RESUMO
Venous thromboembolism (VTE) whether provoked or not can be life-threatening due to an acute increase in load on the right ventricle (RV) from obstruction of the pulmonary artery (PA). Treatment for and prevention of VTE involves anti-thrombotic agents; more specifically, medications targeting the anticoagulation cascade. In spite of the widespread acceptance of anticoagulants in the treatment of VTE, there appears to be an ongoing belief that platelet reactivity contributes to thrombus burden in patients with acute pulmonary embolism (PE). This investigation of 398 patients presenting with acute PE evaluated whether anti-platelet medication use, which consisted mostly of aspirin therapy, at the time of presentation, affects PA thrombus burden, RV load, or short-term patient outcomes. We conclude that platelets may have been erroneously incriminated as direct thrombotic mediators in patients with acute PE since aspirin neither decreased PA thrombus burden, nor did aspirin improve short-term mortality following acute PE.
Assuntos
Inibidores da Agregação Plaquetária/uso terapêutico , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Doença Aguda , Humanos , Embolia Pulmonar/patologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Successful use of anticancer designer drugs is likely to depend on simultaneous combinations of these drugs to minimize the development of resistant cancer cells. Considering the knowledge base of cancer signaling pathways, mechanisms of designer drug resistance should be anticipated, and early clinical trials could be designed to include arms that combine new drugs specifically with currently US Food and Drug Administration (FDA)-approved drugs expected to blunt alternative signaling pathways. In this review, we indicate examples of alternative signal pathways for recent anticancer drugs, and the use of original, Python-based software to systematically identify signaling pathways that could facilitate resistance to drugs targeting a particular protein. Pathway alternatives can be assessed at http://www.alternativesignalingpathways.com, developed with this review article.
Assuntos
Antineoplásicos/uso terapêutico , Desenho Assistido por Computador , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Bases de Dados de Proteínas , Predisposição Genética para Doença , Humanos , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fenótipo , Medicina de Precisão , Valor Preditivo dos Testes , Transdução de Sinais/efeitos dos fármacos , SoftwareRESUMO
BACKGROUND: Genes that fuse to cause cancer have been studied to determine molecular bases for proliferation, to develop diagnostic tools, and as targets for drugs. To facilitate identification of additional, cancer fusion genes, following observation of a chromosomal translocation, we have characterized the genomic features of the fusion gene partners. Previous work indicated that cancer fusion gene partners, are either large or evolutionarily conserved in comparison to the neighboring genes in the region of a chromosomal translocation. These results raised the question of whether large cancer fusion gene partners were also evolutionarily conserved. METHODS AND RESULTS: We developed two methods for quantifying evolutionary conservation values, allowing the conclusion that both large and small cancer fusion gene partners are more evolutionarily conserved than their neighbors. Additionally, we determined that cancer fusion gene partners have more 3' untranslated region secondary structures than do their neighbors. CONCLUSION: Coupled with previous algorithms, with or without transcriptome approaches, we expect these results to assist in the rapid and efficient use of chromosomal translocations to identify cancer fusion genes. The above parameters for any gene of interest can be accessed at www.cancerfusiongenes.com.
Assuntos
Genes Neoplásicos , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética/genética , Regiões 3' não Traduzidas/genética , Algoritmos , Evolução Biológica , Proliferação de Células , Genômica/métodos , HumanosRESUMO
We tallied the number of possible mutant amino acids in proteins thought to be inactivated early in tumorigenesis and in proteins thought to be inactivated late in tumorigenesis, respectively. Proteins thought to be inactivated early in tumorigenesis, on average, have a greater number of alternative, mutant possibilities, which raises the possibility that the sequential order of mutations associated with cancer development reflects the random chance, throughout life, of a mutagen inactivating a larger versus a smaller target. The hypothesis that the temporal order of genetic changes in cancer reflects mutagen target sizes leads to novel considerations of 1) the mechanisms of the acquisition of cancer hallmarks and 2) cancer screening strategies.
