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Biomedical subjects

D Liebermann

Publications and source records attributed to D Liebermann.

At least 19 recordsLinked to original sources
PubMed2000

Locoregional late effects of paravascular thorotrast deposits: results of the german thorotrast study.

PURPOSE: The aim of this study was to assess late effects of long-term exposure to alpha irradiation caused by paravascular Thorotrast deposits. SUBJECTS AND METHODS: 899 patients, who had received the radioactive contrast medium Thorotrast for angiography in the 1930s and 1940s, and 662 controls were followed-up since 1968 every two years by standardized clinical and laboratory examinations. Initially, X-ray plain films of the thorax, upper abdomen and the former injection site were performed. In selected patients the sites of paravascular Thorotrast deposits were evaluated by ultrasonography, CT and MRI. RESULTS: Paravascular Thorotrast deposits were detected in 245 patients. Clinical symptoms related to deposits appeared 10 to 30 years after Thorotrast administration. The severity of symptoms depended on the location and extension of granulomas and were mainly caused by fibrosis, nerve paralysis and vascular changes. Four malignant tumors adjacent to granulomas were observed (one soft tissue sarcoma in the groin, two squamous cell carcinomas of the parotid gland and one lymphoepithelial carcinoma of the nasopharynx). MRI including MRA allowed an accurate determination of tissue damage, whereas the utility of US and CT was restricted due to strong sound attenuation and streak artefacts caused by the high X-ray absorption of Thorotrast. DISCUSSION AND CONCLUSION: Locoregional late effects of paravascular Thorotrast deposits mainly comprise radiation induced, fibrotic tissue destruction. The incidence of malignant tumors, in particular sarcomas, adjacent to deposits, however, is much lower than initially expected.

Adolescent↗
PubMed1999

[Thorotrast-induced liver cancer: results of the German thorotrast study].

AIMS: The X-ray contrast medium Thorotrast, used worldwide between 1930 to 1950 predominantly for arteriography, consisted of a colloidal solution of thorium dioxide. The radioactive thorium-232 (half-life 1.4x10(10) years) is stored lifelong in the organs of the reticulo-endothelial system after intravascular injection, causing chronic exposure to alpha radiation. The aim of the German Thorotrast study is the assessment of radiation late effects and the calculation of risk estimates. MATERIAL AND METHODS: The German Thorotrast study started in 1968 as a cohort study and comprises 2326 Thorotrast patients and 1890 patients of a matched control group. The Thorotrast patients who were still alive at the beginning of the study were examined by X-ray plain films of the upper abdomen and of the injection site of the contrast medium as well as by whole-body counter measurements. At the beginning we offered the patients ultrasound and later on CT and MRI at regular intervals for early detection of liver cancer. RESULTS: To date 454 primary liver cancers have been registered in the group of Thorotrast patients compared to 3 cases in the control group. With the help of modern imaging methods relatively small liver cancers were detected and could be surgically removed. DISCUSSION: There is a correlation between the mean accumulated dose to the liver and the incidence of liver cancer. The cumulative risk for liver malignancies is about 600 diseases per 10(4) persons whose liver was exposed to 1 Gy. Also the incidence of liver cirrhosis is correlated with the mean accumulated dose to the liver.

Alpha Particles↗
PubMed1999

The german thorotrast study: recent results and assessment of risks.

The German Thorotrast study comprises 2,326 patients and 1,890 controls. Forty-eight Thorotrast patients and 239 controls are still alive and are invited for a follow-up examination every 2 years. In the deceased patients, the following neoplastic diseases with excess rates were registered (Thorotrast/controls): liver cancer (454/3); cancer of the bile ducts, including gallbladder (42/7); myeloid leukemia (40/7); myelodysplastic syndrome (30/4); plasmacytoma (10/2); non-Hodgkin's lymphoma (15/5); bone sarcoma (4/1); malignant peritoneal or pleural mesothelioma (9/0). Dose calculations are based on results of whole-body counting, X-ray films, and data obtained from the hospital records on the volume of Thorotrast injected. For liver cancer, the cumulative risk estimate was calculated to be 40 per 10(4) person Sv (radiation weighting factor = 20). These figures are close to the results of the Danish study and are comparable to the results of the Life Span Study of A-bomb survivors after 40 years at risk with 18 to 48 liver cancers per 10(4) person Sv. For hematopoietic malignancies, the cumulative risk was calculated to be about 7 per 10(4) person Sv (radiation weighting factor = 20). This risk estimate is lower by a factor of 10 compared to the results of the Life Span Study.

Adult↗
PubMed1997

Relationship of leg strength and power to ground reaction forces in both experienced and novice jump trained personnel.

METHODS: There were 14 male soldiers who participated in this study examining the relationship of leg strength and power on landing performance. Subjects were separated into two groups. The first group (E, n = 7) were parachute training instructors and highly experienced in parachute jumping. The second group of subjects (N, n = 7) had no prior parachute training experience and were considered novice jumpers. All subjects were tested for one-repetition maximum (1 RM) squat strength and maximal jump power. Ground reaction forces (GRF) and the time to peak force (TPF) at landing were measured from jumps at four different heights (95 cm, 120 cm, 145 cm, and 170 cm). All jumps were performed from a customized jump platform onto a force plate. RESULTS: No differences were seen between E and N in either IRM squat strength or in MJP. In addition, no differences were seen between the groups for time to peak force at any jump height. However, significantly greater GRF were observed in E compared to N. Moderate to high correlations between maximal jump power and GRF (r values ranging from 0.62-0.93) were observed in E. Although maximal jump power and the TPF was significantly correlated (r = -0.89) at only 120 cm for E, it was interesting to note that the correlations between MJP and the time to peak force in E were all negative and that the correlations between these variables in N were all positive. CONCLUSIONS: These results suggest that experienced parachutists may use a different landing strategy than novice jumpers. This difference may be reflected by differences in GRF generated during impact and a more efficient utilization of muscle power during the impact phase of the landing.

Aerospace Medicine↗
PubMed1996

The proto-oncogene c-myc blocks myeloid differentiation independently of its target gene ornithine decarboxylase.

Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, has been shown to be required for entry into and progression through the cell cycle and to be a transcriptional target of the proto-oncogene, c-myc. We show that ODC transcripts and enzyme activity are down-regulated following induction of myeloid differentiation, using M1 myeloblastic leukemic cells and normal cells from bone marrow (BM), and fail to be suppressed when c-myc expression is deregulated. In M1mycer cells, when endogenous c-myc expression has been suppressed following stimulation by interleukin-6 (IL-60), treatment with estrogen and cycloheximide results in induction of ODC transcripts. These data demonstrate that ODC is a c-myc target gene in M1 cells. It was of interest to determine whether deregulated ODC expression would alter the myeloid differentiation program. To answer this question, M1-ODC cell lines constitutively expressing ODC were established. These cells can undergo terminal differentiation and growth arrest following IL-6 stimulation, exactly like parental M1 cells, demonstrating that deregulated ODC expression is not sufficient to block myeloid differentiation. Another question to be answered was whether ODC expression is necessary for the c-myc-mediated block in differentiation. The use of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, indicates that ODC is not necessary for the c-myc-mediated differentiation block.

Animals↗
PubMed1994

Progression of the myeloid differentiation program is dominant to transforming growth factor-beta 1-induced apoptosis in M1 myeloid leukemic cells.

Hematopoiesis is a profound example of cell homeostasis that is regulated throughout life. This process requires the participation of many factors, including positive and negative regulators of growth and differentiation, that determine survival, growth stimulation, differentiation, functional activation, and programmed cell death. Understanding the effects of multiple stimuli on specific cells at the molecular and cellular level is crucial towards understanding how the population of blood cells maintains a homeostatic state. Two appropriate stimuli for analysis, both of which are found in bone marrow, are differentiation-inducing cytokines, which induce terminal differentiation associated with growth arrest, ultimately culminating in programmed cell death, and transforming growth factor-beta 1 (TGF-beta 1), which induces rapid growth arrest and apoptosis of hematopoietic cells. Previously, we have shown, using M1 myeloblastic leukemic cells as a model system, that differentiation-inducing cytokines induce terminal differentiation associated with growth arrest and, only after 5 to 7 days, apoptosis, whereas TGF-beta 1 induces rapid growth arrest and apoptosis. In this report, we show that M1 myeloid leukemic cells treated concomitantly with the differentiation inducer interleukin-6 and TGF-beta 1 undergo terminal differentiation, in which modulators of the MyD118 gene product, previously shown to be a positive regulator of TGF-beta 1-induced apoptosis, are implicated to play a role in protecting the cells from TGF-beta 1-induced apoptosis. Furthermore, using M1 cell variants blocked at different stages after induction of differentiation, including M1myb and M1myc, as well as conditionally blocked M1mycer, it has been shown that the dominance of interleukin-6 to TGF-beta 1-induced apoptosis is dependent on the progression of the differentiation program. Further studies with M1 and the genetically engineered M1 cell variants will be instrumental towards molecularly dissecting the interaction of hematopoietic differentiation with a variety of apoptotic pathways.

Animals↗
PubMed1994

Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways.

Recently, both Bcl-2, which promotes cell survival, and Bax, which promotes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli. We have used M1 myeloid leukemia cells and genetically engineered M1 variants as a model system to study apoptosis induced by two distinct apoptotic stimuli. This includes apoptosis induced by activation of wild type p53 function of a temperature sensitive p53 transgene expressed in M1 cells, which do not express endogenous p53, and apoptosis induced by TGF beta 1. It is shown that the kinetics of apoptosis induced by p53 is more rapid than apoptosis induced by TGF beta 1. It is also shown that ectopic expression of Bcl-2, at levels which blocked TGF beta 1-induced apoptosis of M1 cells, delayed, but did not block, p53-induced apoptosis. Both p53 and TGF beta 1 down-regulated endogenous Bcl-2 expression, but only p53 up-regulated Bax expression, where bax has been identified as a p53 immediate early response gene. Thus, the p53-mediated up-regulation of Bax may provide at least a partial explanation for the more rapid rate of apoptosis induced by p53 compared to by TGF beta 1, as well as for the ineffectiveness of ectopoic Bcl-2 to abrogate p53-mediated apoptosis. These findings provide first insights to the molecular mechanisms which mediate p53-induced apoptosis, identifying bax and bcl-2 as p53 regulated genes, and serve as a paradigm of how the intracellular balance of Bcl-2 to Bax is differentially altered by distinct death stimuli.

Apoptosis↗
PubMed1993

Myeloblastic leukemia cells conditionally blocked by myc-estrogen receptor chimeric transgenes for terminal differentiation coupled to growth arrest and apoptosis.

Conditional mutants of the myeloblastic leukemic M1 cell line, expressing the chimeric mycer transgene, have been established. It is shown that M1 mycer cells, like M1, undergo terminal differentiation coupled to growth arrest and programmed cell death (apoptosis) after treatment with the physiologic differentiation inducer interleukin-6. However, when beta-estradiol is included in the culture medium, M1 mycer cells respond to differentiation inducers like M1 myc cell lines, where the differentiation program is blocked at an intermediate stage. By manipulating the function of the mycer transgene product, it is shown that there is a 10-hour window during myeloid differentiation, from 30 to 40 hours after the addition of the differentiation inducer, when the terminal differentiation program switches from being dependent on c-myc suppression to becoming c-myc suppression independent, where activation of c-myc has no apparent effect on mature macrophages. M1 mycer cell lines provide a powerful tool to increase our understanding of the role of c-myc in normal myelopoiesis and in leukemogenesis, also providing a strategy to clone c-myc target genes.

Animals↗
PubMed1991

Neoplastic diseases induced by chronic alpha-irradiation--epidemiological, biophysical and clinical results of the German Thorotrast Study.

The intravascular injection of the formerly used contrast medium Thorotrast--a colloidal suspension of thorium-dioxide--causes a chronic exposure to alpha-particles especially in the organs of the reticuloendothelial system. The German Thorotrast Study comprises 2326 Thorotrast patients and 1890 contemporary matched patients in the control group to be evaluated. 899 Thorotrast patients and 662 controls had clinical and biophysical follow-up examinations every two years since 1969. The recent most important results of the study are: A high excess rate of primary liver cancer (410/2) was observed beginning after the 15th year of exposure. 31% of the tumors are combined with cirrhosis and 6% with other neoplastic diseases. A clear (mean) dose rate effect relationship exists. The tumor frequency depends on the time of exposure or the cumulative dose to the liver respectively and not primarily on the age at injection. The lowest cumulative doses at 10 years before diagnosis of liver cancer were about 2 Gy. Risk estimates for liver cancer after 40 years of exposure are 500 malignant tumors per 10(4) person-Gy for men and 300 for women. A high excess rate exists also for leukaemias (excluding CLL) starting already 5 years after Thorotrast injection (39/4). The lowest cumulative doses to the red bone marrow at time of death were about 0.5 Gy. According to the present result, an excess rate can be expected for carcinomas of the extrahepatic bile ducts, pancreas, oesophagus, larynx, as well as Non-Hodgkin's lymphomas, bone sarcomas, plasmacytomas and mesotheliomas.

Adolescent↗
PubMed1986

Sequences from sea urchin TU transposons are conserved among multiple eucaryotic species, including humans.

Sequences homologous to various structural domains of the Strongylocentrotus purpuratus TU family of transposons are present in sea urchin species closely related to S. purpuratus and were found in close proximity to each other in linkage patterns that differed for different species. Sequence homologs of the inverted repeat outer domain (IVR-OD) segment were, in addition, present in a sea urchin related only distantly to S. purpuratus and in all other eucaryotic organisms surveyed. In humans, a polymorphic hybridization pattern was seen for genomic DNA obtained from different individuals. Sequence comparisons revealed that repeated sequence motifs similar to those making up the 15-base-pair direct repeat unit of the IVR-OD domain of the TU elements exist in the IVRs of transposons identified in Drosophila melanogaster and maize and in the transcription control regions of certain eucaryotic viral and cellular genes. The remarkable evolutionary conservation of IVR-OD homologs may reflect a biological role for these sequences in DNA transposition, the regulation of gene expression, or both.

Animals↗
PubMed1986

Human homologs of TU transposon sequences: polypurine/polypyrimidine sequence elements that can alter DNA conformation in vitro and in vivo.

We previously have shown that homologs of the outer domain segment of the inverted repeat termini (IVR-OD) of the sea urchin TU transposons are conserved among multiple eucaryotic species, including humans. We report here that two cloned human DNA IVR-OD homologs, Hut2 and Hut17, consist of a series of tandem repeats of the trimer AGG/TCC, forming segments (313 and 221 base pairs in length, respectively) of polypurine/polypyrimidine (pPu/pPy or "Puppy") asymmetry in the two DNA strands; these are punctuated at certain sites with variant trimers, which are different for the two clones. Sequences homologous to the Hut2 pPu/pPy tract exist at multiple sites in the DNA of a wide variety of eucaryotes. Hybridization of human DNA with a Hut2 probe or with a previously described chicken DNA pPu/pPy sequence indicates that pPu/pPy sequences can be grouped into families distinguishable by the extent of their homology with each probe at different hybridization stringencies. Moreover, particular pPu/pPy tracts show species-specific differences in their distribution. Both the Hut2 and Hut17 pPu/pPy tracts are cleaved by S1 nuclease when tested on supercoiled plasmids. Most if not all of the 313-base-pair Hut2 pPu/pPy tract is also sensitive to S1 in its native location in HeLa cell chromatin, indicating that the sequence contains conformational information that can be expressed in vivo. This view is supported by evidence that exogenously derived Hut2 pPu/pPy tracts introduced into mouse L cells and integrated in chromatin can assume an S1-sensitive conformation.

Animals↗
PubMed1986

[Use of computed tomography for quantifying Thorotrast and detecting Thorotrast-induced liver tumors].

242 Thorotrast patients were examined by CT. The mean CT-density-values of the whole liver correlate well (0.72) with the measurements of the radioactivity by total-body-counting. Twenty-one of 24 primary liver tumors were correctly diagnosed by CT. The smallest tumor measured 3 cm in diameter. In 8 patients surgical treatment was possible. The sensitivity of CT for the detection of liver tumors, is higher than the sensitivity of echography.

Adenoma, Bile Duct↗
PubMed1985

Tsp transposons: a heterogeneous family of mobile sequences in the genome of the sea urchin Strongylocentrotus purpuratus.

In the preceding paper (J.B. Cohen, B. Hoffman-Liebermann, and L. Kedes, Mol. Cell. Biol., 5:2804-2813, 1985), we described the nucleotide sequence of ISTU4, which is a member of a new family of repetitive sequences, the Tsp family, present in a higher eucaryote, the sea urchin Strongylocentrotus purpuratus. We provided evidence that individual members of this family can act as transposable elements. Here we describe our structural analysis of the Tsp element family, which numbers about 1,000 members per haploid genome. Hybridization and nucleotide sequence analysis of several genomic Tsp clones demonstrate that structurally most Tsp elements resemble ISTU4. Tsp elements range in size up to about 1.3 kilobase pairs, have terminal domains that are conserved between the various examples studied, and contain a central portion of varying size, which may be extensively diverged. Structurally, however, the central portions are very similar and consist of several approximately 150-base-pairs-long, tandemly arranged, imperfect repeats, which are followed by a truncated repeat. The structural analysis is consistent with the possibility that the individual Tsp elements differ by multiples of these 150-base-pair repeats. One variant genomic clone has a solitary repeat and lacks the truncated repeat. The nucleotide sequences of different repeats of a single Tsp element can diverge extensively. The truncated repeat is divergent from most of the repeats, but in one case it is almost identical to a repeat of the same element. Comparison of the sequences from different elements enabled us to determine the boundaries of each structural domain and allows us to propose that each of these domains may be independent units of genetic information. Analysis of the population of Tsp-related sequences in the S. purpuratus genome by genomic blot hybridization suggests that most Tsp family members share the same overall structure. In addition, there is a structural element, about 70 base pairs long, that appears to interrupt the tandem arrangement of the 150-base-pair repeats at regular intervals.

Animals↗
PubMed1985

TU elements: a heterogeneous family of modularly structured eucaryotic transposons.

We describe here a family of foldback transposons found in the genome of the higher eucaryote, the sea urchin Strongylocentrotus purpuratus. Two major classes of TU elements have been identified by analysis of genomic DNA and TU element clones. One class consists of largely similar elements with long terminal inverted repeats (IVRs) containing outer and inner domains and sharing a common middle segment that can undergo deletions. Some of these elements contain insertions. The second class is highly heterogeneous, with many different middle segments nonhomologous to those of the first-class and variable-sized inverted repeats that contain only an outer domain. The middle and insertion segments of both classes carry sequences that also are found unassociated from the inverted repeats at many other genomic locations. We conclude that the TU elements are modular structures composed of inverted repeats plus other sequence domains that are themselves members of different families of dispersed repetitive sequences. Such modular elements may have a role in the dispersion and rearrangement of genomic DNA segments.

Animals↗
PubMed1982

Regulation and role of different macrophage-and granulocyte-inducing proteins in normal and leukemic myeloid cells.

It has previously been shown that there are different molecular forms of macrophage-and granulocyte-inducing (MGI) proteins; one form, MGI-l, induced the formation of colonies with differentiated cells from normal myeloblasts and another form, MGI-2, induced normal differentiation in MGI+D+ leukemic myeloblasts that no longer require MGI-l to form colonies. The present results indicate that MGI-2 can also induce differentiation (without inducing colony formation) in the normal cells, and that MGI-l induced MIG-2 in the normal but not in the leukemic cells. It is suggested from these results that MGI-2 is the differentiation-inducing protein for normal and leukemic cells whereas MGI-l is the growth-inducing protein that induces colony formation by the normal cells, and that induction of differentiation in the normal cell colonies is due to induction of MGI-2 by MGI-l.

Animals↗