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Biomedical subjects

A Nagy

Publications and source records attributed to A Nagy.

At least 73 records · Page 4Linked to original sources
PubMed2001

Genetic and developmental analysis of X-inactivation in interspecific hybrid mice suggests a role for the Y chromosome in placental dysplasia.

It has been shown previously that abnormal placental growth, i.e., hyper- and hypoplasia, occurs in crosses and backcrosses between different mouse (Mus) species. A locus that contributes to this abnormal development has been mapped to the X chromosome. Unexpectedly, an influence of fetal sex on placental development has been observed, in that placentas attached to male fetuses tended to exhibit a more pronounced phenotype than placentas attached to females. Here, we have analyzed this sex dependence in more detail. Our results show that differences between male and female placental weights are characteristic of interspecific matings and are not observed in intraspecific Mus musculus matings. The effect is retained in congenic lines that contain differing lengths of M. spretus-derived X chromosome. Expression of the X-linked gene Pgk1 from the maternal allele only and lack of overall activity of two paternally inherited X-linked transgenes indicate that reactivation or lack of inactivation of the paternal X chromosome in trophoblasts of interspecific hybrids is not a frequent occurrence. Thus, the difference between male and female placentas seems not to be caused by faulty preferential X-inactivation. Therefore, these data suggest that the sex difference of placental weights in interspecific hybrids is caused by interactions with the Y chromosome.

Animals↗
PubMed2001

Expression and hypoxic regulation of angiopoietins in human astrocytomas.

Vascular endothelial growth factor (VEGF) is a major inducer of tumor angiogenesis and edema in human astrocytomas by its interaction with cognate endothelial-specific receptors (VEGFR1/R2). Tie1 and Tie2/Tek are more recently identified endothelial-specific receptors, with angiopoietins being ligands for the latter. These angiogenic factors and receptors are crucial for the maturation of the vascular system, but their role in tumor angiogenesis, particularly in astrocytomas, is unknown. In this study, we demonstrate that the angiopoietin family member Ang1 is expressed by some of the astrocytoma cell lines. In contrast to VEGF, Ang1 is down regulated by hypoxia. Ang2 was not overexpressed. Expression profiles of low-grade astrocytoma specimens were similar to those of normal brain, with low levels of Ang1, Ang2, and VEGF expression. Glioblastoma multiforme expressed higher levels of Angl, but not to the same degree as pseudopalisading astrocytoma cells around necrotic and hypoxic zones expressed VEGF, as shown in previous studies. Ang2 expression in the highly proliferative tumor vascular endothelium was also increased, as was phosphorylated Tie2/Tek. The expression profile of these angiogenic factors and their endothelial cell receptors in human glioblastomas multiforme was similar to that in a transgenic mouse model of glioblastoma multiforme. These data suggest that both VEGF and angiopoietins are involved in regulating tumor angiogenesis in human astrocytomas.

Angiopoietin-1↗
PubMed2001

In vitro targeting of a cytotoxic analog of luteinizing hormone-releasing hormone AN-207 to ES-2 human ovarian cancer cells as demonstrated by microsatellite analyses.

Targeting of cytotoxic agents represents a modern approach to the treatment of various cancers, that improves the efficacy and reduces peripheral toxicity. Recently we developed a powerful cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AN-207, designed to be targeted to tumors that express LHRH receptors. This analog consists of the superactive derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), linked to [D-Lys6]LHRH carrier. In the present study we investigated the cytocidal effects of AN-207 and AN-201 on the LHRH receptor-positive ES-2 ovarian cancer cells. The targeting of AN-207 to ES-2 cells in the presence of LHRH receptor-negative UCI-107 ovarian cancer cells was also evaluated by semi-quantitative polymerase chain reaction (PCR) amplification of microsatellite markers. Ligand competition assays showed a single class of high-affinity and low-capacity binding sites in ES-2 cells with a mean dissociation constant (KD) of 3.93 +/- 0.1 nM and a mean maximal binding capacity (Bmax) of 271 +/- 26.1 fmol/mg membrane protein. Kinetic assays indicated that AN-207 caused cell death in a concentration- and time-dependent manner in ES-2 cells, but not in UCI-107 cells, while the kinetics of cytotoxic effects of AN-201 were similar in both cell lines. To investigate targeting, ES-2 cells were co-cultured with UCI-107 cells, treated with 10 nM AN-207 or AN-201 for different times and then cultured for 48 h in the absence of cytotoxic agents. Genomic DNA was extracted for microsatellite analyses using different markers. Semi-quantitative analyses of the intensity of the alleles that correspond to each cell line indicated that AN-207 was selectively targeted to ES-2 cells, while AN-201 showed no selectivity for either cell line. These results extend our previous findings that AN-207 can be targeted to ovarian cancers and other tumors that express receptors for LHRH. Cytotoxic analogs of LHRH, such as AN-207, should be considered for treatment of LHRH receptor-positive tumors.

Antineoplastic Agents↗
PubMed2001

Studies on the mechanism of action of a targeted chemotherapeutic drug in living cancer cells by two photon laser scanning microspectrofluorometry.

In this study, we present a spectroscopic study of the entry pattern of a chemotherapeutic drug (AN-152) and its carrier hormone ([D-Lys(6)]LH-RH) into living cancer cells, with the help of our two-photon probes and a home-built localized microspectrofluorometer coupled with two photon laser scanning microscope (TPLSM). Due to the inherent localization ability of TPLSM, we were able to identify the drug and carrier location in different compartments of the cancer cells in vitro. The apparent doxorubicin-assisted nucleic accumulation of AN-152 suggests a possible nuclear action of the drug on cell proliferation.

Antineoplastic Agents↗
PubMed2001

Stem cell bioengineering.

Tissue engineering and cellular therapies, either on their own or in combination with therapeutic gene delivery, have the potential to significantly impact medicine. Implementation of technologies based on these approaches requires a readily available source of cells for the generation of cells and tissues outside a living body. Because of their unique capacity to regenerate functional tissue for the lifetime of an organism, stem cells are an attractive "raw material" for multiple biotechnological applications. By definition they are self-renewing because on cell division they can generate daughter stem cells. They are also multipotent because they can differentiate into numerous specialized, functional cells. Recent findings have shown that stem cells exist in most, if not all, tissues, and that stem cell tissue specificity may be more flexible than originally thought. Although the potential for producing novel cell-based products from stem cells is large, currently there are no effective technologically relevant methodologies for culturing stem cells outside the body, or for reproducibly stimulating them to differentiate into functional cells. A mechanistic understanding of the parameters important in the control of stem cell self-renewal and lineage commitment is thus necessary to guide the development of bioprocesses for the ex vivo culture of stem cells and their derivates.

Adult↗
PubMed2001

The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm.

An organizer population has been identified in the anterior end of the primitive streak of the mid-streak stage embryo, by the expression of Hnf3beta, Gsc(lacZ) and Chrd, and the ability of these cells to induce a second neural axis in the host embryo. This cell population can therefore be regarded as the mid-gastrula organizer and, together with the early-gastrula organizer and the node, constitute the organizer of the mouse embryo at successive stages of development. The profile of genetic activity and the tissue contribution by cells in the organizer change during gastrulation, suggesting that the organizer may be populated by a succession of cell populations with different fates. Fine mapping of the epiblast in the posterior region of the early-streak stage embryo reveals that although the early-gastrula organizer contains cells that give rise to the axial mesoderm, the bulk of the progenitors of the head process and the notochord are localized outside the early gastrula organizer. In the mid-gastrula organizer, early gastrula organizer derived cells that are fated for the prechordal mesoderm are joined by the progenitors of the head process that are recruited from the epiblast previously anterior to the early gastrula organizer. Cells that are fated for the head process move anteriorly from the mid-gastrula organizer in a tight column along the midline of the embryo. Other mid-gastrula organizer cells join the expanding mesodermal layer and colonize the cranial and heart mesoderm. Progenitors of the trunk notochord that are localized in the anterior primitive streak of the mid-streak stage embryo are later incorporated into the node. The gastrula organizer is therefore composed of a constantly changing population of cells that are allocated to different parts of the axial mesoderm.

Animals↗
PubMed2001

Abnormal function of astroglia lacking Abr and Bcr RacGAPs.

Experiments in cultured cells have implicated the molecular switch Rac in a wide variety of cellular functions. Here we demonstrate that the simultaneous disruption of two negative regulators of Rac, Abr and Bcr, in mice leads to specific abnormalities in postnatal cerebellar development. Mutants exhibit granule cell ectopia concomitant with foliation defects. We provide evidence that this phenotype is causally related to functional and structural abnormalities of glial cells. Bergmann glial processes are abnormal and GFAP-positive astroglia were aberrantly present on the pial surface. Older Abr;Bcr-deficient mice show spontaneous mid-brain glial hypertrophy, which can further be markedly enhanced by kainic acid. Double null mutant astroglia are hyper-responsive to stimulation with epidermal growth factor and lipopolysaccharide and exhibit constitutively increased phosphorylation of p38 mitogen-activated protein kinase, which is regulated by Rac. These combined data demonstrate a prominent role for Abr and Bcr in the regulation of glial cell morphology and reactivity, and consequently in granule cell migration during postnatal cerebellar development in mammals.

Animals↗
PubMed2001

Variation of isoenzyme and RAPD patterns in Candida albicans morphological mutants with altered colony ultrastructure.

Molecular typing methods were applied to characterize four stable morphological mutants [1] isolated from a UV-induced unstable mutant colony of Candida albicans. The wild-type strain (ATCC 64385), the intermediate unstable mutant and its four morphologically altered derivatives revealed the same electrophoretic karyotypes. Of the five isoenzymes tested (catalase, malate dehydrogenase, glutamate dehydrogenase, acid phosphatase and 3-glucosidase), glutamate dehydrogenase displayed a different enzyme pattern (with an extra band of lower mobility) in the morphological mutants. In contrast, the random amplification DNA polymorphism patterns of the mutant strains differed in all cases from that of the parental strain. Different primers revealed various degrees of DNA polymorphism; one of them (OPC-8) proved to be useful for differentiation between all examined strains. Differences in genetic alterations between spontaneous and induced mutants, and the applicability of different molecular markers to analyse the consequences of induced mutagenesis in C. albicans are discussed.

Candida albicans↗
PubMed2001

The effect of a low molecular weight inhibitor of lipid peroxidation on ultrastructural alterations to ischemia-reperfusion in the isolated rat heart.

The effects of H290/51, a novel indenoindole derivative inhibitor of lipid peroxidation, on ultrastructural changes during cardiac ischemia-reperfusion injury were investigated. Langendorff-perfused rat hearts were exposed to 30 minutes of global ischemia followed by 20 minutes of reperfusion: Group A: Control hearts with standard buffer perfusion with vehicle added. Group B: H290/51 (10(-6) mol/l) added to buffer throughout stabilisation and reperfusion. In an additional Group C, where hearts were given H290/51, but not subjected to ischemia, the ultrastructure was preserved till the end of reperfusion. Absolute volumes and calculated volume fractions (Vv) of tissue and subcellular components were assessed with quantitative stereologic morphometry. After ischemia the increase in volume of extracellular interstitium was inhibited by H290/51 (247 +/- 80 vs. 159 +/- 50 microl, mean +/- SD, groups A and B, respectively, p<0.05). The Vv (interstitium/myocard) was higher in control hearts (0.318 +/- 0.062 vs. 0.206 +/- 0.067, p<0.05). Vv (cell edema/myocyte) was higher in the control group (0.144 +/- 0.07 vs. 0.083 +/- 0.033, p<0.05). Vv (myocyte/myocard) was higher in group B after ischemia than in the control group (0.622 +/- 0.071 vs. 0.707 +/- 0.052, p<0.05). The decreased Vv (capillary/myocard) after ischemia was inhibited by H290/51. After reperfusion there was no difference between groups. Treatment with H290/51 reduced edema and ensured better preserved sarcolemmal membrane structure during ischemia. The effect was no longer present after reperfusion.

Animals↗
PubMed2001

Reduced oral wound healing in the NOD mouse model for type 1 autoimmune diabetes and its reversal by epidermal growth factor supplementation.

Using the NOD mouse, a model for type 1 diabetes, we examined how reduced concentrations of epidermal growth factor (EGF) in the saliva, after onset of type 1 diabetes, affect oral wound healing. Diabetic NOD/LtJ mice on insulin therapy, prediabetic NOD/LtJ, and age- and sex-matched BALB/cJ mice were given a cutaneous tongue punch and allowed to undergo normal healing. With diabetes onset and a reduction in saliva-derived growth factor levels, the rate of tongue wound healing was reduced compared with nondiabetic NOD/LtJ and healthy BALB/cJ mice. Addition of exogenous EGF to the drinking water did not accelerate the rate of healing in BALB/cJ or prediabetic NOD/LtJ; however, diabetic NOD/LtJ mice exhibited accelerated wound healing similar to healthy mice. These results demonstrate that loss of growth factors from saliva is associated with profoundly reduced oral wound healing, suggesting that therapeutic treatment with topical delivery may be beneficial to patients with type 1 diabetes and oral wound complications.

Animals↗
PubMed2001

Targeting of doxorubicin to ES-2 human ovarian cancers in nude mice by linking to an analog of luteinizing hormone-releasing hormone improves its effectiveness.

Receptors for luteinizing hormone-releasing hormone (LHRH), expressed by ovarian cancers, can be used for targeting chemotherapeutic compounds more selectively to these tumors. We investigated the effects of cytotoxic LHRH analog AN-152, consisting of doxorubicin (DOX)-14-O-hemiglutarate linked to the epsilon-amino group of [D-Lys6]LHRH, on the growth of LHRH receptor-positive ES-2 human ovarian cancer line xenografted into nude mice. A single injection of AN-152, at a dose of 345 nmol/20 g body weight, caused a 34.5% reduction (P<0.05) in tumor growth after 28 days, while its cytotoxic moiety DOX was inactive at the same dose. Since the overexpression of certain growth factors and/or their receptors, such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and HER-2/neu, as well as various oncogenes like c-fos and c-jun, is associated with unfavorable prognosis and contributes to progressive growth of ovarian carcinomas, their mRNA levels were analyzed by RT-PCR. Treatment with AN-152 significantly (P<0.05) reduced the expression of EGFR, VEGF, c-fos and c-jun, to 49%, 48%, 55% and 58% respectively, compared to controls. HER-2/neu mRNA expression was also decreased to non-detectable levels. Conversely, DOX decreased non-significantly the expression levels for EGFR by 32%, VEGF 35%, both c-fos and c-jun approximately 20% and HER-2/neu by only 15%. In conclusion, cytotoxic LHRH analog AN-152 could be considered for chemotherapy of ovarian cancers expressing LHRH receptors.

Animals↗
PubMed2001

[Investigation of oncogene amplification or deletion, and oncoprotein expression in papillary thyroid cancer]

AIM: Assessment of occurrence and possible prognostic significance of c-myc and Ha-ras amplification, p53 deletion and overexpression of cyclin D1, p53 and p21 in papillary thyroid cancer. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tumor tissue from 24 patients were investigated. Dot-blot DNA hybridization was used to detect oncogene amplification or deletion. The expression of oncoproteins was determined by immunohistochemical method. RESULTS: In our samples neither Ha-ras amplification nor p53 deletion were found. Low c-myc amplification (mean: 2.55) occured in 4 cases (17%). p53 protein was detected in 16 samples (66.6%), with p21 expression (chi(2)=7.02, p<0.01) in 6 cases (25%). The p53 expression did not influence the tumor fenotype. Cyclin D1 overexpression was found in 12 cases (50%), it was often associated with p21 expression (chi2=10.1, p<0.001) and in inverse relation to the tumor lymphocytic infiltration (chi(2)=5.35, p<0.05). Increased expression of estrogen receptor was shown in 4 cyclin D1 positive samples (17%). CONCLUSIONS: The p53 detected in our study is likely not to be mutant protein in all cases because its presence was associated with p21 expression that the mutant protein cannot induce and also it did not mean more aggressive tumor phenotype. The connection of cyclin D1 overexpression with the lymphocytic infiltration of the tumor suggests that the increased expression of cyclin D1 means poor prognosis. The coexpression of cyclin D1 and p21 raises the modulative character of the p21 protein, thought to be a tumor suppressor originally, but we find a CDK-independent, estrogen receptor mediated effect of cyclin D1 more likely, which has been described in breast cancer and is also proved by the coexpression of cyclin D1 and estrogen receptor detected here.

Journal Article↗
PubMed2001

Chimaeras and mosaics for dissecting complex mutant phenotypes.

Back at the first half of the 1980s, there was no mammalian experimental embryology in Hungary. One of us, AN, took up the challenge of establishing a small group in the field. In the absence of local information, AN and his former colleague, Andras Paldi (AP), used their tourist passport to visit several laboratories in Western Europe and collect information and advice. This is how AN and AP ended up one day sitting in Anne McLaren's office in the MRC Mammalian Development Unit at University College, London. They never forgot her endless enthusiasm and the way she clearly explained the important points of preimplantation embryo manipulation, chimaera making and embryo transfer. As well as the extremely useful suggestions, which were crucial to starting the lab in Hungary, they also took back her deep love for embryo development. They remember her telling them, 'never waste an embryo--there is always another unanswered question it can solve'. Many who have been lucky and experienced Anne's spirit and advice later realized how useful it was to generate 'new' ideas by following the 'not wasting' principle. Our views on chimaeras presented below definitely contain elements which grew out from this principle.

Animals↗
PubMed2001

[Malignant and semimalignant small intestinal tumors--illustrated by two cases].

The authors review two cases of small bowel tumor. The first patient was operated electively with small bowel carcinoid causing multiplex liver metastases. The second patient was admitted because of massive gastrointestinal bleeding. After some diagnostic procedures bleeding of the small intestine was diagnosed. Urgent operation was performed and a bleeding jejunal tumor was removed. Gastrointestinal stroma cell tumor of the small bowel was found at histology. In connection with the patients some points about malignant small intestine tumors are analysed based on literature.

Aged↗
PubMed2001

Targeting of cytotoxic somatostatin analog AN-238 to somatostatin receptor subtypes 5 and/or 3 in experimental pancreatic cancers.

PURPOSE: The expression of somatostatin receptors (SSTRs) allows the localization and treatment of some tumors with radiolabeled SST analogues. We investigated whether SSTRs on human pancreatic cancer lines xenografted into nude mice can be used for targeting of cytotoxic somatostatin analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to octapeptide carrier RC-121. EXPERIMENTAL DESIGN: AN-238 and AN-201 were administered i.v. to nude mice bearing SW-1990 pancreatic cancers. Tumor growth reduction and survival were analyzed, and cell proliferation and apoptosis were determined with histological methods. The effects of repeated administration of AN-238 and AN-201 were also evaluated on xenografted Panc-1, MiaPaCa-2, CFPAC-1, Capan-1, and Capan-2 pancreatic cancers. The expression of mRNA for SSTR subtypes 2A, 3, and 5 in tumors was analyzed by reverse transcription-PCR, and binding assays were performed. RESULTS: All of the cancer models except MiaPaCa-2 displayed functional receptors for SST. SW-1990 expressed mRNA for SSTR subtypes 3 and 5, whereas various patterns of subtypes 2A, 3, and 5 were found in other pancreatic cancers. Repeated administration of AN-238 at 150 nmol/kg significantly inhibited growth of SW-1990 cancers (93% after 45 days; P = 0.016) and other tumors but not MiaPaCa-2. AN-201 was toxic and less effective. The efficacy of AN-238 was consistent with SSTR expression. CONCLUSIONS: Growth of experimental human pancreatic cancers that express SSTRs can be inhibited by cytotoxic somatostatin analogue AN-238.

Animals↗