Biomedical subjects

A S Schulz

Publications and source records attributed to A S Schulz.

14 recordsLinked to original sources

PubMed1999

Anaemia, thrombocytopenia and coagulopathy due to occult diffuse infantile haemangiomatosis of spleen and pancreas.

UNLABELLED: Diffuse infantile haemangiomatosis of the spleen is a very rare lesion. Large haemangiomas may cause trapping of platelets and coagulation disorders known as Kasabach-Merrit syndrome. We here report the case of an infant with splenic and pancreatic haemangiomatosis presenting with life-threatening thrombocytopenia, anaemia and intravascular coagulation. Diagnosis was hampered by reactive erythroblastosis and non-conclusive radiological findings. While treatment with corticosteroids was ineffective, administration of antithrombin III improved coagulation parameters. After splenectomy the child recovered promptly and has remained free of disease for 3 years to date. CONCLUSION: Occult visceral haemangiomatosis without visible cutaneous haemangiomas should be included in the differential diagnosis of thrombocytopenia, anaemia and consumption coagulopathy. Antithrombin III treatment may be considered to overcome bleeding problems in patients with Kasabach-Merrit syndrome.

Anemia↗

PubMed1998

An oncogenic fusion product of the phosphatidylinositol 3-kinase p85beta subunit and HUMORF8, a putative deubiquitinating enzyme.

Peripheral blood cell DNA from a patient with a chronic myeloproliferative disorder was tested in the tumorigenicity assay. Upon tumor induction in nude mice we isolated a human oncogene by means of genomic cloning, exon trap analysis and cDNA cloning. Sequence analysis revealed a fusion product of the p85beta subunit of phosphatidylinositol (PI) 3-kinase and HUMORF8, a putative deubiquitinating enzyme, which has been generated during the DNA transfection process. Application of the tumorigenicity assay to various p85beta and HUMORF8 cDNA constructs indicated that the recombination of both genes rather than the truncation of one of the fusion partners renders the chimeric protein tumorigenic. Moreover, sequence analysis of human wildtype p85beta revealed an alanine for serine substitution at a site important for the regulation of the lipid kinase activity of PI 3-kinase in human p85alpha. This variation may relate to differences in the mode of signal transduction from both p85 isoforms.

3T3 Cells↗

PubMed1997

Approximation algorithms.

Increasing global competition, rapidly changing markets, and greater consumer awareness have altered the way in which corporations do business. To become more efficient, many industries have sought to model some operational aspects by gigantic optimization problems. It is not atypical to encounter models that capture 10(6) separate "yes" or "no" decisions to be made. Although one could, in principle, try all 2(10(6)) possible solutions to find the optimal one, such a method would be impractically slow. Unfortunately, for most of these models, no algorithms are known that find optimal solutions with reasonable computation times. Typically, industry must rely on solutions of unguaranteed quality that are constructed in an ad hoc manner. Fortunately, for some of these models there are good approximation algorithms: algorithms that produce solutions quickly that are provably close to optimal. Over the past 6 years, there has been a sequence of major breakthroughs in our understanding of the design of approximation algorithms and of limits to obtaining such performance guarantees; this area has been one of the most flourishing areas of discrete mathematics and theoretical computer science.

Journal Article↗

PubMed1997

Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site.

Ufo/Axl belongs to a new family of receptor tyrosine kinases with an extracellular structure similar to that of neural cell adhesion molecules. In order to elucidate intracellular signaling, the cytoplasmic moiety of Ufo/Axl was used to screen an expression library according to the CORT (cloning of receptor targets) method. Three putative Ufo substrates were identified: phospholipase Cgamma1 (PLCgamma), as well as p85alpha and p85beta subunits of phosphatidylinositol 3'-kinase (PI3-kinase). Subsequently, chimeric EGFR/Ufo receptors consisting of the extracellular domains of the epidermal growth factor receptor (EGFR) and the transmembrane and intracellular moiety of Ufo were engineered. Using different far-Western blot analyses and coimmunoprecipitation assays, receptor binding of PLCgamma and p85 proteins as well as GRB2, c-src and lck was examined in vitro and in vivo. Competitive inhibition of substrate binding and mutagenesis experiments with EGFR/Ufo constructs revealed C-terminal tyrosine 821 (EILpYVNMDEG) as a docking site for multiple effectors, namely PLCgamma, p85 proteins, GRB2, c-src and lck. Tyrosine 779 (DGLpYALMSRC) demonstrated an additional, but lower binding affinity for the p85 proteins in vitro. In addition, binding of PLCgamma occurred through tyrosine 866 (AGRpYVLCPST). Moreover, our in vivo data indicate that further direct or indirect binding sites for PLCgamma, GRB2, c-src and lck on the human Ufo receptor may exist.

Blotting, Western↗

PubMed1995

Clonal hematopoiesis as defined by polymorphic X-linked loci occurs infrequently in aplastic anemia.

We evaluated the methylation status of the X-linked gene phosphoglycerate kinase (PGK1) and the DXS 255 locus detected by probe M27 beta to study clonality in acquired aplastic anemia (AA). A total of 30 females were suitable for clonal analysis of peripheral blood polymorphonuclear cells (PMN) and mononuclear cells using a polymerase chain reaction-based procedure in 24 patients and Southern blotting in 9. Overall, 10 of 30 patients exhibited an imbalanced X-inactivation pattern. However, in 4 patients, analysis of constitutional DNA suggested a skewed methylation pattern and 2 further cases had to be excluded because of the lack of an appropriate control. A truly clonal pattern was thus established in 4 of 30 (13%) patients. In 7 patients who later developed clonal disorders of hematopoiesis, X-inactivation analysis did not predict this event in any case. In patients with a paroxysmal nocturnal hemoglobinuria phenotype, there was no correlation between the proportion of phosphatidylinositol glycan anchored protein (PIG-AP)-deficient blood cells and the corresponding X-inactivation pattern. X-inactivation analysis detected clonal hematopoiesis in only 3 of 10 patients with a deficiency in PIG-AP in the cell population under study, but sorting of nucleated cells on the basis of PIG-AP expression showed the clonal nature of PIG-AP-deficient cells. We conclude that the majority of patients with AA show polyclonal hematopoiesis using X-linked clonal analysis, but that minor clonal populations, such as PIG-AP-deficient cells, may not be detected unless sorted cell populations are separately analyzed.

Adolescent↗

PubMed1994

Pre-pre-B acute lymphoblastic leukemia: high frequency of alternatively spliced ALL1-AF4 transcripts and absence of minimal residual disease during complete remission.

We used the polymerase chain reaction (PCR) to detect ALL1-AF4 rearrangements, the molecular hallmark of t(4;11) in a series of 46 pre-pre-B (CD19+, CD24+, CD10/CD20/cylgM/sIgM-) acute lymphoblastic leukemias (ALL). Eighteen patients (39%) exhibited fusion transcripts including 4 of 12 children and 14 of 34 adults. This genetic defect was associated with hyperleukocytosis (median leukocyte count 176 x 10(9)/L) and expression of myeloid-associated antigens (CDw65+). In contrast, only two patients from a group of 67 common (CD19/CD10+, cylgM/sIgM-) and pre-B ALLs (CD19/cylgM+, CD10 +/-, sIgM-) showed ALL1-AF4 mRNA. All PCR-positive cases showed multiple amplification products representing alternative splicing events. Moreover, reciprocal der (4)-derived AF4-ALL1 transcripts were observed in 65% of the cases analyzed. Eight of the 18 pre-pre-B ALL patients with an ALL1-AF4 recombination are currently in complete continuous remission for up to 54 months (median, 26 months). Twelve remission samples were available from seven cases, and all of them lacked evidence of minimal residual disease. Overall this study documents a similarly high incidence of ALL1-AF4 recombinations in children (infants excluded) and adults with pre-pre-B ALL and demonstrates the decline of the leukemic cell clone below the detection level of PCR in a remarkable proportion of patients under intense treatment protocols.

Adolescent↗

PubMed1993

Mutations within the FLR exon of NF1 are rare in myelodysplastic syndromes and acute myelocytic leukemias.

A mutational hotspot in the neurofibromatosis 1 (NF1) gene has recently emerged from the analysis of different malignancies including one patient with myelodysplastic syndrome (MDS). In these cases, Lys 1423 in the GTPase-activating protein (GAP)-related domain of NF1 is substituted which causes a significant reduction of intrinsic GAP activity. We studied 57 MDS patients and 27 cases of acute myelocytic leukemia (AML) for mutations at codon 1423 in the so-called FLR exon of NF1 by an assay based on restriction enzyme digestion. We investigated the entire FLR exon and its flanking intron sequences using single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR) products and sequencing. None of the cases exhibited a codon 1423 mutation. However, a patient with chronic myelomonocytic leukemia (CMML) showed a 3 bp deletion within the splice acceptor region in front of the FLR exon. These data suggest that NF1 exon FLR mutations contribute infrequently to the development of MDS and AML.

Acute Disease↗

PubMed1993

The genomic structure of the human UFO receptor.

Using a DNA transfection-tumorigenicity assay we have recently identified the UFO oncogene. It encodes a tyrosine kinase receptor characterized by the juxtaposition of two immunoglobulin-like and two fibronectin type III repeats in its extracellular domain. Here we describe the genomic organization of the human UFO locus. The UFO receptor is encoded by 20 exons that are distributed over a region of 44 kb. Different isoforms of UFO mRNA are generated by alternative splicing of exon 10 and differential usage of two imperfect polyadenylation sites resulting in the presence or absence of 1.5-kb 3' untranslated sequences. Primer extension and S1 nuclease analyses revealed multiple transcriptional initiation sites including a major site 169 bp upstream of the translation start site. The promoter region is GC rich, lacks TATA and CAAT boxes, but contains potential recognition sites for a variety of trans-acting factors, including Sp1, AP-2 and the cyclic AMP response element-binding protein. Proto-UFO and its oncogenic counterpart exhibit identical cDNA and promoter regions sequences. Possible modes of UFO activation are discussed.

Amino Acid Sequence↗

PubMed1992

The murine ufo receptor: molecular cloning, chromosomal localization and in situ expression analysis.

We have cloned the mouse homologue of the ufo oncogene. It encodes a novel tyrosine kinase receptor characterized by a unique extracellular domain containing two immunoglobulin-like and two fibronectin type III repeats. Comparison of the predicted ufo amino acid sequences of mouse and man revealed an overall identity of 87.6%. The ufo locus maps to mouse chromosome 7A3-B1 and thereby extends the known conserved linkage group between mouse chromosome 7 and human chromosome 19. RNA in situ hybridization analysis established the onset of specific ufo expression in the late embryogenesis at day 12.5 post coitum (p.c.) and localized ufo transcription to distinct substructures of a broad spectrum of developing tissues (e.g. subepidermal cells of the skin, mesenchymal cells of the periosteum). In adult animals ufo is expressed in cells forming organ capsules as well as in connective tissue structures. ufo may function as a signal transducer between specific cell types of mesodermal origin.

Amino Acid Sequence↗

PubMed1992

P53 mutations in myelodysplastic syndromes.

Point mutations in the p53 tumor-suppressor gene are the most frequently identified genetic alterations in human malignancies. In order to evaluate the role of p53 mutations in the multistep process of leukemogenesis we studied 61 patients with myelodysplastic syndromes using single-strand conformation polymorphism analysis of polymerase chain reaction products as well as direct sequencing. Mutant alleles were observed in 1/14 refractory anemia with excess of blasts (RAEB) and 2/5 RAEB in transformation. The three mutations represented G:C to A:T transitions at codon 141 (exon 5) and codons 245 and 248 (exon 7), respectively. These data suggest that p53 mutations may contribute, albeit rarely, to the development of preleukemic disorders of the myeloid cell lineage.

Anemia, Refractory↗

PubMed1992

Friend murine leukaemia virus is integrated at a common site in most primary spleen tumours of erythroleukaemic animals.

A common proviral integration site was identified and characterized in erythroleukaemias induced by Friend murine leukaemia virus (F-MuLV). Using inverse polymerase chain reaction, we found a proviral integration site common to at least 90% of 20 primary tumours tested. This site was identical to Fli-1, a locus recently reported by others to be rearranged in 75% (9/12) of cell lines established from spleens of erythroleukaemic mice and to code for a member of the ets gene family. Our data suggest that about half of the F-MuLV-induced erythroleukaemias contained more than one cell clone with a proviral integration in Fli-1, with different individual integration sites within Fli-1 in each cell clone. All proviruses were found to be integrated in the same transcriptional orientation with respect to flanking cellular DNA. We discuss these findings in relation to multistage models of neoplasm.

Animals↗

PubMed1991

A novel putative tyrosine kinase receptor with oncogenic potential.

We have detected transforming activity by a tumorigenicity assay using NIH3T3 cells transfected with DNA from a chronic myeloproliferative disorder patient. Here, we report the cDNA cloning of the corresponding oncogene, designated UFO, in allusion to the as yet unidentified function of its protein. Nucleotide sequence analysis of a 3116bp cDNA clone revealed a 2682-bp-long open reading frame capable of directing the synthesis of a 894 amino acid polypeptide. The predicted UFO protein exhibits characteristic features of a transmembrane receptor with associated tyrosine kinase activity. The UFO proto-oncogene maps to human chromosome 19q13.1 and is transcribed into two 5.0 kb and 3.2 kb mRNAs in human bone marrow and human tumor cell lines. The UFO locus is evolutionarily conserved between vertebrate species. A 4.0 kb mRNA of the murine UFO homolog is expressed in a variety of different mouse tissues. We thus have identified a novel element of the complex signaling network involved in the control of cell proliferation and differentiation.

Amino Acid Sequence↗

PubMed1988

Integration into the cellular genome of a Friend murine leukaemia virus containing a selectable marker reveals a clonal origin of erythroleukaemia.

We have constructed a selectable Friend murine leukaemia virus (F-MuLV) with a suppressor tRNA (supF) gene integrated into the proviral long terminal repeat. The viral construct was infectious and pathogenic and retained the marker gene when growing in vitro or in vivo. Only a few integration sites of the provirus were detected by Southern blot analysis of the DNA of erythroleukaemic cells. These results indicate that F-MuLV-induced erythroleukaemia is of clonal origin and suggest that insertional mutagenesis is involved in pathogenesis.

Animals↗

PubMed1983

Sequence analysis of Gardner-Arnstein feline leukaemia virus envelope gene reveals common structural properties of mammalian retroviral envelope genes.

We have sequenced the envelope (env) gene and most of the adjacent 3' long terminal repeat (LTR) of Gardner-Arnstein feline leukaemia virus subtype B. The LTR of this virus contains, at corresponding positions, all signal sequence elements known from other retroviral LTRs. The deduced amino acid sequence of the longest open reading frame was compared with env polypeptide sequences of several murine leukaemia viruses. This allowed us to predict the positions of both p12/15env and gp70 polypeptides as well as a hydrophobic leader polypeptide. The env polypeptides of the different viruses show long stretches of homology and similar hydrophilicity profiles in the p12env region and in the carboxy-terminal half of gp70 (constant region). The most extensive variations are confined to certain parts of the amino-terminal half of gp70 (differential region). In this region, however, feline leukaemia virus and murine mink cell focus forming viruses are still closely related. A correspondingly spaced pattern of identical, short amino acid sequences appears in three different parts of the env polyprotein, suggesting its evolution from a primordial env-related precursor by tandem duplications.

Amino Acid Sequence↗