RESUMO
Actinoplanes friuliensis produces the lipopeptide antibiotic friulimicin, which is a cyclic peptide with one exocyclic amino acid linked to a branched-chain fatty acid acyl residue. The structural relationship to daptomycin and the excellent antibacterial performance of friulimicin make the antibiotic an attractive drug candidate. The complete friulimicin biosynthetic gene cluster of 24 open reading frames from A. friuliensis was sequenced and analyzed. In addition to genes for regulation, self-resistance, and transport, the cluster contains genes encoding peptide synthetases, proteins involved in the synthesis and linkage of the fatty acid component of the antibiotic, and proteins involved in the synthesis of the nonproteinogenic amino acids pipecolinic acid, methylaspartic acid, and 2,3-diaminobutyric acid. By using heterologous gene expression in Escherichia coli, we provide biochemical evidence for the stereoselective synthesis of L-pipecolinic acid by the deduced protein of the lysine cyclodeaminase gene pip. Furthermore, we show the involvement of the dabA and dabB genes in the biosynthesis of 2,3-diaminobutyric acid by gene inactivation and subsequent feeding experiments.
Assuntos
Antibacterianos/biossíntese , Micromonosporaceae/genética , Micromonosporaceae/metabolismo , Aminobutiratos/metabolismo , Southern Blotting , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Conjugação Genética , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Eletroforese em Gel de Poliacrilamida , Escherichia coli/metabolismo , Teste de Complementação Genética , Hibridização In Situ , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Família Multigênica , Mutação/genética , Mutação/fisiologia , Ácidos Pipecólicos/metabolismo , Plasmídeos/genéticaRESUMO
Glatiramer acetate (GLAT) is a well tolerated and safe immunomodulatory drug for the treatment of relapsing-remitting multiple sclerosis. The most commonly recognized side effects are localized injection site reactions consisting of pain, pruritus, mild erythema and induration, which sometimes persist for several days. We describe the first case of a biopsy-proven lymphocytic infiltration (T-cell pseudolymphoma) with the clinical appearance of a figured erythema on the ventrolateral thighs in the first four weeks under GLAT treatment, resolving without any evidence of recurrence despite ongoing therapy. A T-cell pseudolymphoma is a very rare side effect of GLAT treatment. For clinical purposes it is important to state that re-exposition after GLAT-induced pseudolymphoma is possible without permanent sequelae.
Assuntos
Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Peptídeos/efeitos adversos , Pseudolinfoma/induzido quimicamente , Dermatopatias/induzido quimicamente , Adulto , Acetato de Glatiramer , Humanos , Hiperpigmentação/induzido quimicamente , Hiperpigmentação/imunologia , Linfócitos/imunologia , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia , Pseudolinfoma/imunologia , Dermatopatias/imunologiaRESUMO
As response to interferon beta (IFNB) treatment, a 50% reduction of the mean relapse rate compared to pretreatment values has been reported. However, individual responses vary considerably, ranging from no reduction in exacerbation frequency to complete suppression of relapses for at least two years. At the moment, valid predictors for IFNB response are lacking. Here we present a prospective evaluation of 33 patients with primary relapsing multiple sclerosis who were followed for two years of IFNB treatment A low interferon gamma (IFG) production before treatment predicted a two-year term without exacerbations in 68.8% of cases correctly, whereas a high pretreatment IFG production implied the risk of at least one relapse in the first two years in 70.6%. These preliminary results encourage further evaluation of IFG as predictor of an IFNB treatment response.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Interferon beta/administração & dosagem , Interferon gama/metabolismo , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Up to now, the expression of the tumor-associated Thomsen-Friedenreich (TF) antigen in colorectal carcinoma has not been thoroughly investigated with particular emphasis on its correlation with established clinicopathologic characteristics and classifications as well as its prognostic relevance. METHODS: Formalin fixed, paraffin embedded specimens from 264 patients with colorectal carcinoma were stained using an avidin-biotin complex-peroxidase assay. As primary monoclonal antibodies (MAbs), A78-G/A7, which binds to TFalpha and TFbeta antigen irrespective of its carrier, and BW835, which detects TFalpha on MUC1 repeat peptide, were applied. RESULTS: MAbs A78-G/A7 and BW835 labeled 64.8% and 58. 0%, respectively, of carcinomas. None of the binding patterns correlated with gender, tumor localization, or growth type. Only BW835 reactivity exhibited a significant correlation with increasing pTNM staging and histologic grading. Staining of the MAb A78-G/A7 was significantly stronger in carcinomas that contained a mucinous component. In univariate survival analysis, in addition to pTNM staging and histologic grading, reactivity with A78-G/A7 as well as BW835 were significantly correlated with lower survival probability. Multivariate analysis according to the Cox proportional hazards model revealed only pTNM staging, histologic grading, and A78-G/A7 staining to be independent prognostic factors. CONCLUSIONS: According to these results, TF disaccharide represents a cancer-associated antigen in colorectal carcinoma that exhibits qualities of a prognostic marker. As demonstrated by BW835 staining, it is obviously coexpressed with MUC1 peptide core in a great number of cases. These results suggest that TF, in addition to MUC1, might also serve as a useful target antigen in the treatment of patients with colorectal carcinoma.
Assuntos
Antígenos de Neoplasias/imunologia , Antígenos Glicosídicos Associados a Tumores/imunologia , Carcinoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma/imunologia , Carcinoma/mortalidade , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de TempoRESUMO
In addition to the tumor suppressor gene p53, Cyclin Dependent Kinases (CDK) are well known to influence the cell cycle in normal human tissues and various neoplasias as well. The purpose of our present study was to evaluate the expression of the CDK-inhibitor p21/waf1/cip1 in colorectal cancer with special emphasis on the prognostic impact. Between 1985 and 1991, 294 patients (median age, 65 years) underwent surgical operative therapy for colorectal cancer. Formalin-fixed and paraffin-embedded tumor specimens were investigated. For immunohistochemistry the Catalysed Reporter Deposition (CARD) technique was performed. The survival probability was calculated and possible prognostic risk factors were tested using multivariate analysis. The p21/ waf1/cip1 staining pattern was positive in 197 (67%) specimens and negative in 97 (33%) samples. No significant correlation could been calculated between p21/waf1/cip1 expression and other variables such as age, sex, WHO-Classification, localisation, grading, TNM-classification or UICC-stage. Patients with a positive staining reaction had a significantly better survival (p < 0.0052). Moreover, p21/waf1/cip1 was shown to be an independent prognostic parameter by multivariate analysis (p < 0.022). In contrast with these findings, the p53 tumor status had no impact on survival. P21/ waf1/cip1 appears to be an independent prognostic parameter in colorectal cancer and is associated with a favorable survival. This feature may be related to a cell cycle arrest in the G1 phase induced by p21/waf1/cip1, resulting in lower tumor cell proliferative activity.