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ERJ Open Res ; 3(3)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28845429


In chronic hypersensitivity pneumonitis (CHP), lack of improvement or declining lung function may prompt use of immunosuppressive therapy. We hypothesised that use of azathioprine or mycophenolate mofetil with prednisone reduces adverse events and lung function decline, and improves transplant-free survival. Patients with CHP were identified. Demographic features, pulmonary function tests, incidence of treatment-emergent adverse events (TEAEs) and transplant-free survival were characterised, compared and analysed between patients stratified by immunosuppressive therapy. A multicentre comparison was performed across four independent tertiary medical centres. Among 131 CHP patients at the University of Chicago medical centre (Chicago, IL, USA), 93 (71%) received immunosuppressive therapy, and had worse baseline forced vital capacity (FVC) and diffusing capacity, and increased mortality compared with those who did not. Compared to patients treated with prednisone alone, TEAEs were 54% less frequent with azathioprine therapy (p=0.04) and 66% less frequent with mycophenolate mofetil (p=0.002). FVC decline and survival were similar between treatment groups. Analyses of datasets from four external tertiary medical centres confirmed these findings. CHP patients who did not receive immunosuppressive therapy had better survival than those who did. Use of mycophenolate mofetil or azathioprine was associated with a decreased incidence of TEAEs, and no difference in lung function decline or survival when compared with prednisone alone. Early transition to mycophenolate mofetil or azathioprine may be an appropriate therapeutic approach in CHP, but more studies are needed.

Int J Radiat Biol ; 82(6): 421-33, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16846977


PURPOSE: To examine the effect of the amino acid tyrosine on oxidatively or direct-type damaged DNA damage when it is present in a DNA binding ligand. MATERIALS AND METHODS: We made use of tetralysine ligands to ensure binding to DNA and to condense the DNA, and simulated direct-type damage by using gamma irradiation in the presence of thiocyanate ions. These ligands contained an additional C terminal amino acid. Phenylalanine was used as a control for tyrosine. These ligands were used in conjuction with a plasmid substrate to quantify strand break yields. Base damage yields were estimated by measuring the strand break yield after incubation of the plasmid with the bacterial base excision repair enzyme formamidopyrimidine-DNA N-glycosylase (FPG). RESULTS: When the condensing ligand contains an additional tyrosine or tryptophan residue, the plasmid is protected against the effects of a single electron oxidation, as assayed by sensitivity to a base excision repair enzyme. This protection is significantly greater in condensed plasmid where the amino acid residues are in close proximity to the DNA, and can be observed even when only a small fraction of the ligand contains tyrosine. CONCLUSIONS: Bound tyrosine residues located in close proximity to DNA are capable of reversing oxidative DNA damage far more efficiently than when present unbound in the bulk solution. This suggests that tyrosine residues in DNA binding proteins may participate in the repair of DNA that has been oxidatively damaged by ionizing radiation.

Peptídeos Catiônicos Antimicrobianos/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Tirosina/farmacologia , Sítios de Ligação , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , DNA-Formamidopirimidina Glicosilase/farmacologia , Relação Dose-Resposta a Droga , Raios gama , Ligantes , Fenilalanina/química , Fenilalanina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/efeitos da radiação , Tiocianatos/farmacologia , Fatores de Tempo , Triptofano/química , Triptofano/farmacologia , Tirosina/química