Biomedical subjects

U Brennscheidt

Publications and source records attributed to U Brennscheidt.

24 records · Page 2Linked to original sources

PubMed1990

Molecular organization of the human Raf-1 promoter region.

A genomic DNA fragment containing the Raf-1 promoter region was isolated by using a cDNA extension clone. Nucleotide sequencing of genomic DNA clones, primer extension, and S1 nuclease assays have been used to identify the 5' ends of Raf-1 RNAs. Consistent with its ubiquitous expression, the Raf-1 promoter region had features of a housekeeping gene in that it was GC-rich (HTF-like), lacked TATA and CAAT boxes, and contained heterogeneous RNA start sites and four potential binding sites for the transcription factor SP1. In addition, an octamer motif (ATTTCAT), a potential binding site for the octamer family of transcription factors, was located at -734 base pairs. The Raf-1 promoter region drove reporter gene expression 30-fold over the promoterless reporter in Cos 7 cells.

Base Sequence↗

PubMed1990

Gamma-interferon interrupts growth stimulation in chronic myelogenous leukemia established by endogenous granulocyte colony-stimulating factor.

We have previously shown that maturing neoplastic cells from patients with stable phase chronic myelogenous leukemia (SP CML) constitutively produce granulocyte colony-stimulating factor (G-CSF) and are also receptive for this molecule. G-CSF functions as an endogenous growth factor in SP CML, and thus is responsible for divisions in maturing leukemic cells leading to an expansion of the compartment of mature cells. In the investigations to be reported below, the effects of various hematopoietic inhibitor molecules on the expression of the G-CSF gene by SP CML bone marrow cells enriched for promyelocytes/myelocytes were examined at the mRNA and protein level. We show that exposure of SP CML bone marrow promyelocytes/myelocytes to recombinant human (rh) interferon (IFN)-gamma but not to rh IFN-alpha, rh tumor necrosis factor (TNF)-alpha, and rh lymphotoxin (LT) leads to downregulation of G-CSF expression and interruption of the G-CSF-mediated endogenous growth stimulation. The action of G-CSF takes place at the posttranscriptional level and involves an acceleration of decay of steady-state levels of G-CSF transcripts in the malignant cell population.

Bone Marrow↗

PubMed1990

raf oncogenes in carcinogenesis.

There are three active raf genes in man and at least two in Xenopus and Drosophila. The mammalian c- and A-raf genes have 16 coding exons, which span 40 and 20 kb, respectively. B-raf is larger and extends over greater than 46 kb. Human c-raf-1 maps to chromosome 3p25 and A-raf-1 to Xp21. c-raf-1 RNA is present in many tissues, while A-raf and B-raf expression is restricted. A- and c-raf encode cytoplasmic ser/thr protein kinases of 68 and 74 kDa, which contain three conserved regions (CR). CR1 and 2 are in the amino terminal half, CR1 comprises the presumed ligand binding site, and CR3 represents the carboxy terminal kinase domain. All three genes can be artificially activated by deletions, provided CR3 is preserved. However, only c-raf-1 occurs naturally in truncated versions, such as v-raf and v-mil in the acutely transforming retroviruses 3611-MSV and MH2. raf transformation can also be affected by point mutation, suggesting that this mechanism may activate c-raf-1 as an oncogene in carcinogenesis.

Animals↗

PubMed1989

Loss of heterozygosity at the c-raf locus in small cell lung carcinoma.

The c-raf-1 oncogene is located at chromosome 3p25, near a region known to be specifically deleted in patients with renal cell carcinoma and small cell lung carcinoma (SCLC). From cytogenetic analyses of SCLC cell lines, we have estimated that one c-raf-1 allele was deleted in approximately 80% of the cases. However, c-raf-1 was generally thought to be distal to the most common deletion in SCLC, 3p14-23. Using restriction site polymorphisms (RFLPs) located within the c-raf-1 locus, we have examined DNA from 84 human lung carcinomas. In an analysis of 11 paired (normal versus tumor) SCLC DNA samples, all five informative cases showed loss of heterozygosity at this locus in the corresponding tumor sample. Analysis of 73 unpaired lung carcinoma DNAs showed that out of 31 non-SCLC samples, 19% were heterozygous for the BglI polymorphism and 25% showed heterozygosity with TaqI. However, all of the 42 SCLC samples were homozygous for both of these RFLPs. This striking loss of heterozygosity at the c-raf-1 locus in SCLC indicates that one allele of c-raf-1 is deleted in SCLC. The kinase activity of the c-raf protein appears to be constitutively activated in these cells. Whether this apparent activation results from genetic or epigenetic events is under investigation.

Carcinoma, Small Cell↗

PubMed1984

Palmar fibromatosis (Dupuytren's contracture). Ultrastructural and enzyme histochemical studies of 43 cases.

Forty three cases of palmar fibromatosis were studied by light and electron microscopy, enzyme histochemistry, and ultrastructural immunohistochemistry. By electron microscopy most of the cells composing the nodules in both the proliferative and the involutional stages were identical to myofibroblasts. The myofibroblasts in the involutional nodules often possessed microfilament aggregates probably representing contraction of micro(actin)filaments in the cytoplasm. The proliferative nodules revealed small perivascular haemorrhages and haemosiderin deposits accompanied by accumulation of macrophages and some lymphocytes; these inflammatory cells possibly secrete a certain growth factor inducing proliferation of genetically abnormal fibroblasts and myofibroblasts. Diaminopeptidase IV was detected in myofibroblasts and fibroblasts by enzyme histochemistry and ultrastructural immunohistochemistry; the enzyme may play a role in the metabolism of intercellular substances. Some perivascular mesenchymal cells, interpreted as variants of myofibroblasts, had moderate activity of alkaline phosphatase.

Acid Phosphatase↗

PubMedDate not supplied

Dacarbazine and interferon alpha for stage IV malignant melanoma.

Based on encouraging reports of improved response rates with the use of dacarbazine (DTIC) in combination with recombinant interferon alpha-2a (rIFN-alpha-2a) in patients with metastatic malignant melanoma, we conducted a phase II study to determine the efficacy and feasibility of this treatment regimen. 31 patients were treated with an induction dose of rIFN-alpha-2a at 15 MIU/ m2 intravenously (i.v.) daily for 5 days per week for 3 consecutive weeks followed by a continuous maintenance dose of 10 MIU/m2 subcutaneously (s.c.) given 3 days per week; starting on day 22, in conjunction with rIFN-alpha-2a s.c., DTIC was started at a dose of 200 mg/m2 i.v. for 5 continuous days completing a 28-day cycle. Therapy was continued until progression was evidenced. Of the 29 evaluable patients, 7 (24.1%) achieved an objective response (complete plus partial remission) with the highest responses occurring in those patients assessed with pulmonary metastases. The median duration to treatment failure was 2.6 months, while the median survival was 6.9 months. Our data reveal that using rIFN-alpha-2a plus DTIC in combination does not yield better results than those achieved when using DTIC alone. However, 3 of the 7 responders experienced long-term survival ranging up to 42 months. Whether this benefit is achieved by the addition of rIFN-alpha-2a can only be answered by large randomized clinical trials. Conflicting results with some of the current literature are discussed.

Adult↗