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A Mucha

Publications and source records attributed to A Mucha.

10 recordsLinked to original sources
PubMed2006

A phosphonamidate containing aromatic N-terminal amino group as inhibitor of leucine aminopeptidase-design, synthesis and stability.

Fully deprotected phosphonamidate dipeptides, predicted as effective inhibitors of cytosolic leucine aminopeptidase, showed unexpected instability in water solution at pH below 12. Their hydrolysis rate was strictly correlated with basicity of the N-terminal amino group. To improve this feature a phosphonamidate analogue containing less basic, aromatic 2-aminophenylphosphonate residue in P1 position of the inhibitor was designed. The target compound was synthesised starting from diethyl 2-nitrophosphonate in several step procedure. The decrease in basicity of the terminal amino moiety of the modified analogue in fact resulted in satisfactory improvement of hydrolytic stability of the P-N bond. The developed phosphonamidate was proved to be fully resistant to hydrolysis above pH 7. Surprisingly, tested in enzymatic assays towards leucine aminopeptidase (optimum pH 8.5), it did not exhibit inhibition activity up to milimolar concentration. The explanation could be that diminishing the basic character of the terminal amino group may result in a change of its affinity towards the zinc ions.

Drug Design↗
PubMed2005

Predictors of elevated blood lead levels among 3-year-old Ukrainian children: a nested case-control study.

OBJECTIVES: Lead is common in the general population. However, data are lacking for the Ukraine and many other countries from the former Soviet Union (FSU). In this study we evaluate the level of blood lead among 212 Ukrainian children and determine predictors of elevated lead levels. We also describe the health effects associated with elevated blood lead. METHODS: A nested case-control study from a prospective cohort of Ukrainian 3-year-old children was conducted in March 1998. Blood assays were analyzed for lead by labs at the Centers for Disease Control and using portable examination kits. We evaluated predictors of elevated blood lead (blood levels in the upper quartile >4.65 microg/dL) using a multivariable logistic regression model. The model included socioeconomic status, parent occupation, environmental tobacco smoke, hygiene, diet, and health status. RESULTS: The geometric mean lead level was 3.15 microg/dL (range, 0.7--22.7). In our adjusted model, we observed a strong association between lead levels in the upper quartile and children whose fathers worked manual labor jobs in industries associated with lead exposures [adjusted odds ratio (OR)=2.25; P=0.025] and mothers who smoke indoors (adjusted OR=2.87; P=0.047). Daily hygiene and dietary habits were not associated with elevated lead levels. No increased risks of overall morbidity or lead-associated illness were observed (anemia, dental caries, renal disease, cardiovascular diseases, and musculoskeletal complaints). CONCLUSION: This is the first study to describe lead levels and associated variables among Ukrainian children in the peer-reviewed literature. Elevated lead levels in these children were associated with paternal occupation and mothers smoking indoors. At age 3 no adverse health effects were observed. More data are needed to determine the level of heavy metal contamination in children from the Ukraine and many other former Soviet nation-states.

Adult↗
PubMed2000

[Prognostic factors in radiotherapy for hypopharyngeal cancer].

This paper presents influence of selected prognostic factors on results of hypopharyngeal cancer radiotherapy used as only treatment in 97 patients irradiated in Centre of Oncology-Institute in Gliwice between 1980-1987. One-variant analysis showed statistically significant influence of gender, decrease of haemoglobin level during radiotherapy and higher T and N stages. Multivariant analysis demonstrated, that only locoregional status and treatment time has decisive importance on radiotherapy results. Thus, better results of treatment depend on lower T and N stages and correct radiotherapy time.

Adult↗
PubMed2000

[The effectiveness of combined treatment for laryngeal cancer in Silesia region during the years 1987-1996].

Between 1987-1996, 484 patients with laryngeal cancer were treated by surgery and adjuvant radiotherapy. The 25-30% therapeutic gain was noted when to compare the first period of the study (1987-1992) with the second (1993-1996). The increment of effectiveness of combined treatment for larynx cancer is probably the result of better quality of surgical procedures and individualization of radiation treatment.

Adult↗
PubMed2000

[[Radical radiotherapy in patients with laryngeal cancer in clinical material of Institute Oncology in Gliwice treated in year 1990-1996].

This paper presents influence of selected prognostic factors on results of laryngeal cancer radiotherapy used as the only treatment in 541 patients irradiated in Centre of Oncology-Institute in Gliwice between 1990-1996. The 3-year actuarial disease-free survival was 47.5% for supraglottic cancer and 67% for glottic cancer. Primary tumour localisation in glottis correlates with more favourable prognosis than that in supraglottic. For extralaryngeal involvement the most favourable prognosis was infiltration of cartilages and the worst one for the hypopharyngeal and oropharyngeal involvement. Pretreatment tracheostomy significantly correlates with the worst results.

Adult↗
PubMed2000

[Head and neck lymph node metastases from unknown primary site].

The aim of this paper was to evaluate the group of 50 patients with cervical nodes metastases from unknown primary site treated between 1980-1995 in Maria Sk_odowska-Curie Memorial Institute of Oncology in Gliwice. There were 42 males and 8 females ranging in age from 26 to 85 years (median 60). 24 patients underwent combined therapy (surgery with postoperative radiotherapy), 22 underwent radiotherapy. Only 4 patients were treated with surgery alone. 3-years DFS rates were 59% in group treated with combined method, and 10% in group treated only with radiation therapy (p = 0.003). After a median follow up of 39 months 10 primary tumors were discovered--8 in head and neck region, 2 in lower respiratory tracts. DFS rate in group with discovered primary tumors was 40%.

Adult↗
PubMed1999

Role of the S1' subsite glutamine 215 in activity and specificity of stromelysin-3 by site-directed mutagenesis.

The influence of Gln215 in stromelysin-3 (MMP-11), a residue located in the S1' subsite, was determined by producing three single mutants of this position. As compared to wild-type stromelysin-3, the kinetic parameters K(M) and k(cat) for the degradation of the fluorogenic substrate Dns-Pro-Leu-Ala-Leu-Trp-Ala-Arg-NH(2) (Dns-Leu) by these mutants indicated that the Gln/Leu substitution led to a 4-fold decrease in catalytic efficiency, whereas the mutations Gln/Tyr and Gln/Arg increased this parameter by a factor 10. The cleavage of alpha1-protease inhibitor (alpha1-PI), a natural substrate of stromelysin-3, by these mutants was also determined. Their relative activities for the degradation of alpha1-PI correspond to those observed with the synthetic substrate Dns-Leu. The catalytic efficiency of wild-type stromelysin-3 and its mutants to cleave the P1' analogue of Dns-Leu, containing the unusual amino acid Cys(OMeBn) (Dns-Cys(OMeBn)), was also determined. The values of the specificity factor, calculated as the ratio (k(cat)/K(M))Dns-Cys(OMeBn))/(k(cat)/K(M))Dns-Leu, were observed to vary from 26 for the wild-type stromelysin-3 to 120 for the Gln/Leu mutant and 25 for the Gln/Arg mutant. The Gln/Tyr mutant did not cleave the substrate when its P1' position is substituted by the unusual amino acid Cys(OMeBn). Altogether these observations established that both the catalytic activity and the specificity of stromelysin-3 are dependent on the nature of the residue in position 215. Finally, the cleavage efficiency of the Dns substrates by three representative matrixins, namely, MMP-14 (215 = Leu), MMP-1 (215 = Arg), and MMP-7 (215 = Tyr), was determined. Interestingly, the trends observed for these enzymes were similar to those established for the three mutants of stromelysin-3, pointing out the influence of position 215 toward the selectivity in this family of enzymes.

Animals↗
PubMed1999

Phosphinic pseudo-tripeptides as potent inhibitors of matrix metalloproteinases: a structure-activity study.

Several phosphinic pseudo-tripeptides of general formula R-XaaPsi(PO(2)-CH(2))Xaa'-Yaa'-NH(2) were synthesized and evaluated for their in vitro activities to inhibit stromelysin-3, gelatinases A and B, membrane type-1 matrix metalloproteinase, collagenases 1 and 2, and matrilysin. With the exception of collagenase-1 and matrilysin, phosphinic pseudo-tripeptides behave as highly potent inhibitors of matrix metalloproteinases, provided they contain in P(1)' position an unusual long aryl-alkyl substituent. Study of structure-activity relationships regarding the influence of the R and Xaa' substituents in this series may contribute to the design of inhibitors able to block only a few members of the matrix metalloproteinase family.

Kinetics↗
PubMed1998

Membrane type-1 matrix metalloprotease and stromelysin-3 cleave more efficiently synthetic substrates containing unusual amino acids in their P1' positions.

The influence of the substrate P1' position on the specificity of two zinc matrix metalloproteases, membrane type-1 matrix metalloprotease (MT1-MMP) and stromelysin-3 (ST3), was evaluated by synthesizing a series of fluorogenic substrates of general formula dansyl-Pro-Leu-Ala-Xaa-Trp-Ala-Arg-NH2, where Xaa in the P1' position represents unusual amino acids containing either long arylalkyl or alkyl side chains. Our data demonstrate that both MT1-MMP and ST3 cleave substrates containing in their P1' position unusual amino acids with extremely long side chains more efficiently than the corresponding substrates with natural phenylalanine or leucine amino acids. In this series of substrates, the replacement of leucine by S-para-methoxybenzyl cysteine increased the kcat/Km ratio by a factor of 37 for MT1-MMP and 9 for ST3. The substrate with a S-para-methoxybenzyl cysteine residue in the P1' position displayed a kcat/Km value of 1.59 10(6) M-1 s-1 and 1.67 10(4) M-1 s-1, when assayed with MT1-MMP and ST3, respectively. This substrate is thus one of the most rapidly hydrolyzed substrates so far reported for matrixins, and is the first synthetic peptide efficiently cleaved by ST3. These unexpected results for these two matrixins suggest that extracellular proteins may be cleaved by matrixins at sites containing amino acids with unusual long side chains, like those generated in vivo by some post-translational modifications.

Amino Acids↗