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Biomedical subjects

M Tiefenthaler

Publications and source records attributed to M Tiefenthaler.

26 records · Page 2Linked to original sources
PubMed1999

Differential effects of cladribine and gemcitabine on erythroid and granulocytic progenitors from patients with chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a clonal neoplastic disease that originates in a pluripotent stem cell. Selection of normal progenitors by graft-purging may improve the outcome after autologous transplantation. In our methylcellulose assays, the nucleoside analogs cladribine (2-CdA) and gemcitabine (dFdC) showed more prominent inhibitory effects on CML than normal bone marrow (BM) progenitors. For dFdC, however, long-term incubations were necessary to achieve complete inhibition. Deoxycytidine kinase, the key enzyme of both 2-CdA and dFdC metabolisms, was only partially responsible for this differential sensitivity. We suggest that 2-CdA and dFdC might be helpful in purging of CML BM cells before autologous BM transplantation. Further studies on more primitive cells are warranted.

Antimetabolites, Antineoplastic↗
PubMed1999

Cytotoxic activities of hypocretenolides from Leontodon hispidus.

The hypocretenolides are a small group of sesquiterpene lactones with an unusual ring structure and are constituents of several species from the tribe Lactuceae of the family Asteraceae. In the present communication we report on the cytotoxic effects of three hypocretenolides (1-3) from Leontodon hispidus on: (a) eight solid-tumor cell lines (A431, HEP2, MCF7, OVCAR3, SK28, SK37, SW872, ZR75-1), tested by a (3)H-thymidine incorporation assay; (b) two different leukemia cell lines (GTB, HL60), measured by a MTT assay; and (c) CD34(+) bone-marrow cells, assessed by scoring the number of colonies derived from primitive and late erythroid progenitors (BFU-E and CFU-E) as well as from granulocytic/macrophagic progenitor cells (CFU-GM). The aglycon 14-hydroxyhypocretenolide (1) exhibited pronounced activities, although its beta-D-glucoside (2) showed no activity, even at the highest concentration tested (2 microM). 14-Hydroxyhypocretenolide-beta-D-glucoside-4',14' '-hydroxyhypocretenoate (3), the ester of the glucoside esterified with the open-chain form of the aglycon, was the most potently cytotoxic substance and proved to be even more active than the positive-control substance helenalin.

Adult↗
PubMed1997

A comparison of the antiproliferative properties of recombinant human IFN-alpha 2 and IFN-omega in human bone marrow culture.

We compared the antiproliferative effects in vitro of recombinant preparations of interferon-alpha 2c (IFN-alpha 2) and IFN-omega on the formation of colonies from bone marrow progenitor cells. Both IFNs led to statistically indistinguishable dose-dependent inhibitory effects when tested on bone marrow cells derived from 8 normal donors or from 7 patients with chronic myelogenous leukemia (CML). With both IFNs, the cells from CML patients appeared slightly but not significantly more sensitive to inhibition than the cells from normal donors. These results suggest that under some circumstances, IFN-omega may prove an effective treatment for CML, for example, in those becoming resistant to IFN-alpha 2 because of the formation of neutralizing antibodies.

Bone Marrow↗
PubMed1996

Austrian report on longitudinal outcome in phenylketonuria.

Forty years after Horst Bickel first treated a patient suffering from phenylketonuria (PKU) our aim is to assess the current treatment of Austrian patients. A total of 70 children -60 with PKU and 10 with hyperphenylalaninaemia (HPA)-aged 6-16 years were investigated in terms of somatic and intellectual parameters. Their development is normal (PKU: mean IQ = 95.40; HPA: mean IQ = 101.85) owing to strict dietary control, above all during their first 6 years of life. A comparison of the IQ data of 17 PKU children and their healthy siblings at the age 6 years showed significant correlations in verbal, performance and IQ measurements. Austrian PKU patients do achieve normal IQ values but these measurements fail to guarantee the quality of dietary control. IQ is influenced by a number of variables: genetic, social environment, education and furtherance, motivation for performance, etc., and, in PKU patients, dietary control. The only currently known way of maintaining and improving dietary compliance in PKU patients and their families remains good informative counselling about the disease and psychosocial support.

Adolescent↗
PubMed1994

Tin-mediated heme oxygenase gene activation and cytochrome P450 arachidonate hydroxylase inhibition in spontaneously hypertensive rats.

The effect of SnCl2 on the transcription of the heme oxygenase gene in spontaneously hypertensive rats was examined using cDNA for the rat heme oxygenase (HO-1). An increase in renal HO-1 mRNA levels was observed in response to SnCl2 treatment. Quantitative evaluation by scanning densitometry demonstrated a maximal increase in HO-1 mRNA 24-fold over control at 8 hours after SnCl2 administration. Nuclear runoff assay using isolated renal nuclei from SnCl2-treated rats revealed an active HO-1 gene transcription. Transcription of HO-1 in rat kidney was greatly increased within 3 hours of administration of SnCl2, as evidenced by the level of [alpha 32P]UTP incorporation into nuclear RNA. As a consequence of activation of the HO-1 gene transcription, renal enzyme activity increased eightfold at 16 hours after SnCl2, and reached maximal activity of 16-fold over control at 32 hours after injection. No significant change in cytochrome P450 fatty acid omega-hydroxylase (P450 4A) mRNA was observed after SnCl2 administration. Cytochrome P450-arachidonic acid omega/omega-1 hydroxylase(s) activity (formation of 20- and 19-HETE) was significantly reduced 24 hours after SnCl2 administration and remained lower than the control level 48 and 72 hours after injection. In addition, blood pressure was reduced from 151 +/- 2.5 mm Hg to 133 +/- 2.3 mm Hg after 48 hours of SnCl2 treatment. The reduction in blood pressure preceded natriuresis. It is concluded that SnCl2 induces activation of the HO-1 gene, which is followed by elevation in enzyme activity and a decrease in cytochrome P450-arachidonic acid omega-hydroxylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The hematopoietic stromal microenvironment promotes retrovirus-mediated gene transfer into hematopoietic stem cells.

In this study we report on the establishment of novel conditions which permit efficient retrovirus-mediated gene transfer of human adenosine deaminase (ADA) into murine hematopoietic progenitors. Using Southern blot analysis and an ADA probe, we demonstrated that prestimulation of bone marrow cells over an in vitro culture of adherent stromal cell layers (ACLs) for two days provides favorable conditions for gene transfer in the absence of exogenous growth factors. In bone marrow transplant recipients reconstituted with retrovirally-marked cells, ADA was detected in spleen, thymus and bone marrow cells of the recipients eight months after transplantation. These observations were also seen in transplants of embryonal hematopoietic stem cells. By using different incubation protocols, it was found that the developmental fate of hematopoietic stem cells varied with the presence of exogenous growth factors or an ACL in the prestimulation phase. Polyclonal hematopoiesis with multiple clones appearing simultaneously was revealed in mice reconstituted with growth factor-stimulated cells four months after transplantation. This was detected by multiple integration patterns of ADA integration into the genomes of individual colony forming units-spleen (CFU-S) in transplantation recipient mice. In contrast, two to five months after transplantation, polyclonal hematopoiesis was not observed in mice reconstituted with cells infected in the absence of growth factors. It appears that utilization of the bone marrow microenvironment through the use of an ACL results in a narrower spectrum of integration patterns, suggesting that a type of oligoclonal or monoclonal hematopoiesis is occurring. These studies demonstrate that an ACL provides novel conditions for successful gene transfer and stable integration of the vector into the genome. Use of an ACL may be advantageous for successful hematopoietic stem cell gene therapy.

Adenosine Deaminase↗
PubMed1991

Human complement factor H. Tissue specificity in the expression of three different mRNA species.

Using cDNA clones H-19 and H-46, we have shown previously that three different mRNA species (4.3 kb, 1.8 kb and 1.4 kb) for complement factor H are expressed constitutively in human liver. Here we report data suggesting that the expression of these different factor-H mRNA species is regulated by tissue-specific control mechanisms. Total RNA and poly(A)-enriched RNA from various human tissues (heart, lung, temporal cortex, kidney, spleen, bone marrow and muscle) various cell lines (HepG2, HepG3, HepG4, Hep3B, H-4, Jurkat, Molt4, H-9, KHos24Os, A-431, U937, Mono Mac 6 and Raji) and from primary cultures of peripheral blood monocytes, fibroblasts and human umbilical vein endothelial cells (HUVEC) were investigated for the expression of factor-H mRNA. In RNA preparations from extrahepatic tissue, factor-H mRNA was only detected in biopsies from the lung. Using 20 micrograms total RNA isolated from all 13 cell lines it was not possible to detect any factor-H mRNA, while mRNA for factor H was expressed in monocytes, HUVEC and fibroblasts. When expressed in extrahepatic tissues, only the 4.3-kb and the 1.8-kb mRNA species were detected, while the 1.4-kb mRNA is expressed abundantly in liver. Interferon-gamma did not induce the expression of factor-H mRNA in any of the cell lines tested. On the other hand, tumour necrosis factor-alpha induced the expression of the 4.3-kb mRNA species in U937 cells. In HUVEC and fibroblasts the relative quantities of the 4.3-kb and the 1.8-kb mRNA species and the regulatory effects of interferon-gamma, interleukin-1, dexamethasone and retinoic acid on their expression showed significant tissue specificity.

Blotting, Northern↗