Search PubMed⌕ Search

Biomedical subjects

M Peter

Publications and source records attributed to M Peter.

At least 91 records · Page 5Linked to original sources
PubMed1997

Impairment of 11 beta-hydroxylase but not 21-hydroxylase in adrenal 'incidentalomas'.

Recent reports have shown an exaggerated response of 17-hydroxyprogesterone in up to 70% of patients with incidentally detected adrenal adenomas ('incidentalomas'). This has been explained by pre-existing 21-hydroxylase deficiency which may be a pathogenetic factor in the development of adrenal tumours. However, other defects in steroidogenesis, such as mild 11 beta-hydroxylase deficiency, could also result in increased 17-hydroxyprogesterone secretion. We therefore studied the glucocorticoid and mineralocorticoid pathways in patients with adrenal 'incidentalomas' by measuring multiple adrenal steroids before and after 1-24 ACTH stimulation. Twenty patients with adrenal 'incidentalomas' (14 females, 6 males) and 27 healthy controls (14 females, 13 males) were studied. All subjects underwent a 1-24 ACTH stimulation test (250 micrograms i.v.) with determination of progesterone, 11-deoxycorticosterone, corticosterone, 17-hydroxyprogesterone, 11-deoxycortisol and cortisol at 0 and 60 min. All steroids were measured by RIA after extraction and HPLC. Patients with 'incidentalomas' had higher stimulated concentrations of 17-hydroxyprogesterone (21.6 +/- 8.4 vs 4.2 +/- 0.3 nmol/I; P < or = 0.001), 11-deoxycortisol (8.1 +/- 1.2 vs 3.6 +/- 0.3 nmol/I; P < or = 0.001), progesterone (8.28 +/- 2.82, vs 1.08 +/- 0.15 nmol/I; P < or = 0.001), and 11-deoxycorticosterone (2.1 +/- 0.39 vs 0.78 +/- 0.12 nmol/I; P = 0.002) compared with controls. In contrast, cortisol and corticosterone concentrations were not different. There was evidence for impairment of 11 beta-hydroxylase activity by an increased 11-deoxycortisol/ cortisol ratio (0.012 +/- 0.003 vs 0.005 +/- 0.001 in controls; P = 0.002) and 11-deoxycorticosterone/ corticosterone ratio (0.04 +/- 0.003 vs 0.015 +/- 0.003; P = 0.003). The conclusions reached were that patients with adrenal 'incidentalomas' have increased responses of precursors of the mineralocorticoid and glucocorticoid pathway including 17-hydroxyprogesterone after stimulation with ACTH. This seems to be caused by impairment of 11 beta-hydroxylase activity rather than by impaired 21-hydroxylase activity in these tumours.

17-alpha-Hydroxyprogesterone↗
PubMed1997

Malignant melanoma of the soft parts (clear-cell sarcoma): confirmation of EWS and ATF-1 gene fusion caused by a t(12;22) translocation.

We report on the cytogenetic and molecular analysis of a malignant melanoma of the soft parts (MMSP). A t(12;22)(q13;q12) was found as the only structural chromosomal change, and this provides additional support for the important role of this translocation in MMSP development. Molecular analysis revealed in frame fusion between exon 10 of the Ewing's sarcoma oncogene (EWS) and codon 110 of ATF-1. In previously analyzed MMSPs, junctions were observed between EWS exon 8 and ATF-1 codon 65. The present data thus indicate that, as in Ewing's sarcoma, different fusion proteins can occur in MMSP. The presence of the EWS/ATF-1 fusion gene in the tumor cells was demonstrated by dual color fluorescence in situ hybridization on interphase nuclei. Our data provide additional support for the specific association of the t(12;22) and the resulting EWS/ATF-1 gene fusion in MMSP. This particular genetic aberration, therefore, serves as a strong diagnostic marker for MMSP. We conclude that detection of the t(12;22) by cytogenetic or molecular analysis is useful in establishing or confirming the diagnosis of MMSP.

Activating Transcription Factor 1↗
PubMed1997

[Simulation of in vivo study conditions for comparing the possibilities and limits of mammography in various breast implants].

Especially in breast reconstruction after mastectomy, subcutaneous mastectomy, or extensive lumpectomy, the radiological properties of breast implants play an important role. Mammography is still the gold standard for follow-up diagnostics as well as for preventive diagnostics, and the interpretation of these films is greatly influenced by the type of the implant filler material. In this study, in vivo conditions are simulated, and standard mammography techniques applied to examine the effects of various types of implants on the readability of mammography films using semiquantitative measurements as well as subjective judgement by independent radiologists.

Breast Implants↗
PubMed1996

Functional analysis of the interaction between the small GTP binding protein Cdc42 and the Ste20 protein kinase in yeast.

STE20 encodes a protein kinase related to mammalian p65Pak which functions in several signal transduction pathways in yeast, including those involved in pseudohyphal and invasive growth, as well as mating. In addition, Ste20 plays an essential role in cells lacking Cla4, a kinase with significant homology to Ste20. It is not clear how the activity of Ste20 is regulated in response to these different signals in vivo, but it has been demonstrated recently that binding of the small GTP binding protein Cdc42 is able to activate Ste20 in vitro. Here we show that Ste20 functionally interacts with Cdc42 in a GTP-dependent manner in vivo: Ste20 mutants that can no longer bind Cdc42 were unable to restore growth of ste20 cla4 mutant cells. They were also defective for pseudohyphal growth and agar invasion, and displayed reduced mating efficiency when mated with themselves. Surprisingly, however, the kinase activity of such Ste20 mutants was normal when assayed in vitro. Furthermore, these alleles were able to fully activate the MAP kinase pathway triggered by mating pheromones in vivo, suggesting that binding of Cdc42 and Ste20 was not required to activate Ste20. Wild-type Ste20 protein was visualized as a crescent at emerging buds during vegetative growth and at shmoo tips in cells arrested with alpha-factor. In contrast, a Ste20 mutant protein unable to bind Cdc42 was found diffusely throughout the cytoplasm, suggesting that Cdc42 is required to localize Ste20 properly in vivo.

Amino Acid Sequence↗
PubMed1996

AACR-ISREC joint symposium "Cancer and the cell cycle' January 17-20, 1996, Lausanne, Switzerland.

It has become apparent in the recent years that defects in regulatory systems of the eukaryotic cell cycle contribute, in a major way, to the evolution of a neoplastic phenotype in mammalian cells. The American Association of Cancer Research (AACR) and the Swiss Institute for Experimental Cancer Research (ISREC) jointly organized a meeting, held last January in Lausanne/Switzerland, to discuss recent results in cell cycle research and their implications for cancer.

Cell Cycle↗
PubMed1996

An EWS/ERG fusion with a truncated N-terminal domain of EWS in a Ewing's tumor.

As a result of chromosome translocations, the EWS gene is fused to a variety of transcription factors in human solid tumors. Up to now, gene fusions of EWS with 6 different partners have been described. In all fusions presently reported the entire N-terminal domain of EWS (NTD-EWS) composed of 265 amino acids encoded by the first 7 exons of EWS was always included in the chimeric proteins, suggesting that the integrity of this domain was mandatory for the oncogenic property of the fusion proteins. We report the molecular characterization of a Ewing tumor demonstrating a reciprocal t(21;22)(q22;q12) translocation. No EWS/ERG fusion transcript could be detected with previously reported RT-PCR primers. However, Southern-blot experiments demonstrated that the EWS gene was disrupted within a 2-kb PstI genomic fragment including exon 7. PCR amplification and sequence of the translocation junction fragments indicated that the breakpoint was localized within exon 7 of EWS. The resulting fusion gene encoded a chimeric protein in which a truncated NTD-EWS was linked, in frame, to the ETS DNA-binding domain of ERG. This observation indicates that, to avoid false negative results, RT-PCR-based diagnosis of tumors with EWS fusion transcripts should now include the search for such rare variants. It also suggests that the amino-terminal portion of the NTD-EWS, but not its carboxy terminal part, might be fundamental for the oncogenicity of the chimeric proteins.

Adolescent↗
PubMed1996

Clinical relevance of loss heterozygosity of the short arm of chromosome 1 in neuroblastoma: a single-institution study.

Neuroblastoma is characterized by a wide variability of its clinical course, and considerable effort has been made to identify factors determining outcome in this disease. In a series of 82 patients from a single institution, we have investigated the prognostic impact of multiple clinical, biological and genetic parameters. Univariate testing showed that advanced stage of disease, abdominal localization of the primary tumor, elevated urinary dopamine levels, N-myc amplification (NMA) and loss of heterozygosity of chromosome lp (LOH lp) were related to a poor outcome. Most of these parameters were strong indicators of treatment failure in children younger than 12 months of age but none of them, apart from stage, had a significant prognostic impact in patients older than 12 months at diagnosis. Interestingly, the shorter survival time associated with the presence of lp deletions or NMA appears to be more strongly linked to a poorer outcome after relapse or progression than to a shorter progression-free interval. Although different types of LOH lp have been described in neuroblastoma and may be associated with different biological features, as suggested by a different pattern of catecholamine secretion, tumors with LOH lp present an aggressive clinical behavior, regardless of the type of LOH lp. In this study, LOH lp is an indicator of poor prognosis and identifies a larger population at risk than NMA alone.

Chromosomes, Human, Pair 1↗
PubMed1996

N-MYC amplification, loss of heterozygosity on the short arm of chromosome 1 and DNA ploidy in retinoblastoma.

Recurrent genetic alterations different from the alteration of the RB1 gene on chromosome 13q14 have been described in retinoblastoma, including structural alterations on the short arm of chromosome 1 and amplification of the N-MYC oncogene. These two genetic alterations are major prognostic factors in neuroblastoma, another embryonic neuro-ectodermal tumour. In order to assess the frequency of these alterations and their possible association with clinical parameters in retinoblastoma, we studied a series of 46 retinoblastoma tumour samples. Ploidy was assessed by flow cytometry, N-MYC copy number was evaluated by a spot-blot procedure using the pNb-1 probe and loss of heterozygosity was investigated by PCR analysis at mini- and microsatellites located on the short arm of chromosome 1. Most tumours were in the diploid or near diploid range; only one case exhibited tetraploidy. N-MYC amplification was observed in only one of the 45 tumours. Loss of heterozygosity on the short arm of chromosome 1 was observed in 9/43 tumours (21%); in particular, its incidence was higher in metastatic than in localised disease (P < 0.05). We suggest that alterations of one or several genes on chromosome 1p might play a role in the oncogenesis or progression of retinoblastoma. Analysis of the long term follow-up of these and additional patients should determine the prognostic value of this parameter.

Child, Preschool↗
PubMed1996

Prenatal diagnosis of congenital adrenal hypoplasia.

Congenital adrenal hypoplasia is a rare disorder and one of the possible causes of low maternal plasma and/or urine estriol during pregnancy. We studied 2 cases pre- and postnatally. Dehydroepiandrosteronesulfate (DHAS) and estriol (E3) studied longitudinally in maternal plasma were at or below the lower limit of the normal range. Prior to substitution treatment, an ACTH test revealed low plasma levels of aldosterone, cortisol and all their precursors, with no rise after ACTH. ACTH plasma levels were elevated. It is possible to detect congenital adrenal hypoplasia prenatally in families at risk by repeated measurements of DHAS and estriol in maternal plasma during pregnancy.

Adrenal Insufficiency↗
PubMed1996

Congenital hypoaldosteronism: the Visser-Cost syndrome revisited.

In 1964, H. K. A. Visser and W. S. Cost were the first to suggest a defect of the terminal aldosterone (Aldo) biosynthesis in patients with hypoaldosteronism. In the last years, the molecular basis of the terminal Aldo biosynthesis has been elucidated. Aldo biosynthesis requires 11beta-hydroxylation of 11-deoxycorticosterone to form corticosterone, hydroxylation at position C-18 to form 18-hydroxycorticosterone (18-OHB), and finally oxidation at position C-18. One single cytochrome P450 enzyme (P450aldo) catalyzes all three reactions in the zona glomerulosa. The coding gene is termed CYP11B2. Two inborn errors of terminal Aldo biosynthesis characterized by overproduction of corticosterone and deficient synthesis of Aldo have been described. Corticosterone methyl oxidase deficiency type I (CMO I) is distinguished by decreased production of 18-OHB while CMO II is characterized by overproduction of 18-OHB and an elevated ratio of 18-OHB to Aldo. Both disorders are inherited by an autosomal recessive trait and cause salt-wasting and failure to thrive in early infancy. Our present series includes 14 CMO deficient infants diagnosed by multisteroid analysis (RIA after extraction and automated high performance gel chromatography) which provides precise biochemical criteria for the differentiation of the two CMO variants. So far, three different mutations within the CYP11B2 gene in patients with P450aldo deficiency have been described. Introduction of these mutations into a CYP11B2 cDNA expression vector construct and subsequent expression in COS cells revealed loss of 11beta-hydroxylase, 18-hydroxylase, and 18-dehydrogenase activity of P450aldo. Further molecular studies on more P450aldo-deficient patients might clarify in the future the still existing discrepancies in CYP11B2 (P450aldo) structure-function relationship.

Aldosterone↗
PubMed1996

CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

Accurate knowledge of the molecular basis of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a prerequisite for genetic counseling, prenatal diagnosis, and treatment. Analysis of nine patients suffering from severe manifestations of this disorder led to the identification of seven novel mutations in their CYP11B1 genes. A Caucasian patient was homozygous for the missense mutation R448H, previously found only in Jews of Moroccan origin. An Iranian patient was found to be homozygous for a different mutation in the same codon, R448C. Of four unrelated patients, two were homozygous for a nonsense mutation (W247X), whereas two others were compound heterozygotes for W247X in combination with either R448H or E371G. Two other patients were homozygous for either the missense mutation A331V or an in-frame CTG insertion adjacent to codon 464 (InsCTG464). One patient was a compound heterozygote for two mutations in exon 2, a 28-bp deletion (delta 28bpEx2) and the missense mutation V129M. All of the missense mutations and the CTG insertion caused a complete loss of steroid 11 beta-hydroxylating activity when expressed in cultured cells. These data support previous suggestions of mutational hot spots in CYP11B1 and confirm that severe clinical manifestations are associated with complete loss of enzymatic activity.

Adrenal Hyperplasia, Congenital↗
PubMed1995

A multiplex PCR assay for routine evaluation of deletion of the short arm of chromosome 1 in neuroblastoma.

Deletions of the short arm of chromosome 1 (1p) are frequent alterations in neuroblastoma. Although a consensus region of deletion has been mapped to chromosome subband 1p36, recent studies suggest that several distinct loci on this chromosome may be involved in neuroblastoma. Moreover, different patterns of deletion might be associated with different clinical and biological characteristics of the tumours. These findings emphasise the importance of assessing the localisation and the extent of the deletions in neuroblastoma. We developed a technique which allows analysis of loss of heterozygosity at multiple loci on 1p in a single step, making use of a multiplex PCR method. Primers specific for six microsatellite loci mapped in the different regions of interest on 1p were used for simultaneous amplification of DNA, and loss of heterozygosity was determined after separation of the alleles by denaturing polyacrylamide gel electrophoresis. This technique enables a simple analysis of the position and extent of 1p deletions, and can be used for routine evaluation of 1p status in neuroblastoma.

Chromosome Deletion↗
PubMed1995

Sensitive detection of occult Ewing's cells by the reverse transcriptase-polymerase chain reaction.

Recently, Ewing's tumours have been shown to carry specific hybrid transcripts resulting from the fusion of the EWS gene with FLI-1 or ERG genes. Based on the sensitivity and specificity of the detection of these alterations by the reverse transcriptase-polymerase chain reaction technique, we have developed an assay to search for small numbers of Ewing cells in various sites from patients with Ewing's tumour. This method enables the detection of fewer than one tumour cell per million blood mononuclear cells. A total of 28 primary sites and 51 peripheral samples from 36 patients were investigated. Tumour cells could be detected in 4/18 blood samples, 4/15 bone marrow aspirates and 2/18 peripheral stem cell harvests. EWS/FLI-1 and EWS/ERG transcripts being observed in eight and two cases respectively. The type of fusion transcript detected in peripheral site(s) was identical to that observed in the primary site. At diagnosis 5/16 patients (31%) demonstrated either circulating tumour cells or/and occult bone marrow metastasis. After induction therapy, tumour cells were detected in 3/21 patients. This highly sensitive method should be a relevant tool to allow a more accurate clinical assessment of the dissemination of Ewing's tumours.

Base Sequence↗
PubMed1995

Visual outcome after transsphenoidal surgery for pituitary adenomas.

We have reviewed the records of 53 patients with visual impairment secondary to pituitary macroadenomas and studied the visual outcome after surgery. After transsphenoidal procedures visual field defects improved in 89% of the patients and visual acuity improved in 82%. There were 13 cases of acute symptomatic intratumoural haemorrhage (pituitary apoplexy) in this series. After surgery, visual defects improved in all these cases even when the delay between the onset of symptoms and surgery was long.

Adenoma↗
PubMed1995

FAR1 is required for oriented polarization of yeast cells in response to mating pheromones.

Cell polarization involves specifying an area on the cell surface and organizing the cytoskeleton towards that landmark. The mechanisms by which external signals are translated into internal landmarks for polarization are poorly understood. The yeast Saccharomyces cerevisiae exhibits polarized growth during mating: the actin cytoskeleton of each cell polarizes towards its partner, presumably to allow efficient cell fusion. The external signal which determines the landmark for polarization is thought to be a gradient of peptide pheromone released by the mating partner. Here we described mutants that exhibit random polarization. Using two assays, including a direct microscope assay for orientation (Segall, J. 1993. Proc. Natl. Acad. Sci. USA. 90:8332-8337), we show that these mutants cannot locate the source of a pheromone gradient although they are able to organize their cytoskeleton. These mutants appear to be defective in mating because they are unable to locate the mating partner. They carry mutations of the FAR1 gene, denoted far1-s, and identify a new function for the Far1 protein. Its other known function is to promote cell cycle arrest during mating by inhibiting a cyclin-dependent kinase (Peter, M., and I. Herskowitz. 1994. Science (Wash. DC). 265:1228-1232). The far1-s mutants exhibit normal cell cycle arrest in response to pheromone, which suggests that Far1 protein plays two distinct roles in mating: one in cell cycle arrest and the other in orientation towards the mating partner.

Alleles↗