated with domperidone. We carried out continuous ECG monitoring of 18 children receiving domperidone intravenously in a dose of 1 mg/kg body weight. No serious dysrhythmias were noted during 379 h of recording. Single premature beats, transient sinus pauses, and nodal block were occasionally associated with vomiting and were no more common than would be expected in a population of normal children.

Adolescent↗