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Biomedical subjects

L René

Publications and source records attributed to L René.

At least 19 recordsLinked to original sources
PubMed2000

Mechanism-based inactivation of VanX, a D-alanyl-D-alanine dipeptidase necessary for vancomycin resistance.

VanX is a zinc-dependent D-Ala-D-Ala amino dipeptidase required for high-level resistance to vancomycin. The enzyme is also able to process dipeptides with bulky C-terminal amino acids [Wu, Z., Wright, G. D., and Walsh, C. T. (1995) Biochemistry 34, 2455-2463]. We took advantage of this observation to design and synthesize the dipeptide-like D-Ala-D-Gly(SPhip-CHF(2))-OH (7) as a potential mechanism-based inhibitor. VanX-mediated peptide cleavage generates a highly reactive 4-thioquinone fluoromethide which is able to covalently react with enzyme nucleophilic residues, resulting in irreversible inhibition. Inhibition of VanX by 7 was time-dependent (K(irr) = 30+/-1 microM; k(inact) = 7.3+/- 0.3 min(-1)) and active site-directed, as deduced from substrate protection experiments. Nucleophilic compounds such as sodium azide, potassium cyanide, and glutathione did not protect the enzyme from inhibition, indicating that the generated nucleophile inactivates VanX before leaving the active site. The failure to reactivate the dead enzyme by gel filtration or pH modification confirmed the covalent nature of the reaction that leads to inactivation. Inactivation was associated with the elimination of fluoride ion as deduced from (19)F NMR spectroscopy analysis and with the production of fluorinated thiophenol dimer 12. These data are consistent with suicide inactivation of VanX by dipeptide 7. The small size of the VanX active site and the presence of a number of nucleophilic side chains at the opening of the active site gorge [Bussiere, D. E., et al. (1998) Mol. Cell 2, 75-84] associated with the high observed partition ratio of 7500+/-500 suggest that the inhibitor is likely to react at the entrance of the active site cavity.

Bacterial Proteins↗
PubMed1997

Synthesis of N-glyoxylyl peptides and their in vitro evaluation as HIV-1 protease inhibitors.

A series of novel synthetic peptides containing an N-terminal glyoxylyl function (CHOCO-) have been tested as inhibitors of HIV-1 protease. The N-glyoxylyl peptide CHOCO-Pro-Ile-Val-NH2, which fulfills the specificity requirements of the MA/CA protease cleavage site together with the criteria of transition state analogue of the catalyzed reaction, was found to be a moderate competitive inhibitor although favorable interactions were visualized between its hydrated form and the catalytic aspartates using molecular modeling. Increasing the length of the peptide sequence led to compounds acting only as substrates.

Amino Acids↗
PubMed1977

[Is unilateral total lobectomy adequate treatment for a single malignant thyroid nodule? 67 patients operated upon between 5 and 18 years age (author's transl)].

In the treatment of thyroid carcinoma, there is still some discussion about the best operation for a solitary and well encapsulated nodule. 18 years ago, it was decided to treat every case of "cold" thyroid nodule by total lobectomy and isthmectomy. 56 patients were reevaluated 5 to 18 years after such limited operation for malignant nodules. 8 of them died between the 19 th month and the 14 th year after surgery, the death being possibly related to the thyroid cancer in only 4 patients, but without any clinical evidence of local recurrence. Among 50 surviving patients, only one controlateral recurrence was observed, two years after lobectomy; it was treated by surgical totalisation of thyroidectomy, without any new recurrence after 10 more years. These results (although the small number of cases, and too short follow-up exclude definitive conclusions) are comparable to those obtained by a more aggresive surgical approach, but have the great advantage of total absence of any functional sequellae. So are we encouraged to go further in the experience of a rather conservative surgery in the treatment of uninodular thyroid carcinoma.

Adolescent↗
PubMed1976

[Thyroid cancers masked by hyperthyroidism. 12 cases].

The main object of this report was to attract again attention to the fact that obvious hyperthyroidism does not exclude the possibility of associated thyroid carcinoma, although this is an exceptional association. The 12 cases presented here may be added to about 30 cases found in the world literature. They were observed over a period of 13 years by the same surgical team and correspond to 0,3 p. 100 of all thyroid operations, 1 p. 100 of operated cases of hyperthyroidism and 3,6 p. 100 of cases of thyroid carcinoma. Contrary to most published cases, 11 or these cases out of 12, presented, clinically, mainly as hyperthyroidism the carcinotous lesion was either palpabale clinically in the form of a very small nodule (6 cases) or totally latent and discovered operation or even on histology as in 5 cases. Hyperthyroidism produced in 3 cases the classical picture of Graves' disease, in 6 cases that of toxic nodular goiter and, in 2 cases, that of a solitary toxic adenoma. The hyperplasia and the carcinoma were always in anatomically different areas. There is no apparent physiopahtological link and the classical notion of para-neoplastic hyperthyroidism seems debatable in most cases presented here, even in the cases of diffuse hyperfunctional hyperplasia. In any case, whatever the pathogenesis of this association, its possibility should be brought to mind in a case of hyperthyroidism. Surgery should always be advised in cases of toxic adenoma and in Graves' disease when the goiter is irregular and, especially, when a nodule is found. The course and prognosis seem to be mainly dictated by the histological type and the local spread or distant spread of the carcinoma, hyperthyroidism does not aggravate seriously the prognosis.

Adult↗