RESUMO
Assuntos
Busca de Comunicante , Tuberculose Pulmonar , Humanos , Setor Privado , Índia/epidemiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/prevenção & controle , Programas de Rastreamento/métodosRESUMO
BACKGROUND: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer. PATIENTS AND METHODS: Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR). RESULTS: In phase I (n=12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine. CONCLUSION: Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , Vimblastina/uso terapêutico , VinorelbinaRESUMO
Defects in myocardial bioenergetics have been reported in patients with cardiomyopathy but their molecular basis and role in pathophysiology remain unclear. We sought to establish a molecular basis for cardiac mitochondrial respiratory enzyme abnormalities frequently present (75%) in a group of 16 children (including 2 neonates) with end-stage cardiomyopathy. Decreased specific activity levels were found in complexes I, III, IV and V but not in II, the only complex that is entirely nuclear encoded. Sequence analysis of cardiac mtDNA revealed 4 patients harbouring heteroplasmic mtDNA mutations in cytb, tRNAArg, and ND5 at highly conserved positions. These mutations were present neither in controls nor in patients without enzymatic defect. In addition, 4 patients exhibited marked reduction in cardiac mtDNA levels. The basis for respiratory enzyme abnormalities can be explained in a subset of our patients as a result of either pathogenic mtDNA mutation or depletion. Patients harbouring both DNA and enzymatic defects fulfil rigorous criteria defining mitochondrial cardiomyopathy.
Assuntos
Cardiomiopatias/genética , Proteínas de Transporte , Miopatias Mitocondriais/genética , Adenosina Trifosfatases/metabolismo , Adolescente , Pré-Escolar , Grupo dos Citocromos b/genética , DNA Mitocondrial/química , Complexo I de Transporte de Elétrons , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/metabolismo , Mitocôndrias Cardíacas/enzimologia , ATPases Mitocondriais Próton-Translocadoras , Mutação , NADH NADPH Oxirredutases/metabolismo , RNA de Transferência de Arginina/genética , Análise de Sequência de DNARESUMO
Previous studies in our laboratory demonstrated significant changes in bovine heart mitochondrial bioenergetics during fetal growth and development. To further understand mitochondrial biogenesis in early human development, the activity and subunit content levels of specific mitochondrial enzymes in fetal and neonatal heart were determined. Comparing early gestation (EG, 45-65 day) later gestation (LG, 85-110 day) and neonate (birth-1 month), specific activity of citrate synthase (CS), a Krebs cycle enzyme showed a 2 fold increase from EG to LG and a 2 fold increase from LG to neonate. Specific activities of complex IV and complex V increased similarly 1.8-2 fold from EG to LG. However during the later fetal period from LG to neonate, complex IV activity increased only 1.3 fold and complex V showed no significant increase. Peptide content of COX-II subunit increased 2 fold from EG to LG and by 3.5 fold from LG to neonate. Levels of COX-IV and ATP synthase alpha subunits were undetectable in EG hearts, clearly detectable in LG heart and 3 fold increased from LG to neonate. Unexpectedly, mitochondrial transcription factor A (mt-TFA) levels were not significantly different during these developmental stages. Mitochondrial DNA (mtDNA) levels increased 1.8 fold from EG to LG, and 3.8 fold increase from EG to neonate and correlated with CS activity levels. In conclusion, these data indicate coordinated regulation of some nuclear-encoded (COX-IV and CS activity) and mitochondrial components (COX-II and mtDNA), and strongly suggest that mitochondrial content increases particularly during the early fetal cardiac development and reveal a distinct pattern of regulation for mt-TFA.
Assuntos
Coração Fetal/enzimologia , Coração/embriologia , Mitocôndrias Cardíacas/enzimologia , ATPases Mitocondriais Próton-Translocadoras , Análise de Variância , Western Blotting , Citrato (si)-Sintase/metabolismo , DNA Mitocondrial/análise , Desenvolvimento Embrionário e Fetal , Coração Fetal/crescimento & desenvolvimento , Coração Fetal/metabolismo , Ventrículos do Coração , Humanos , Recém-Nascido , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , ATPases Translocadoras de Prótons/metabolismoRESUMO
BACKGROUND: Previous studies have shown that mitochondrial DNA (mtDNA) mutations are often present in patients with myocardial dysfunction. We sought to assess the prevalence and significance of heart mtDNA sequence changes in patients with idiopathic dilated cardiomyopathy (DCM). METHODS AND RESULTS: DNA sequence of all the transfer ribonucleic acid (tRNA), ribosomal RNA (rRNA), and structural genes in cardiac mtDNA of 28 patients with DCM was determined and compared with a control group that had no evidence of heart disease. An increased number of point mutations were found in DCM cardiac mtDNA when compared with controls. Both novel and previously reported mutations were found in mitochondrial tRNA and structural genes. One of these mutations was heteroplasmic and resulted in changing a highly conserved nucleotide in tRNAArg. Novel, heteroplasmic mtDNA mutations (n = 4) specifying changes in moderate to highly conserved amino acid residues were found in COII, COIII, ND5, and cytb. These novel mtDNA mutations were found only in patients with severe reduction in mitochondrial enzyme activities. CONCLUSIONS: Our results indicate that a high incidence of mtDNA nucleotide sequence changes in both tRNA and structural genes are present in DCM. Five heteroplasmic mutations were detected that both changed evolutionarily conserved residues (which may impair the function of proteins or tRNAs) and were associated with specific enzymatic defects. These mutations could play an important role in the pathogenesis of cardiomyopathy.
Assuntos
Sequência de Bases/genética , Cardiomiopatia Dilatada/genética , DNA Mitocondrial/análise , DNA Mitocondrial/genética , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , RNA de Transferência/análise , RNA de Transferência/genética , Adolescente , Adulto , Biópsia , Cardiomiopatia Dilatada/classificação , Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Dilatada/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , DNA Ribossômico/análise , DNA Ribossômico/genética , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Análise de Sequência de DNA , Índice de Gravidade de DoençaRESUMO
A group of 25 children (5 months to 20 years of age) presenting with intractable seizures, developmental delay, and severe hypotonia, who did not fall into the known categories of mitochondrial encephalomyopathies, underwent muscle biopsy for evaluation of mitochondrial function and were compared with age-matched control subjects. Biopsied skeletal muscle was analyzed for six mitochondrial enzyme-specific activities, mitochondrial DNA point mutations and deletions, and mitochondrial DNA levels. The data reveal a high incidence of specific mitochondrial enzyme activity defects. Reduced activity levels were evident in complex I (11 patients), III (24 patients), IV (nine patients), and V (10 patients). Two patients also exhibited pronounced reduction in mitochondrial DNA levels (80% reduction compared with control subjects). Two patients manifested increased levels of 5-kb and 7.4-kb mitochondrial DNA deletions. Pathogenic mutations previously described in association with mitochondrial encephalomyopathies were not evident. The data suggest that mitochondrial dysfunction, including extensive defects in specific enzyme activities, may be frequently present in children with seizures, developmental delay, and hypotonia that do not fall within the known mitochondrial encephalomyopathies. These mitochondrial deficiencies can be primarily ascertained by biochemical analysis and are rarely accompanied by mitochondrial ultrastructural changes. The molecular basis of these defects, their role in these disorders, and potential treatment warrant further study.
Assuntos
DNA Mitocondrial/análise , Deficiências do Desenvolvimento/enzimologia , Mitocôndrias Musculares/enzimologia , Hipotonia Muscular/enzimologia , Músculo Esquelético/química , Oxirredutases/metabolismo , Convulsões/enzimologia , Adulto , Biópsia , Criança , Pré-Escolar , DNA Mitocondrial/genética , Deficiências do Desenvolvimento/genética , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Lactente , Masculino , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/metabolismo , Encefalomiopatias Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/genética , Hipotonia Muscular/genética , Convulsões/genética , Deleção de SequênciaRESUMO
Little information is presently available concerning mitochondrial respiratory and oxidative phosphorylation function in the normal human heart during growth and development. We investigated the levels of specific mitochondrial enzyme activities and content during cardiac growth and development from the early neonatal period (10-20 days) to adulthood (67 years). Biochemical analysis of enzyme specific activities and content and mitochondrial DNA (mtDNA) copy number was performed with left ventricular tissues derived from 30 control individuals. The levels of cytochrome c oxidase (COX) and complex V specific activity, mtDNA copy number and COX subunit II content remained unchanged in contrast to increased citrate synthase (CS) activity and content. The developmental increase in CS activity paralleled increasing CS polypeptide content, but was neither related to overall increases in mitochondrial number nor coordinately regulated with mitochondrial respiratory enzyme activities. Our findings of unchanged levels of cardiac mitochondrial respiratory enzyme activity during the progression from early childhood to older adult contrasts with the age-specific regulation found with CS, a Krebs cycle mitochondrial enzyme.
Assuntos
Proteínas de Transporte , Coração/crescimento & desenvolvimento , Mitocôndrias Cardíacas/fisiologia , Adenosina Trifosfatases/metabolismo , Fatores Etários , Respiração Celular/fisiologia , Citrato (si)-Sintase/química , DNA Mitocondrial/análise , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Dosagem de Genes , Ventrículos do Coração/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Mitocôndrias Cardíacas/enzimologia , ATPases Mitocondriais Próton-Translocadoras , Análise de RegressãoRESUMO
Mitochondrial enzyme activities were examined in cardiac tissues of turkeys with spontaneous inbred cardiomyopathy. Marked declines in specific enzyme activities were noted for respiratory complexes III and V ranging from 65-90% of the control values. No significant differences in complexes I, IV and citrate synthase nor in mitochondrial DNA copy number were detected. These results suggest that specific mitochondrial enzyme defects occur in cardiac tissues during spontaneous inbred turkey cardiomyopathy.