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Biomedical subjects

A Nagy

Publications and source records attributed to A Nagy.

At least 235 records · Page 13Linked to original sources
PubMed1993

Evaluation of biological activities of new LH-RH antagonists (T-series) in male and female rats.

A series of new highly potent LH-RH antagonists (T-series) has been synthesized in our laboratory. Among these analogs, antagonists [Ac-D-Nal(2), D-Phe(4Cl)2, D-Pal(3)3, D-Lys(A2pr(Car)2)6, D-Ala10]LH-RH (T-140); [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Lys(A2pr(Ac)2)6, D-Ala10]LH-RH (T-148); [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Lys(A2pr(For)2)6, D-Ala10]LH-RH (T-151) and [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Lys(A2bu(For)2)6, D-Ala10]LH-RH (T-159) were the most powerful. Antagonists T-140, T-148 and T-151 produced a complete blockade of ovulation in normal cycling rats at a dose of 1.5 micrograms/rat and antagonist T-159 at a dose of only 0.75 micrograms/rat. The inhibitory effects of compounds T-148, T-151 and T-159 on gonadotropin and sex steroid secretion were investigated in male and female rats. To determine their effect on LH levels in castrated male and ovariectomized female rats, T-148, T-151 and T-159 were injected subcutaneously in doses of 0.625 and 2.5 micrograms/rat. Blood samples were taken at different intervals for 48 h. All three compounds at either dose caused a significant (P < 0.01) decrease in LH levels for more than 6 h. Significant (P < 0.01) inhibition of LH lasted for more than 24 h following a dose of 2.5 micrograms sc of all 3 antagonists in both male and female rats. Serum FSH levels were also suppressed significantly for more than 48 h in castrated male rats by all three antagonists at a dose of 5 micrograms/rat sc.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

ADP-ribosylation of the neuronal phosphoprotein B-50/GAP-43.

The neuronal phosphoprotein B-50/GAP-43 is associated with growth and regeneration within the nervous system and its posttranslational status can be correlated with its cellular localization during growth and regeneration. Recently, B-50 has been shown to interact with certain G protein subunits. Regulation of G protein-mediated signal transduction may involve ADP-ribosylation in vivo. In the present study we have demonstrated that B-50 is a substrate for endogenous ADP-ribosyltransferases. The results are discussed with respect to the possible interaction of B-50 with G proteins, but also with regard to the posttranslational modification of B-50 by all major regulatory mechanisms that act at, or through, the neuronal membrane.

Adenosine Diphosphate Ribose↗
PubMed1993

Effect of luteinizing hormone-releasing hormone analogs containing cytotoxic radicals on the function of rat pituitary cells: tests in a long term superfusion system.

A novel class of targeted chemotherapeutic agents based on cytotoxic compounds linked to LHRH analogs was tested in a long term superfusion system in order to determine their effects on different types of rat pituitary cells. The compounds investigated included two cytotoxic LHRH agonists, T-98 ([D-Lys6]LHRH coupled to glutaryl-2-(hydroxymethyl)anthraquinone (G-HMAQ)) and T-107 ([D-Lys6]LHRH linked to doxorubicin (DOX) through glutaric acid spacer), and two cytotoxic LHRH antagonists T-121 and T-144, both containing two residues of G-HMAQ. The analogs were infused for 24 h at pharmacological (micromolar) concentrations. The secretions of LH, GH, and PRL cells after a short (2-h) and a long (20-h) recovery period following the treatment were compared to those before the analog infusion. All four cytotoxic LHRH analogs selectively decreased the stimulated LH response, while basal secretions of LH, GH, and PRL as well as the stimulated release of GH and PRL were not influenced in spite of the high doses applied and the long duration of exposure. The inhibitory effects of cytotoxic agonists and antagonists were significantly greater than those of their parent peptides. Equimolar concentrations of cytotoxic compounds alone (DOX or G-HMAQ), however, caused functional damage to all types of cells tested. To evaluate the mechanisms of the observed inhibitory actions, we compared the amount of LH released in response to 1) a specific stimulus to receptors (3 nM LHRH), 2) membrane depolarization with 100 MM KCl, not involving the receptor, and 3) the extraction of cells with 0.01 N HCl at the end of experiment. Cytotoxic LHRH agonists and their carriers caused depletion of LH pools, while cytotoxic LHRH antagonists or their parent peptides decreased the available binding sites for LHRH. The inhibitory effect of DOX on stimulated secretion of LH, GH, and PRL in our system could be due to an action on cell membranes. Our work indicates that in the pituitary cell superfusion system, targeted cytotoxic conjugates, based on LHRH analogs, selectively affect LH cells, in contrast to unconjugated cytotoxic compounds, which also damage GH and PRL cells.

Amino Acid Sequence↗
PubMed1992

[Results of extended resection of tumors of the colon and rectum].

The postoperative lethality and 5 year survival of elective extended colon resections in 59 locally advanced colorectal tumour cases has been evaluated. The operation has been extended for one adjacent organ in 47 (Groups I.) and for two or more organs in 12 cases (Groups. II.). The postoperative lethality was 47/1 and 12/2 respectively (P less than 0.01). However the 5 year survival proved to be similar--42% and 40% respectively in both patients group. The 5 year survival of patients group I. and II. was not significantly different comparing to the "simple" elective colorectal resections on the patients in Dukes C stadium operated on in the same period of time. Significantly better 5 year survival has been observed in the patients groups. I. and II. comparing to the outcome of the elective palliative (anus prae and ileo- or colo-colostomies) colorectal operations. The results certify the value of the radical surgical procedures in the locally advanced tumor cases.

Colectomy↗
PubMed1992

Cytotoxic analog of somatostatin containing methotrexate inhibits growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice.

Nude mice bearing xenografts of MIA PaCa-2 human pancreatic cancer cell line were treated for 4 weeks with AN-51, a somatostatin octapeptide analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121) containing methotrexate attached to the alpha-amino group of D-Phe in position 1. Control groups of mice received saline, RC-121 or methotrexate. Drugs were given in equimolar doses by daily s.c. injections. After 7 days of treatment with 25 micrograms/day of AN-51, tumor growth was completely inhibited although the treatment had to be suspended because of toxic side effects, especially on the gastrointestinal tract, accompanied by major weight loss of the animals. Mice were allowed to recover for 1 week and treatment was continued with 12.5 micrograms/day AN-51. After 2 weeks of additional therapy, tumor volume, percentage change in tumor volume, and tumor weights were significantly decreased, compared with controls, only in the group treated with AN-51. Methotrexate and RC-121 also inhibited tumor growth, but their effects were not statistically significant. AN-51 retained its hormonal activity and decreased serum growth hormone levels in mice. Binding affinity of AN-51 for somatostatin receptors on MIA PaCa-2 cells was found to be 2.5-times lower than that of parent compound RC-121. This is the first report on inhibition of human pancreatic cancer growth in vivo by somatostatin analogs carrying cytotoxic radicals.

Animals↗
PubMed1992

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines. Some cytotoxic analogues also significantly suppressed the growth of mammary and prostate cancers in vivo in animal models.

Amino Acid Sequence↗
PubMed1992

Effect of luteinizing hormone-releasing hormone analogs containing cytotoxic radicals on growth of estrogen-independent MXT mouse mammary carcinoma in vivo.

Cytotoxic luteinizing hormone-releasing hormone (LH-RH) analogs, AJ-004 (agonist [D-Lys6]LH-RH linked to methotrexate (MTX)), T-98 ([D-Lys6]LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone) (G-HMAQ) and T-121/B (antagonist containing two residues of G-HMAQ) were tested in female BDF1 mice bearing MXT ((3.2)/Ovex) estrogen-independent mammary tumors. All three cytotoxic LH-RH analogs, administered from Alzet Osmotic Minipumps for 3 weeks, produced a significant inhibition of tumor growth. The effects of T-98 and T-121/B were superior to those obtained by treatment with equimolar doses of cytotoxic moiety anthraquinone or the LH-RH carrier alone. We assume that cytotoxic LH-RH analogs have a combined hormonal and cytotoxic activity with a reduced toxicity after administration in vivo. This is the first demonstration of in vivo tumor inhibition by targeted LH-RH analogs bearing cytotoxic radicals.

Amino Acid Sequence↗
PubMed1992

A satellite III sequence shared by human chromosomes 13, 14, and 21 that is contiguous with alpha satellite DNA.

We report the isolation of a clone (pTR9) from a human chromosome 21 lambda phage library, which was found to contain two distinct components: (1) a previously unreported subfamily of human satellite III (pTR9-s3; 1,485 bp) and (2) an alpha satellite sequence (pTR9-alpha; 250 bp) containing 1.5 copies of a 171-bp alphoid unit that shows 88.4% homology to a previously reported alpha satellite consensus sequence. The two components are separated by two direct repeats of 9 bp. Use of the polymerase chain reaction (PCR) to amplify across the junction between pTR9-s3 and pTR9-alpha established that these two sequences are contiguous in total human genomic DNA and in DNA derived from somatic cell hybrids carrying human chromosomes 13, 14, or 21. A related, but considerably more diverged, sequence was also detected on chromosome 15. Southern analysis of somatic cell hybrids at high stringency revealed a common structure of the pTR9-s3 sequence on chromosomes 13, 14, and 21 but not on 15 or 22. This sequence should be useful for the study of the structural organisation of the centromere of these chromosomes and the mechanism of their involvement in Robertsonian translocations.

Base Sequence↗
PubMed1992

[Inclusion cysts. Case report].

Inclusion cysts which are developmental anomalies can be seen either along the midpalatine raphe or on the dental ridges as well as on other areas of the palate in newborns. Based on their localisation and histology these are classified into three types (Epstein's pearls, Bohn's nodules, Dental lamina cysts). These are often taken as natal or neonatal teeth. No treatment is indicated since the lesions will spontaneously disappear few weeks after birth.

Female↗
PubMed1992

Prognostic data of the second follow-up in childhood wheezy bronchitis.

206 non-selected children who had wheezy bronchitis before two years of age were observed in the first follow-up (1985) about 9 years after their clinical wheezy episode. Among them 31 patients (15%) showed bronchial hyperreactivity (B.H.) after acetylcholine challenge and 9 children became asthmatic. In the second follow-up (1988) 28 children who had B.H. and randomly 17 children who did not have B.H. participated. The prognosis of wheezy bronchitis is good, there was no new asthmatic child at this time. The B.H. was found to diminish only in 7 cases. During the last 3 years wheezy episodes developed only in 5 asthmatic patients. The skin prick test (SPT) positivity did not change (26% versus 29%). The familial atopy in the group B.H. is higher (43%) than in the group non B.H. (23%) but the difference is not significant (X2 = 1.72). No significant correlation was found between the familial atopy and SPT positivity. The familial smoking is higher in the group B.H. (78% versus 64%) but no significant influence on the B.H. (X2 = 1.03) could be detected.

Bronchitis↗
PubMed1991

Long-term reconstitution of the mouse hematopoietic system by embryonic stem cell-derived fetal liver.

Murine embryonic stem (ES) cells are permanent blastocyst-derived cell lines capable of contributing to a wide variety of tissues, including the germ line, after injection into host blastocysts. Recently, we have shown that ES cells can produce all of the cells of the developing fetus after aggregation with developmentally compromised tetraploid embryos. Completely ES cell-derived embryos die perinatally, but the liver of these embryos is a source of entirely ES cell-derived hematopoietic progenitors. We have taken 14- to 15-day fetal liver cells from ES cell-tetraploid chimeras and reconstituted the hematopoietic system of lethally irradiated adult recipient mice. ES cell-derived hematopoietic stem cells were capable of long-term (greater than 6 months) repopulation of irradiated recipients, and all hematopoietic cell lineages analyzed (erythrocytes, T cells, mast cells, and macrophages) were derived exclusively from ES cells in such recipients. Thus, ES cells retain the capacity to differentiate into all hematopoietic cell types after prolonged passage in culture. This approach should provide a direct route to the production of mice whose hematopoietic cells carry genetic alterations that would be lethal if passed through the germ line.

Animals↗
PubMed1991

Inefficient muscarinic transduction in cardiomyopathic Syrian hamsters.

Regulation of cyclic AMP (cAMP) production and muscarinic binding were studied in highly washed left ventricular membranes from spontaneously cardiomyopathic Syrian hamsters (TO strain). Basal production of cAMP was decreased relative to that in random-bred (RB) controls, with proportionally similar decreases in stimulated production elicited by 7 beta-deacetyl-7 beta-(gamma-N-methylpiperazino)-butyryl forskolin and by the beta-adrenergic agonist isoproterenol. GTP-stimulated production of cAMP was inhibited fully by the muscarinic agonist carbachol in tissue from controls, but only partially in tissue from TO hamsters. Total muscarinic binding, as revealed by N-[3H]methylscopolamine, was similar in the two strains. Competition between carbachol and the radioligand revealed at least three classes of sites for the agonist, the apparent affinities of which were insensitive to the disease. Upon the addition of guanylyl imidodiphosphate (GMP-PNP, 0.1 mM), there was a disease-dependent redistribution such that the sites appeared to be predominantly of low affinity for the agonist in RB tissue and predominantly of medium affinity in TO tissue. The potency of GMP-PNP in mediating the change in carbachol binding apparently was unaffected by the disease. The loss of muscarinic regulation of cAMP production in TO left ventricular tissue appears to reflect a disease-related change in the coupling of muscarinic receptors to inhibitory GTP-binding proteins.

Adenylyl Cyclases↗
PubMed1991

Vaccina treatment in some hospital infections.

Phenol-treated vaccine was prepared from the usual hospital strains and patients with colorectal cancer were immunized intramuscularly 7-10 days prior to the operation. The efficiency of the vaccine treatment was judged by the incidence of wound infections. The best results were obtained in patients whose previously estimated immunoreactivity was strong or normal. Immunospecificity could not be detected in the above treatment. The frequent and inappropriate use of antibiotics in hospitals increases the number of resistant hospital bacterial strains. Apart from Staphylococci and Streptococci, different Gram-negatives--such as Klebsiella, Serratia, Pseudomonas, Proteus and E. coli strains--have been found in the hospitals and in the patients. Due to the resistance, it is difficult to find antibiotics against them. This fact puts forward the possibility of immunization especially by vaccination.

Bacterial Vaccines↗
PubMed1990

[Causes and management of local tumor recurrence after low resection of the rectum].

The postoperative course of 64 patients resected with EEA stapler because of their midrectal cancer have been followed. 13 (20.3%) local tumor recurrence have been observed in the first 24 postoperative months. 5 patients could be rectum exstirpated at the reexploration, only colostomy was performed in 8 cases. All the inoperabel patients have died in a year, but 3 of the exstirpated ones overlived this time. A direct connection have been observed between the Dukes stadium and the differentiation of the tumor, the distance of the distal resection line from the lower end of the tumor and the probability of the local recurrence. No connection has been found between the distance of the tumor from the linea dentata and the local tumor recurrence. On the basis of the oncological observations the deep rectal resection can be performed only by tumors in stadium Dukes A and B, if the tumor is well differentiated, there are no signs for local propagation or lymph node metastases, and more then 2 cm distal distance can be kept by the resection from the lower and of the tumor. In all other cases the rectum exstirpation must be the method of choice.

Humans↗