RESUMEN
Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a reduction of antiviral host responses would favor the use of adenoviral vectors in cancer immunotherapy. In this review, we describe the structural and molecular features of nonreplicating adenoviral vectors, the current limitations to their use, and strategies to modify adenoviral tropism, highlighting the approaches that may allow for the systemic administration of gene therapy.
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Abstract Background: Prosthesis-patient mismatch (PPM) is associated with worse outcomes. Objective: Determine the frequency and evaluate preoperatory variables independently associated with severe PPM in a tertiary hospital focused on Public Health Care. Methods: A total of 316 patients submitted to aortic valve replacement, who had echocardiography performed within the first 30 days after surgery, were retrospectively analyzed. The indexed effective orifice area (iEOA) of the prosthesis was used to classify the patients into three groups, according to PPM, considering body mass index (BMI): severe PPM (iEOA) < 0.65 cm2/m2), mild to moderate PPM (iEOA, 0.65 cm2/m2 - 0.85 cm2/m2) and without PPM (iEOA > 0.85 cm2/m2) for a BMI < 30 kg/m2 and severe PPM (iEOA) < 0.55 cm2/m2), mild to moderate (iEOA, 0.55 cm2/m2- 0.70 cm2/m2) and without PPM (iEOA > 0.7 cm2/m2) for a BMI > 30 kg/m2. Statistical significance was considered when p < 0.05. Results: iEOA was obtained in 176 patients. The frequency of severe and moderate PPM was 33.4% and 36.2%, respectively. Severe PPM patients were younger and had larger BMI, but smaller left ventricular outflow tract diameter (LVOTD). The independent variables used to predict severe PPM were male gender, BMI > 25 kg/m2, age < 60 years, LVOTD < 21 mm, and rheumatic etiology with an area under the ROC curve of 0.82. Conclusion: The frequency of severe PPM is high in a Brazilian population representative of the Public Health System, and it is possible to predict PPM from preoperative variables such as rheumatic valvular disease, gender, BMI, age and LVOTD.
Resumo Fundamento: A desproporção entre o tamanho da prótese aórtica-paciente (DPP) está associada a maior mortalidade. Objetivo: Determinar a frequência e avaliar variáveis pré-operatórias associadas à DPP acentuada no cenário da saúde pública em hospital terciário. Métodos: 316 pacientes submetidos à troca valvar aórtica (TVA), com ecocardiograma realizado nos primeiros 30 dias após cirurgia, foram analisados retrospectivamente. A área de orifício efetivo indexado (AOEi) da prótese foi utilizada para classificar os pacientes em três grupos de acordo com a DPP, considerando o índice de massa corporal (IMC): DPP acentuada (AOEi) < 0,65 cm2/m2, DPP discreta a moderada (AOEi, 0,65 cm2/m2 - 0,85 cm2/m2) e sem DPP (iEOA > 0,85 cm2/m2) para IMC < 30 kg/m2 e DPP acentuada (AOEi) < 0,55 cm2/m2), discreta a moderada (AOEi, 0,55 cm2/m2 - 0,70 cm2/m2) e sem DPP (AOEi > 0,7 cm2/m2) para IMC > 30 kg/m2. Significância estatística foi considerada com p < 0,05. Resultados: A AOEi foi obtida em 176 pacientes. A frequência de DPP acentuada foi de 33,4% e moderada de 36,2%. Pacientes com DPP acentuada foram mais jovens e com maior IMC, mas menor diâmetro da via de saída do ventrículo esquerdo (DVSVE). As variáveis independentes que podem predizer DPP acentuada são: gênero masculino, IMC > 25 kg/m2, idade < 60 anos, DVSVE < 21 mm e etiologia reumática com área sob a curva ROC de 0,82. Conclusão: A frequência de DPP acentuada é alta em uma população brasileira submetida à TVA no Sistema Público de Saúde. Os principais determinantes de DPP acentuada são: valvopatia reumática, gênero masculino, IMC alto, idade < 60 anos e menor DVSVE.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Prótesis Valvulares Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Enfermedades de las Válvulas Cardíacas/cirugía , Reoperación , Ecocardiografía , Estudios Transversales , Estudios Retrospectivos , Resultado del Tratamiento , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Hospitales PúblicosRESUMEN
BACKGROUND: Prosthesis-patient mismatch (PPM) is associated with worse outcomes. OBJECTIVE: Determine the frequency and evaluate preoperatory variables independently associated with severe PPM in a tertiary hospital focused on Public Health Care. METHODS: A total of 316 patients submitted to aortic valve replacement, who had echocardiography performed within the first 30 days after surgery, were retrospectively analyzed. The indexed effective orifice area (iEOA) of the prosthesis was used to classify the patients into three groups, according to PPM, considering body mass index (BMI): severe PPM (iEOA) < 0.65 cm2/m2), mild to moderate PPM (iEOA, 0.65 cm2/m2 - 0.85 cm2/m2) and without PPM (iEOA > 0.85 cm2/m2) for a BMI < 30 kg/m2 and severe PPM (iEOA) < 0.55 cm2/m2), mild to moderate (iEOA, 0.55 cm2/m2- 0.70 cm2/m2) and without PPM (iEOA > 0.7 cm2/m2) for a BMI > 30 kg/m2. Statistical significance was considered when p < 0.05. RESULTS: iEOA was obtained in 176 patients. The frequency of severe and moderate PPM was 33.4% and 36.2%, respectively. Severe PPM patients were younger and had larger BMI, but smaller left ventricular outflow tract diameter (LVOTD). The independent variables used to predict severe PPM were male gender, BMI > 25 kg/m2, age < 60 years, LVOTD < 21 mm, and rheumatic etiology with an area under the ROC curve of 0.82. CONCLUSION: The frequency of severe PPM is high in a Brazilian population representative of the Public Health System, and it is possible to predict PPM from preoperative variables such as rheumatic valvular disease, gender, BMI, age and LVOTD.
Asunto(s)
Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas/métodos , Prótesis Valvulares Cardíacas , Adulto , Anciano , Estudios Transversales , Ecocardiografía , Femenino , Prótesis Valvulares Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Hospitales Públicos , Humanos , Masculino , Persona de Mediana Edad , Reoperación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Parkinson's disease (PD) is a highly complex brain disorder regarding clinical presentation, pathogenesis, and therapeutics. The cardinal motor signs, i.e., rigidity, bradykinesia, and unilateral tremors, arise in consequence of a progressive neuron death during the prodromal phase. Although multiple transmission systems are involved in disease neurobiology, patients will cross the line between the prodromal and early stage of diagnosed PD when they had lost half of the dopaminergic nigrostriatal cells. As the neurons continue to die ascending the neuroaxis, patients will face a more disabling disease with motor and nonmotor signs. Shedding light on molecular mechanisms of neuron death is an urgent need for understanding PD pathogenesis and projecting therapeutics. This work examined the expression of microRNAs in the striatum of parkinsonian rats chronically exposed to rotenone (2.5 mg/Kg, i.p., daily for 10 days). Rotenone caused motor deficits, the loss of TH(+) cells in the nigrostriatal pathway, and a marked microgliosis. This parkinsonian rat striatum was examined at 26 days after the last rotenone injection, for quantification of microRNAs, miR-7, miR-34a, miR-26a, miR-132, miR-382, and Let7a, by qPCR. Parkinsonian rats presented a significant increase in miR-26a and miR-34a (1.5 and 2.2 fold, respectively, P < 0.05), while miR-7 (0.5 fold, P < 0.05) and Let7a were downregulated. This work reports for first time microRNAs aberrantly expressed in the striatum of rotenone-induced parkinsonian rats, suggesting that this dysregulation may contribute to PD pathogenesis. Beyond revealing new clues of neurodegeneration, our findings might prime further studies targeting miRNAs for neuroprotection or even for diagnosis proposal.