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Biomedical subjects

M Peter

Publications and source records attributed to M Peter.

At least 73 records · Page 4Linked to original sources
PubMed1998

Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing's tumor. Société Française d'Oncologie Pédiatrique.

PURPOSE: Gene fusions that result from the chromosome translocations observed in Ewing's tumor (ET) provide tumor-specific markers that can be used to detect the presence of tumor cells in peripheral blood (PB), bone marrow (BM), and stem cell collection (SCC). These markers were used to evaluate, at diagnosis, a series of 67 ET patients. PATIENTS AND METHODS: RNA was extracted from nucleated cells from PB and BM and a nested reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to search for EWS-FLI-1 or EWS-ERG fusion transcripts that resulted from the t(11;22) or t(21;22) translocations, respectively. RESULTS: At diagnosis, 16 of 62 (26%) patients had circulating tumor cells. This was not correlated with any clinical parameter. In contrast, Ewing's cells were detected by RT-PCR in BM in 14 of 43 (33%) patients and were associated with the presence of clinically detectable metastases and a statistically significant unfavorable outcome in univariate analysis. There was no correlation between the RT-PCR results in PB and in BM. CONCLUSION: These results suggested that the monitoring of BM but not of PB by RT-PCR might constitute an important criterion for the staging, at diagnosis, of patients with ET. Further studies should appreciate the relationship or independence of this marker toward other classical prognostic factors in ET, particularly to the presence of clinically detectable metastases.

Adolescent↗
PubMed1998

Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene.

X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with glycerol kinase deficiency (GKD) and Duchenne's muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne's muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates' persisting fetocortex. Aldosterone deficiency usually preceded cortisol deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional truncated DAX-1 protein. Two brothers with primary adrenal insufficiency and a medical history that strongly suggested AHC had no mutation in the DAX-1 gene. Thus, additional, as yet unknown genes must play a part in normal adrenal cortical development.

Adrenal Insufficiency↗
PubMed1998

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies.

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

Base Sequence↗
PubMed1998

Cytogenetic and molecular analysis of a t(1;22)(p36;q11.2) in a rhabdoid tumor with a putative homozygous deletion of chromosome 22.

Malignant rhabdoid tumors are rare and aggressive neoplasms of childhood, occurring in the kidney or in various extrarenal locations. Most cytogenetic studies of these tumors have shown the frequent involvement of chromosome 22, including translocations and/or deletions, with a critical region for a rhabdoid tumor gene mapping to chromosome segment 22q11, close to BCR. We report a case of an extrarenal rhabdoid tumor with a t(1;22)(p36;q11.2) that was associated with deletions of chromosomes 1 and 22. We have performed fluorescence in situ hybridization to bracket the translocation breakpoints on both chromosomes and microsatellite analysis to establish the deletion of chromosome 22 more precisely. The chromosome 22 translocation breakpoint is localized close to BCR, in the region covered by the overlapping YACs 446B5 and 361D9, and it is associated with a proximal hemizygous deletion of approximatively 2 Mb. On chromosome 1, the translocation breakpoint maps to a 25 cM region, proximal to D1Z2 and distal to PND, and is also associated with an estimated deletion of 8 Mb. Moreover, microsatellite analysis has demonstrated a homozygous deletion of chromosome 22 for three contiguous loci, immediately distal to BCR. This result suggests that a tumor suppressor gene involved in rhabdoid tumor oncogenesis could be localized in this region of chromosome 22.

Chromosomes, Human, Pair 1↗
PubMed1997

Novel Cdc42-binding proteins Gic1 and Gic2 control cell polarity in yeast.

Cdc42p, a Rho-related GTP-binding protein, regulates cytoskeletal polarization and rearrangements in eukaryotic cells, but the effectors mediating this control remain unknown. Through the use of the complete yeast genomic sequence, we have identified two novel Cdc42p targets, Gic1p and Gic2p, which contain consensus Cdc42/Rac interactive-binding (CRIB) domains and bind specifically to Cdc42p-GTP. Gic1p and Gic2p colocalize with Cdc42p as cell polarity is established during the cell cycle and during mating in response to pheromones. Cells deleted for both GIC genes exhibit defects in actin and microtubule polarization similar to those observed in cdc42 mutants. Finally, the interaction of the Gic proteins and Cdc42p is essential, as mutations in the CRIB domain of Gic2p that eliminate Cdc42p binding disrupt Gic2p localization and function. Thus, Gic1p and Gic2p define a novel class of Cdc42p targets that are specifically required for cytoskeletal polarization in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Phosphorylation- and ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor Far1p in budding yeast.

Cyclin-dependent kinase inhibitors (CKIs) play key roles in controlling the eukaryotic cell cycle by coordinating cell proliferation and differentiation. Understanding the roles of CKIs requires knowledge of how they are regulated both through the cell cycle and in response to extracellular signals. Here we show that the yeast CKI, Far1p, is controlled by ubiquitin-dependent proteolysis. Wild-type Far1p was stable only in the G1 phase of the cell cycle. Biochemical and genetic evidence indicate that its degradation required the components of the G1-S ubiquitination system, Cdc34p, Cdc4p, Cdc53p, and Skp1p. We isolated a mutant form of Far1p (Far1p-22) that was able to induce cell cycle arrest in the absence of alpha-factor. Cells that overexpress Far1-22p arrested in G1 as large unbudded cells with low Cdc28p-Clnp kinase activity. Wild-type Far1p, but not Far1-22p, was readily ubiquitinated in vitro in a CDC34- and CDC4-dependent manner. Far1-22p harbors a single amino acid change, from serine to proline at residue 87, which alters phosphorylation by Cdc28p-Cln2p in vitro. Our results show that Far1p is regulated by ubiquitin-mediated proteolysis and suggest that phosphorylation of Far1p by the Cdc28p-Clnp kinase is part of the recognition signal for ubiquitination.

Anaphase-Promoting Complex-Cyclosome↗
PubMed1997

Polymerase chain reaction compared with dot blotting for the determination of N-myc gene amplification in neuroblastoma.

The magnitude of N-myc amplification (NMA) influences the treatment strategy of localized neuroblastomas. Reliable assays are therefore needed for all types of tumor samples. The aim of this comparative study of 119 tumor samples was to determine whether a polymerase chain reaction (PCR)-based assay could replace the current dot blot assay as a routine and reliable means of determining NMA. The 2 assays exhibited comparable sensitivity and were completely concordant for samples containing at least 20% neuroblastoma cells. In their present state, both assays remain semi-quantitative since an absolute quantification of the N-myc copy number in clinical samples is limited by uncertainty about the amplification level of reference cell lines and by the estimation of the proportion of malignant cells. However, PCR offers several advantages over dot blotting, such as feasibility on minute samples, simplicity, standardization, rapidity and cost effectiveness.

Cost-Benefit Analysis↗
PubMed1997

Bni1p, a yeast formin linking cdc42p and the actin cytoskeleton during polarized morphogenesis.

The Saccharomyces cerevisiae BNI1 gene product (Bni1p) is a member of the formin family of proteins, which participate in cell polarization, cytokinesis, and vertebrate limb formation. During mating pheromone response, bni1 mutants showed defects both in polarized morphogenesis and in reorganization of the underlying actin cytoskeleton. In two-hybrid experiments, Bni1p formed complexes with the activated form of the Rho-related guanosine triphosphatase Cdc42p, with actin, and with two actin-associated proteins, profilin and Bud6p (Aip3p). Both Bni1p and Bud6p (like Cdc42p and actin) localized to the tips of mating projections. Bni1p may function as a Cdc42p target that links the pheromone response pathway to the actin cytoskeleton.

Actins↗
PubMed1997

A new member of the ETS family fused to EWS in Ewing tumors.

As a result of chromosome translocations, the EWS gene is fused to a variety of transcription factors in human solid neoplasia. In Ewing tumors EWS can be fused to four different members of the ETS family, namely FLI-1, ERG, ETV1 and E1AF. We have identified a new member of the ETS family, called FEV, which is fused to EWS in a subset of Ewing tumors. FEV encodes a 238 amino acid protein which contains an ETS DNA binding domain closely related to that of FLI-1 and ERG. However, the N-terminal portion of FEV is only 42 amino acids long which suggests that FEV is lacking important transcription regulatory domains contained in FLI-1 and ERG N-terminal parts. The C-terminal end of FEV is rich in alanine residues which may indicate that FEV is a transcription repressor. The FEV gene is encoded by three exons and is located on chromosome 2. FEV expression was only detected in adult prostate and small intestine but not in other adult nor in fetal tissues, thus indicating that FEV has a restricted expression pattern. Following a scheme similar to previously described translocations in Ewing tumors, a t(2;22) chromosome translocation fuses the N-terminal domain of EWS to the ETS DNA binding domain of FEV.

Adult↗
PubMed1997

The regulation of cyclin-dependent kinase inhibitors (CKIs).

Inhibitors of cyclin-dependent kinases (CKIs) play key roles in coordinating cell proliferation and development. They also function to control critical cell cycle transitions and as effectors of checkpoint pathways. The activity of CKIs is tightly controlled through the cell cycle and in response to various signals. Regulation generally affects the levels or availability of the CKIs rather than changing their intrinsic activities. Mechanisms controlling CKI function include the regulation of transcription, translation and proteolysis. In addition some signals appear to induce sequestration of CKIs within the cells, thereby changing their ability to interact with specific targets.

Animals↗
PubMed1997

A higher rate of hyperandrogenic disorders in female-to-male transsexuals.

In an effort to elucidate the aetiology of female-to-male transsexualism (FM-TS) 12 out of an annual sample of 16 untreated female-to-male transsexuals (FMT), aged 19 years 7 months (19;7) to 44 years 8 months (44;8) [median age (M) 27;5] were assessed by means of sexual-medical questionnaires, physical and endocrinological examination. The control group consisted of 15 healthy women (CF), aged 19 years 2 months (19;2) to 36 years 1 month (36;1) (M 22;7) without gender identity disorder, who were not under hormonal medication (including contraceptives). Baseline levels of testosterone (T; ng/dl), androstenedione (A4; ng/dl), dehydroepiandrosterone sulfate (DHEAS; ng/ml), luteinizing hormone (LH; IU/l), follicle stimulating hormone (FSH; IU/l), and sex-hormone binding globuline (SHBG; microgram/dl) were measured. A standard single-dose ACTH stimulation test (250 micrograms ACTH IV; Synacthen) was performed with all subjects. Aldosterone (ALDO), corticosterone (B), deoxycorticosterone (DOC), progesterone (PROG), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (S), cortisol (F), cortisone (E), pregnenolone (PREG) and 17-hydroxypregnenolone (OHPREG) were assessed before and 60 min after ACTH stimulation. Transvaginal ultrasound was performed in nine out of 12 FMT (20;11 to 44;8, M 27;5; m 29.1 +/- 7.5) but not in CF. Results showed that 10 FMT (83.3%) and five CF (33.3%) were above normal values for at least one of the measured androgens. Baseline levels of T and A4 were significantly higher in FMT than in CF (T: 54.0 +/- 13.8 vs. 41.1 +/- 12.8; A4: 244.8 +/- 73.0 vs. 190.5 +/- 49.3; p < .05), whereas DHEAS, SHBG, LH and FSH did not differ between the groups. Unbound T (T/SHBG ratio) was higher in FMT (72.0 +/- 67.6) than in CF (26.4 +/- 15.1). Baseline levels of 17OHP, OHPREG and DOC were higher in FMT than in CF (p < .05). After ACTH stimulation 17OHP and OHPREG remained higher in FMT than in CF (p < .05). Single case analysis of ACTH stimulation test together with physical examination revealed symptoms for non-classical congenital adrenal hyperplasia (NC-CAH) in six FMT (50%) and two CF (13.3%). Eight out of nine FMT who were assessed by means of transvaginal ultrasound (i.e. 88.9%; 50.0% of 16) had polycystic ovaries (PCO). Oligomenorrhoea or menstrual dysregularities (81.7% of 16 FMT vs. 0% of CF), hirsutism (56.2% of 16 FMT vs. 13.3% of 15 CF) and adiposity (25.0% vs. 0%) were frequent in FMT, but not in CF. Hyperandrogenism with polycystic ovarian syndrome (PCOS) and adrenocortical hyperresponsiveness to ACTH seems to be a common finding in FMT. This offers support for a hormonal factor in the genesis of FM-TS. Because the prevalence of PCOS and NC-CAH in the female population is higher than FM-TS, the true nature of this factor and its interaction with environmental influences remains unknown.

Adrenocorticotropic Hormone↗
PubMed1997

[New biological prognostic factors of soft tissue sarcoma. SFOP (Société française d'oncologie pédiatrique)].

Malignant tumors of soft tissue constitute a very heterogeneous group of tumors which is composed of more than 50 different entities derived from either the mesenchyme or the neuroectoderm. Diagnostic problems can be linked to the difficulty to firmly establish the diagnosis of malignancy and to the precise determination of the type of sarcoma. The prognostic is largely dependent on local and distant extension of the cancer. The study of the genotype of tumor cells has enabled the detection and characterization of genetic alterations. These alterations, frequently chromosome translocations, are specific markers for subgroups of tumors and can thus be of clinical relevance. These markers can be detected by cytogenetic, in situ hybridization or molecular biology techniques. The specificity of these alterations for tumor cells and the possibility to detect them with the highly sensitive polymerase chain reaction (PCR) technique have enabled development of tests aimed at the detection of tumor cells within potential metastatic sites.

Genetic Markers↗
PubMed1997

Anthropometrical measurements and androgen levels in males, females, and hormonally untreated female-to-male transsexuals.

To elucidate the relationship between body build, androgens, and transsexual gender identity, anthropometric measurements were assessed in 15 hormonally untreated female-to-male-transsexuals (FMT). Nineteen healthy women (CF) (X = 22 years; 2 months), and 21 healthy men (CM) (X = 23; 7) were enrolled as controls. Baseline levels of testosterone (T; ng/dl), androstenedione (A4; ng/dl), dehydroepiandrosterone sulfate (DHEAS; ng/ml), and sex-hormone binding globulin (SHBG; microgram/ml) were assessed in 12 FMT, 15 CF, and in all CM. No control was under hormonal medication (including contraceptives). Absolute measurements in FMT were in accordance with their biological sex: they showed only small differences from the CF. However, FMT differed from CF in 7 of 14 sex-dimorphic indices of masculinity/femininity in body build. Of these 14 indices, 9 did not show a difference between FMT and CM. Hence, FMT presented a more masculine body build, particularly in fat distribution and bone proportions. Levels of T and A4 were significantly higher in FMT than in CF (T: 54.0 +/- 13.8 vs. 41.1 +/- 12.8; A4: 244.8 +/- 73.0 vs. 190.5 +/- 49.3), while DHEAS was higher in CM (3335 +/- 951) than in CF (2333 +/- 793) and in FMT (2679 +/- 1089). Altogether, 83.3% of FMT and 33.3% of CF were above normal values for at least one measured androgen. SHBG in FMT (1.21 +/- 0.70) and CF (1.87 +/- 0.91) was higher than in CM (0.49 +/- 0.18) and tended to be higher in CF than in FMT. Unbound T (T/SHBG ratio) was higher in FMT (72.0 +/- 67.6) than in CF (26.4 +/- 15.1) and correlated positively with manly body shape. Findings are discussed in relation to etiology of transsexualism.

Adult↗
PubMed1997

The influence of mode of delivery on hematologic values in the umbilical vein.

A variable white blood cell count without clinical signs of sepsis or hematological disorders is often observed in newborns. The intention of this study was to investigate the effect of mode of delivery on hematologic measurements, especially white blood cell count in the umbilical vein. 121 term newborns were investigated prospectively. They were subdivided into three groups: spontaneous births (n = 83), vacuum extraction (n = 19) and cesarean sections (n = 19). The mode of delivery influenced the leukocyte count and the precursor cells. The mean leukocyte counts after spontaneous birth (14.6 +/- 4.0 leukocytes/nl) and after vacuum extraction (16.6 +/- 7.4 leukocytes/nl) were significantly higher than after cesarean section (12.1 +/- 4.4 leukocytes/nl; p < 0.05). The precursors of leukocytes were also significantly higher in infants with vacuum extraction (1.06 +/- 0.83 cells/nl) than in spontaneously delivered infants (0.54 +/- 0.47 cells/nl). An inverse relationship between the number of leukocytes and the arterial cord blood pH was observed (p < 0.05). No significant differences were observed in the effect of mode of delivery on erythrocyte and platelet counts.

Cesarean Section↗
PubMed1997

Evidence for endocrinological abnormalities in heterozygotes for adrenal 11 beta-hydroxylase deficiency of a family with the R448H mutation in the CYP11B1 gene.

In about 5% of cases of classical congenital adrenal hyperplasia, steroid 11 beta-hydroxylase deficiency is the underlying defect. In two publications, no biochemical abnormalities have been reported in obligate heterozygotes for 11 beta-hydroxylase deficiency. We found the typical plasma steroid pattern of 11 beta-hydroxylase deficiency and identified the R448H mutation in the CYP11B1 gene in a boy presenting with pseudoprecocious puberty at age 2 yr. Both parents and an older sister were genotyped and were heterozygous carriers for the R448H mutation in CYP11B1. In contrast to the data reported in the literature, we found increased responses of plasma 11-deoxycortisol and 11-deoxycorticosterone in the short term ACTH test in the three family members heterozygous for the R448H mutation.

Adrenal Glands↗
PubMed1997

Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997.

We studied two of the three patients with a hereditary defect in the biosynthesis of aldosterone originally described by Visser and Cost in 1964. All three presented as newborns with salt-losing syndrome and failure to thrive. The original biochemical studies showed a defect in the 18-hydroxylation of corticosterone. According to the nomenclature proposed by Ulick, this defect would be termed corticosterone methyl oxidase deficiency type I. We measured plasma steroids in the untreated adult patients and performed molecular genetic studies. Aldosterone and 18-OH-corticosterone were decreased, whereas corticosterone and 11-deoxycorticosterone were elevated, thus confirming the diagnosis of corticosterone methyl oxidase deficiency type I. Cortisol and its precursors were in the normal range. Genetic defects in the gene CYP11B2 encoding aldosterone synthase (P450c11Aldo) have been described in a few cases. We identified a homozygous single base exchange (G to T) in codon 255 (GAG) causing a premature stop codon E255X (TAG). This mutation destroys a Aoc II restriction site. Digestion of a PCR fragment containing exon 4 of CYP11B2 (261 bp) with this restriction enzyme revealed in the two patients homozygous for the E255X mutation only a 261-bp fragment, whereas the heterozygous parents had three fragments (261 bp from the mutant allele and 194 and 67 bp from the wild-type allele). The mutant enzyme had lost the five terminal exons containing the heme binding site, and thus there was a loss of function enzyme. We conclude that the biochemical phenotype of these prismatic cases of congenital hypoaldosteronism can be explained by the patients genotype.

18-Hydroxycorticosterone↗
PubMed1997

Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex.

Major histocompatibility complex (MHC) class II antigens are expressed on adrenocortical cells of the zona reticularis and have been shown to be a marker of dignity. This suggests a correlation to the zellular differentiation of the adrenal cortex. Therefore, we immunohistochemically investigated the MHC class II expression in the context of the ontogenesis of the zonal and cellular differentiation in fetal, postnatal, childhood, and adult adrenals. Cell types and cell turnover were studied using specific immune markers (including expression of CD95/ Fas), in situ end labeling of apoptosis, and electron microscopy. We show that prenatal (fetal and definitive) steroid cells, as well as postnatal adrenals, reveal no expression of MHC class II. In childhood, these antigens first appear by the fourth year, in parallel with the differentiation of reticularis cells. The expression index in childhood was 7.43% +/- 2.78 (mean +/- SEM), in adult adrenals 18.63% +/- 3.14 (third decade), and 15.15% +/- 1.26 (fourth through sixth decade). In conclusion, MHC class II expression and the development of the functional maturation of the adult adrenal cortex occur simultaneously. The expression of MHC class II on steroid cells may thus be involved in potential immune-adrenal interactions.

Adrenal Cortex↗