-Practical implementation of stress echocardiography--what should be monitored?-.
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Contraindications↗
Biomedical subjects
M Schartl
Publications and source records attributed to M Schartl.
Association between the melanoma-inducing receptor tyrosine kinase Xmrk and src family tyrosine kinases in Xiphophorus.
Melanoma formation in the fish Xiphophorus is an in vivo model for the function of receptor tyrosine kinases (RTKs) in tumor development. The overexpression and high activity of the RTK Xmrk (Xiphophorus melanoma receptor kinase) is responsible for the formation of hereditary malignant melanoma in this fish, but the mechanism by which Xmrk signals cell proliferation has not been elucidated. Remarkably, in earlier experiments an elevated level of a pp60c-src related kinase activity was found in the melanomas. In order to evaluate the significance of src family SH2 domain interactions in the intracellular signalling of Xmrk, we determined its relative binding affinity to the ubiquitous general RTK substrate, PLC gamma, and to the Xiphophorus cytoplasmic kinases Xsrc, Xfyn and Xyes. Recombinant Xmrk purified from baculovirus infected Sf9 cells bound with high affinity to the SH2 domains of PLC gamma and Xfyn in vitro. The affinity of Xmrk to Xsrc and Xyes SH2 domains was 5- to 10-fold lower. Coprecipitation experiments revealed that the Xmrk/Xfyn interaction occurred also in melanoma cells. Moreover, stimulation of the Xmrk kinase activity was paralleled by an increase in Xfyn activity. These results suggest that in malignant melanoma of Xiphophorus the highly activated Xmrk may enhance the activity of Xfyn through direct interaction and that both kinases are linked in a signal transduction pathway.
Amino Acid Sequence↗
Human malignant melanoma. A genetic disease?
BACKGROUND: Human hereditary malignant melanoma, comprising 5% of all cases of malignant melanoma, occurs in association with other malignancies, predominantly in families with dysplastic nevus syndrome. Additionally, higher incidences of malignant melanoma have been reported in individuals with genetic disorders such as ataxia telangiectasia and xeroderma pigmentosum. The results and observations as reported in the literature on the involvement of oncogenes and chromosomal aberrations in the development of malignant melanoma are reviewed and compared with the authors' own experimental and clinical experience. RESULTS: Numerous chromosomal regions, as on chromosomes 1 and 9, were altered. The long arm of chromosome 6 was affected in 60% of melanomas. Introduction of a normal copy of chromosome 6 resulted in loss of tumorigenicity in vitro. True melanoma genes were evident in two animal models: the Sinclair swine and the teleost fish Xiphophorus. In the Xiphophorus system, the crossing-conditioned elimination of a tumor suppressor gene led to the uncontrolled activity of a dominantly acting oncogene in certain hybrids. The causative oncogene, Xmrk, encodes a receptor tyrosine kinase closely related to human epidermal growth factor receptor (EGFR). Among the numerous studied human oncogenes, mutations in the extensively investigated ras family are the result rather than the cause of malignant transformation. High expression of nuclear oncogenes simply may be a common feature of rapidly dividing cells. The receptor tyrosine kinase EGFR may be involved in late stage melanoma; the human exon with homology to Xmrk shows elevated transcription levels in 80% of human melanoma metastases. Deletions of the tumor suppressor gene MTS 1 may be important for melanoma formation, whereas deletions of p53 appear to be of minor relevance. CONCLUSION: Scientific progress in treating and diagnosing malignant melanoma will largely depend on experimental approaches to define relevant genetic changes by functional analysis rather than descriptive phenomenology and correlative observations.
Animals↗
Spontaneous melanoma formation in nonhybrid Xiphophorus.
Melanoma in hybrids of Xiphophorus is due to the unrestricted activity of a cellular oncogene locus, Tu, encoding the growth factor receptor gene Xmrk. In nonhybrid parental fish, Tu is controlled by a tumor suppressor gene. Thus, its restricted activity leads there only to a nonmalignant, species- and population-specific macromelanophore spot pattern. Prompted by enigmatic reports on nonhybrid Xiphophorus with pigmentation abnormalities resembling melanoma, we have studied pigmentation in descendants of wild-caught fish and purebred laboratory stocks derived from wild populations. Whereas most stocks exhibiting macromelanophore patterns never developed pigmentation abnormalities, an exceptional situation for some nonhybrids was found. In X. variatus carrying the macromelanophore pattern "punctatus-2" and in X. cortezi with "spotted caudal," expressivity of the pigmentation gene ranges from a few black spots to extreme melanosis and eventually to malignant melanoma. In X. maculatus with the mutant pigmentation gene striped" carrying in addition the micromelanophore pattern "anal fin black" or "lower comet," testosterone-dependent melanoma develop originating from the corresponding micromelanophore pattern. The tumors are highly malignant and express a melanoma-associated antigen. Overexpression of the Xmrk oncogene appears as the underlying molecular mechanism for tumor induction. These findings clearly demonstrate that tumors can also develop in purebred wild-type fish. The classical model for formation of hereditary melanoma in Xiphophorus hybrids does not explain the development of melanoma in the absence of hybridization. However, their existence gives additional support to the reasoning that the Xmrk oncogene associated with the macromelanophore locus is potentially injurious.
Animals↗
Melanoma formation in Xiphophorus: a model system for the role of receptor tyrosine kinases in tumorigenesis.
Cancer is one of the most frequent fatal human diseases. It is a genetic disease, and molecular analysis of the genes involved revealed that they belong to several distinct classes of molecules, one of which is the receptor tyrosine kinases. Neoplastic transformation is regarded as the result of a multistep process and, in most cases, it is hard to evaluate what the initial events in tumor formation are. What makes it difficult to approach this question is the paucity of animals models for tumorigenesis allowing investigation of the mechanisms leading to uncontrolled cell proliferation. Melanoma formation in Xiphophorus is one of these model systems. Here, overexpression and activation of a receptor tyrosine kinase causes neoplastic transformation of pigment cells. Xiphophorus provides all the advantages of a well-characterized genetic system. In addition, some crucial components of the transformation pathway have been identified at the molecular level. As a vertebrate, Xiphophorus might serve as a model system to aid understanding, in more general terms, of the mechanisms of tumorigenesis in human diseases.
Animals↗
Platyfish and swordtails: a genetic system for the analysis of molecular mechanisms in tumor formation.
Inspired by recent reports, many geneticists would agree that it is worth looking into aquaria or even replacing the Drosophila bottles in their laboratories with fish tanks. Indeed, encouraging results from large-scale mutagenesis screens in zebrafish have promoted this organism to a prominent position in the research of vertebrate developmental biology. Some other small aquarium fish species still inhabit side streams or backwaters of science, like the zebrafish did before, serving smaller communities of researchers as tools in fields such as developmental biology and neurobiology. One such type of fish is Xiphophorus, which offers a genetic system for the analysis of molecular mechanisms in tumorigenesis.
Animals↗
Diagnosis of coronary artery disease and viable myocardium by stress echocardiography. Diagnostic accuracy of different stress modalities.
Stress echocardiography is being used more commonly for routine clinical diagnosis of coronary artery disease. In addition to physical treadmill or bicycle exercise echocardiography, pharmacological stress echocardiography with dobutamine and dipyridamole has also gained increasing significance over the past few years. Numerous studies have proven that these methods diagnose coronary artery disease accurately (exercise echocardiography: sensitivity 71 to 98%, specificity 64 to 100%, dobutamine echocardiography; sensitivity 54 to 96%, specificity 66 to 95%; dipyridamole echocardiography: sensitivity 57 to 74%, specificity 80 to 100%), but no direct comparison has hitherto been able to prove the superiority of any one of these protocols. However it is recognized that the skill and experience of the echocardiographer performing this study has an influence on the accuracy of the technique.
Coronary Disease↗
Intravascular ultrasound imaging in patients with acute myocardial infarction.
Myocardial infarction is the result of acute thrombotic occlusion of a coronary artery secondary to rupture of an atherosclerotic plaque. Intracoronary ultrasonic examinations (ICUS) were performed in patients with acute myocardial infarction in order to describe intraluminal ultrasonic findings at the site of an acute coronary occlusion. Coronary angiography and ICUS studies were performed consecutively within 6 h after the onset of chest pain in 50 patients with acute myocardial infarction (AMI) prior to percutaneous coronary angioplasty (PTCA). Following angiographic documentation of a proximal occlusion, a 3.5 mechanical ultrasound catheter (30 MHz) was advanced successfully through the lesion in 42 of 50 patients (84%). In 37 of the 42 patients (88.1%), ICUS differentiated between pulsatile, low echogenic, intraluminal material suggesting thrombus, and mural more highly echogenic atherosclerotic plaque. A negative imprint of the ICUS catheter was documented within the low echogenic material in 25 of 42 (60%) patients with AMI. Low echogenic intraluminal material was found in 31 of 42 (73.4%) segments proximal to the highly echogenic plaque and in 28 of 42 (66.7%) segments distal to it, indicating pre- and post-stenotic thrombus in AMI. The plaque appeared eccentric in 32 of 42 patients (76.2%) with AMI. Cross-sectional area stenosis due to highly echogenic plaque averaged 48 +/- 14%. Calcification of plaque was evident in 35 of 42 patients (83.3%) and the surface of the plaque was rough in 30 of 42 (42.4%). Fissures were found in 10 (23.8%) and a dissection was detected in four (9.5%) cases.
Adult↗
Evidence for an unusual ZW/ZW'/ZZ sex-chromosome system in Scardinius erythrophthalmus (Pisces, Cyprinidae), as detected by cytogenetic and H-Y antigen analyses.
Fifty-seven individuals of the European cyprinid fish species Scardinius erythrophthalmus were sexed by gonad histology, and their karyotypes were analyzed by Giemsa staining and C-banding. The chromosome number in somatic metaphase plates was 2n = 50. Karyotypes of all gonadal male animals were identical, consisting of 48 small meta- or submetacentric chromosomes and a pair of large metacentric chromosomes (ZZ males). Of the 33 gonadal females, 16 had a karyotype similar to the males' (ZW' females) and 17 had a heteromorphic pair of chromosomes, including a large metacentric Z chromosome and a small acrocentric W chromosome (ZW females). H-Y antigen typing with cells obtained from a variety of tissues revealed that the homogametic ZZ males were H-Y negative and the heterogametic ZW females were H-Y positive in all tissues tested. In contrast, ZW' females showed no expression of the H-Y antigen in somatic cells but were H-Y positive in ovarian cells. These results suggest that the ZW/ZW'/ZZ sex chromosomes of S. erythrophthalmus represent an unusual system of sex determination and that H-Y antigen expression is coupled with the heterogametic sex. Whether the ZW' individuals are indeed heterogametic females or actually sex-reversed ZZ males, in which chromosomal sex determination is overruled by external factors, is discussed.
Animals↗
[Model systems for investigation of genetic factors in tumorigenesis].
The steadily rising public concern about the number and amounts of carcinogenic agents in our environment has led to a decline in interest in another aspect of tumorigenesis, namely the involvement of genetic factors in the processes that lead to malignant tumors. It is becoming evident that both the noxious influences in the environment and the genetic make-up of cells or the whole individual are involved in cancerous processes to a similar extent. The usefulness of experimental animal models for analysis of the extreme complexity of the molecular mechanisms underlying tumor formation is demonstrated by recent results in experimental oncology.
Animals↗
Neurotrophin-6 is a new member of the nerve growth factor family.
During vertebrate development, many neurons depend for survival and differentiation on their target cells. The best documented mediator of such a retrograde trophic action is the neurotrophin nerve growth factor (NGF). NGF and the other known members of the neurotrophin family, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) are conserved as distinct genes over large evolutionary distances. Here we report the cloning of neurotrophin-6 (NT-6), a new member of this family from the teleost fish Xiphophorus. NT-6 distinguishes itself from the other known neurotrophins in that it is not found as a soluble protein in the medium of producing cells. The addition of heparin (but not chondroitin) effects the release of NT-6 from cell surface and extracellular matrix molecules. Recombinant purified NT-6 has a spectrum of actions similar to NGF on chick sympathetic and sensory neurons, albeit with a lower potency. NT-6 is expressed in the embryonic valvulla cerebelli; expression persists in some adult tissues. The interaction of NT-6 with heparin-binding molecules may modulate its action in the nervous system.
Amino Acid Sequence↗
Autocrine stimulation of the Xmrk receptor tyrosine kinase in Xiphophorus melanoma cells and identification of a source for the physiological ligand.
The melanoma-inducing gene of Xiphophorus fish encodes the Xmrk receptor tyrosine kinase. Using a highly specific antiserum produced against the recombinant receptor expressed with a baculovirus, it is shown that Xmrk is the most abundant phosphotyrosine protein in fish melanoma and thus highly activated in the tumors. Studies on a melanoma cell line revealed that these cells produce an activity that considerably stimulates receptor autophosphorylation. The stimulating activity induces receptor down-regulation and can be depleted from the melanoma cell supernatant by the immobilized recombinant receptor protein. The fish melanoma cells can thus be considered autocrine tumor cells providing a source for future purification and characterization of the Xmrk ligand.
Animals↗
Recurrent origin of a sexually selected trait in Xiphophorus fishes inferred from a molecular phylogeny.
Darwin believed that sexual selection accounts for the evolution of exaggerated male ornaments, such as the sword-like caudal fin extensions of male fishes of the genus Xiphophorus, that appear detrimental to survival. Swordtails continue to feature prominently in empirical work and theories of sexual selection; the pre-existing bias hypothesis has been offered as an explanation for the evolution of swords in these fishes. Based upon a largely morphological phylogeny, this hypothesis suggests that female preference to mate with sworded males arose in ancestrally swordless species, thus pre-dating the origin of the sword itself and directly driving its evolution. Here we present a molecular phylogeny (based on mitochondrial and nuclear DNA sequences) of Xiphophorus which differs from the traditional one: it indicates that the sword originated and was lost repeatedly. Our phylogeny suggests that the ancestor of the genus is more likely to have possessed a sword than not, thus questioning the applicability of the pre-existing bias hypothesis as an explanation for the evolution of this sexually selected trait.
Animals↗
Sex chromosome polymorphism and heterogametic males revealed by two cloned DNA probes in the ZW/ZZ fish Leporinus elongatus.
In order to study the divergence of teleost sex chromosomes, subtractive cloning was carried out between genomic DNA of males and females of the rainbow trout (XX/XY) and of Leporinus elongatus (ZW/ZZ). Inserts cloned in a plasmid vector were individually tested on Southern blots of DNA of males and females for sex specificity. No sex-specific insert was obtained from trout, but two out of ten inserts cloned from L. elongatus showed sex-specific patterns in this species: one corresponds to a sequence present on both Z and W chromosomes, while the other is W specific. Sequences of these two inserts show neither clear homology with other known sequences, nor an open reading frame. They cross-hybridize with the genomic DNA of Leporinus friderici, but without sex-specific patterns. Twenty-four L. elongatus adults were sexed by gonadal observation, chromosomed examination and Southern hybridization with one or the other insert. Ten males and 11 females had chromosomes and hybridization patterns typical of their sex. One ZW female was recognized as a male with the W-specific probe. This was also the case for two unusual ZW males, one having a male hybridization pattern with the other probe. These three atypical individuals may result from single genetic exchanges between four regions of the Z and the W, giving rise to three atypical W chromosomes. Finding males with such atypical heterochromosomes in a female heterogametic species may indicate that a gradual transition occurs between the heterogametic systems.
Animals↗
Male polymorphism in Limia perugiae (Pisces: Poeciliidae).
The male-polymorphic poeciliid fish, Limia perugiae, a small teleostean endemic to the southeast of the Caribbean island Hispañola, consists of three male size morphs with uniform females. Large males differentiate at a size varying between 25 and 38 mm; intermediate males, between 21 and 25 mm. Under competition, large males exhibit an elaborate courtship display, whereas small males show only a sneak-chase behavior. Intermediate males adapt their tactics to the respective competitors. However, all male morphs can switch from courtship display to sneak-chase behavior. In large mating groups with four males of different size and five or six virgin females, large dominant alpha-males as well as small subordinate delta-males did not produce any offspring. Unexpectedly, all progeny were sired exclusively by the intermediate subordinate beta- and gamma-males. Breeding experiments with the three male morphs can best be explained by a model of Y-linked genes for small and large size which are both suspended by the activity of an autosomal recessive repressor responsible for the development of intermediate males. The dominant allele of the recessive repressor, in either its homoorits heterozygous state, activates the Y-chromosomal genes for large or small size, respectively. Accordingly, intermediate males may produce male offspring of all size classes, depending on the presence of either the Y-linked gene or the autosomal repressor.
Agonistic Behavior↗
Quantitative assessment of peripheral and coronary artery lesions before and after balloon angioplasty: a comparison of intravascular ultrasound and angiography.
Intravascular ultrasound and conventional angiography were used to determine the degree of stenosis before and after angioplasty in 25 consecutive patients with peripheral arterial occlusive disease and 15 selected patients with coronary artery disease. Angiographic determinations of the luminal area and percent stenosis were made with the help of an automatic detection system, and the same parameters were evaluated planimetrically in the ultrasound studies. Following angioplasty of peripheral lesions, angiography demonstrated a significantly greater increase in mean luminal area (10.8 +/- 7.8 mm2 vs 5.8 +/- 4.0 mm2; P < 0.05) and a greater reduction in degree of stenosis (26% +/- 16% vs 14% +/- 11%; P < 0.05) than did the ultrasonic investigation. There was a significant but moderate correlation between values for the luminal area determined by angiography and ultrasound before angioplasty (r = 0.75; SEE = 4.8 mm2) and in normal proximal segments of coronary arteries (r = 0.79; SEE 4.1 mm2). Following angioplasty there was no significant correlation between angiographic findings and those determined by intravascular ultrasound in peripheral or coronary lesions. These results suggest that angiography and intravascular ultrasound are fundamentally different imaging and analysis techniques. Following angioplasty, conventional angiography rarely demonstrated dissection or intraluminal filling defects, while intravascular ultrasound detected plaque rupture and the presence of intraluminal atheroma in almost all cases. Quantitative determinations of luminal area and degree of stenosis rely on indirect measures with conventional angiography, while these parameters are determined directly by intravascular ultrasound.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The conservation of neurotrophic factors during vertebrate evolution.
Neurotrophic factors are a family of extracellular ligands that affect the differentiation, survival (by inhibition of apoptosis) and maintenance of function of neuronal cells in vertebrates. The family includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5). The survival specificities of NGF and BDNF for different classes of chick neurons are maintained from the fish to the mammalian proteins, implying a conserved interaction with neuronal cell surface receptors (of the Trk family). However, the quantitative effect of a fish neurotrophin can differ significantly from that of the mammalian orthologue.
Amino Acid Sequence↗
Evolutionary origin and molecular biology of the melanoma-inducing oncogene of Xiphophorus.
Melanoma formation in platyfish/swordtail hybrids of genus Xiphophorus is due to overexpression of the receptor tyrosine kinase oncogene Xmrk. This gene is the molecular equivalent to the Tu-locus of platyfish formerly identified by Mendelian genetics. The supposed evolutionary origin of the Xmrk oncogene is a nonhomologous recombination event in the 5' region of the corresponding Xmrk protooncogene with an anonymous sequence, D. This event led to a gene duplication of Xmrk, whereby the new copy obtained a novel promoter derived from D. Inactivity of this promoter in parental fish warrants lack of tumorigenicity of the Xmrk oncogene in wild playfish. In hybrids, however, the promoter is active. This leads to the pigment cell transforming overexpression of Xmrk.
3T3 Cells↗