RESUMO
Background: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and ß2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 µg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 µM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 µM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and ß2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.
RESUMO
Peripheral arterial disease is atherosclerotic occlusive disease of the lower extremity arteries and afflicts hundreds of millions of individuals worldwide. Its most severe manifestation is chronic limb-threatening ischemia (Petersen et al. (Science 300(5622):1140-2, 2003)), which is associated with severe pain at rest in the limbs, which progresses to necrosis, limb amputation, and/or death of the patient. Consequently, the care of these patients is considered a financial burden for both patients and health systems. Multidisciplinary endeavors are required to address this refractory disease and to find definitive solutions that lead to improved living conditions. Revascularization is the cornerstone of therapy for preventing limb amputation, and both open vascular surgery and endovascular therapy play a key role in the treatment of patients with CLI. Around one-third of these patients are not candidates for conventional surgical treatment, however, leading to higher amputation rates (approaching 20-25% at one year) with high morbidity and lower quality of life. Advances in regenerative medicine have enabled the development of cell-based therapies that promote the formation of new blood vessels. Particularly, mesenchymal stem cells (MSCs) have emerged as an attractive therapeutic agent in various diseases, including CLI, due to their role in tissue regeneration and immunomodulation. This review discusses the characteristics of MSCs, as well as their regenerative properties and their action mechanisms on CLI.
Assuntos
Salvamento de Membro , Células-Tronco Mesenquimais , Isquemia Crônica Crítica de Membro , Humanos , Isquemia/terapia , Extremidade Inferior/irrigação sanguínea , Extremidade Inferior/cirurgia , Qualidade de Vida , Fatores de Risco , Resultado do TratamentoRESUMO
El avance de la ciencia y tecnología en los últimos años dio lugar a la necesidad de dar respuesta a una mayor cantidad de preguntas en investigación de forma más eficiente. Esto ha provocado la generación de nuevos diseños en investigación, dando origen a los "protocolos maestros". A diferencia de los diseños tradicionales en los que en cada ensayo clínico se prueba habitualmente un solo fármaco, en una única población, con una patología determinada, los protocolos maestros utilizan una estructura con un diseño de ensayo clínico y un protocolo para evaluar simultáneamente múltiples fármacos y/o enfermedades, en múltiples sub-estudios. Entre estos novedosos diseños se pueden mencionar tres tipos: canasta (basket), paraguas (umbrella) y plataforma (platform) los cuales serán analizados en este artículo. Debido a su complejidad, el abordaje de estos nuevos modelos de ensayo clínico requiere la revisión y actualización permanente de los estándares vigentes y una constante discusión por parte de las diferentes agencias regulatorias a nivel mundial. Estos diseños no deben considerarse a priori como medios para reducir la rigurosidad de la planificación de los ensayos clínicos ni disminuir los estándares regulatorios, sino como herramientas para gestionar situaciones experimentales complejas. Desde el punto de vista regulatorio, para poder analizar y dar respuesta a estos desafíos, ANMAT cuenta, actualmente, con espacios de intercambio que permiten crear el ámbito apropiado de discusión científica-regulatoria que aliente el desarrollo de nuevos medicamentos, pero manteniendo estrictos estándares de calidad éticos y científicos. En esta revisión se plantea la necesidad de conocer en detalle estos nuevos diseños analizando sus potenciales beneficios y limitaciones
The need to answer a greater number of questions more efficiently has led to the generation of new designs in research, giving rise to the "master protocols". This term refers to a clinical trial design created to evaluate multiple hypotheses through substudies that are developed simultaneously and that may contain an adaptive design. Among these novel designs, three types can be mentioned: basket, umbrella and platform which will be analyzed in this article. Due to their complexity, the approach of these new clinical trial designs requires the continuing revision and updating of the current standards and a constant discussion by the different regulatory agencies worldwide. From the regulatory point of view, in order to analyze and satisfy these challenges, ANMAT currently has exchange spaces that allow the creation of the appropriate field of scientific-regulatory discussions that encourage the development of new medicines, while maintaining strict standards of ethical and scientific quality. This revision raises the need to know in detail these new designs analyzing their potential benefits and limitations.
Assuntos
Mudança Social , Protocolos Clínicos , Ensaio ClínicoRESUMO
BACKGROUND: Body motion evaluation (BME) by markerless systems is increasingly being considered as an alternative to traditional marker-based technology because they are faster, simpler, and less expensive. They are increasingly used in clinical settings in patients with movement disorders; however, the wide variety of systems available makes results conflicting. RESEARCH QUESTION: The objective of this study was to determine whether a markerless 3D motion capture system is a useful instrument to objectively differentiate between PD patients with DBS in On and Off states and controls and its correlation with the evaluation by means of MDS-UPDRS. METHODS: Six PD patients who underwent deep brain stimulation (DBS) bilaterally in the subthalamic nucleus were evaluated using BME and the Unified Parkinson's Disease Rating Scale (UPDRS-III) with DBS turned On and Off. BME of 16 different movements in six controls paired by age and sex was compared with that in PD patients with DBS in On and Off states. RESULTS: A better performance in the BME was correlated with a lower UPDRS-III score. There was no statistically significant difference between patients in Off and On states of DBS regarding BME. However, some items such as left shoulder flexion (p=0.038), right shoulder rotation (p=0.011), and left trunk rotation (p=0.023) were different between Off patients and healthy controls. SIGNIFICANCE: Kinematic data obtained with this markerless system could contribute to discriminate between PD patients and healthy controls. This emerging technology may help to clinically evaluate PD patients more objectively.
RESUMO
PURPOSE: Pre-eclampsia is a multisystem disorder characterized by new-onset hypertension and proteinuria during pregnancy. Pre-eclampsia remains a major cause of maternal death in low-income countries. Vitamin D has a very diverse biological role in cardiovascular diseases. This study will evaluate the association of vitamin D levels and relevance to pre-eclampsia. METHODS: We conducted a case-control study of women recruited from the GenPE (Genetics and Pre-eclampsia) Colombian registry. This is a multicenter case-control study conducted in eight Colombian cities. 25-Hydroxyvitamin D (25(OH)D) concentration was measured using liquid-chromatography-tandem mass spectrometry from 1013 women with pre-eclampsia and 1015 mothers without pre-eclampsia (controls). RESULTS: Fifty-two percent of women with pre-eclampsia were vitamin D deficient. The 25(OH)D concentrations were significantly lower in the pre-eclampsia (mean 29.99â¯ng/mL; 95% CI: 29.40-30.58â¯ng/mL) group compared to controls (mean 33.7â¯ng/mL; 95% CI: 33.20-34.30â¯ng/mL). In the unadjusted model, maternal vitamin D deficiency, defined by maternal 25(OH)D concentration <30â¯ng/mL, was associated with an increased probability of suffering from pre-eclampsia (OR 2.10; 95% CI, 1.75-2.51). After adjusting for covariates, a similarly increased probability of having pre-eclampsia was observed (OR 2.18; 95% CI, 1.80-2.64) among women with vitamin D deficiency, relative to controls. CONCLUSION: Although the results suggest that low maternal concentrations of 25(OH)D increase pre-eclampsia risk, this evidence may not be indicative of a causal association. Future studies are needed to confirm a definite causal relationship between concentrations of vitamin D and the risk of pre-eclampsia, by means of powered clinical trials.
Assuntos
Pré-Eclâmpsia/epidemiologia , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Adolescente , Adulto , Estudos de Casos e Controles , Causalidade , Colômbia/epidemiologia , Feminino , Humanos , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/etiologia , Gravidez , Sistema de Registros , Fatores de Risco , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Adulto JovemRESUMO
To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a three-dimensional similarity search. After determining the TanimotoCombo index of similarity with 1, eight compounds from the PXR library and two ZINC compounds were selected for biological evaluation. The P-gp inhibition study showed that compounds 7, 8, and 9 successfully increased intracellular doxorubicin (DOX) accumulation in the P-gp overexpressed Lucena 1 cells from 25, 12.5, and 6.25 µM, respectively. Among a series of analogues of 9, compounds 26-30 were shown to be active, with 26 and 27 causing a significant increase in DOX accumulation from 1.56 µM and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 µM, respectively. Molecular modeling studies showed that both compounds bind to the P-gp at transmembrane helices (TMH) 4, 5, and 6, with 27 also showing contacts with TMH 3.
RESUMO
P-glycoprotein (P-gp) is a membrane protein associated with multidrug resistance (MDR) due to its key role in mediating the traffic of chemotherapeutic drugs outside cancer cells, leading to a cellular response that hinders efforts toward successful therapy. With the aim of finding agents that circumvent the MDR phenotype mediated by P-gp, 15 compounds isolated from native and naturalized plants of Argentina were screened. Among these, the non-cytotoxic lignan (±) pinoresinol successfully restored sensitivity to doxorubicin from 7 µM in the P-gp overexpressed human myelogenous leukemia cells, Lucena 1. This resistance-reversing effect was confirmed by competitively increasing the intracellular doxorubicin accumulation and by significantly inhibiting the efflux of doxorubicin and, to a lesser extent, that of rhodamine 123. The activity obtained was similar to that observed with verapamil. No such results were observed in the sensitive parental K562 cell line. To gain deeper insight into the mode of action of pinoresinol, its effect on P-gp function and expression was examined. The docking simulations indicated that the lignan bound to P-gp at the apex of the V-shaped transmembrane cavity, involving transmembrane helices 4, 5, and 6, and partially overlapped the binding region of tariquidar, which was used as a positive control. These results would shed some light on the nature of its interaction with P-gp at molecular level and merit further mechanistic and kinetic studies. In addition, it showed a maximum 29% activation of ATP hydrolysis and antagonized verapamil-stimulated ATPase activity with an IC50 of 20.9 µM. On the other hand, pinoresinol decreased the presence of P-gp in the cell surface. Derivatives of pinoresinol with improved activity were identified by docking studies. The most promising one, the non-cytotoxic 1-acetoxypinoresinol, caused a reversion of doxorubicin resistance from 0.11 µM and thus higher activity than the lead compound. It also caused a significant increase in doxorubicin accumulation. Results were similar to those observed with verapamil. The results obtained positioned these compounds as potential candidates for effective agents to overcome P-gp-mediated MDR, leading to better outcomes for leukemia chemotherapy.
RESUMO
BACKGROUND: The increasing burden associated with dengue in Latin America makes it essential to understand the community's interest in acquiring vaccines, as an input to plan its introduction in endemic regions. The objective of this study is to learn the felt demand for dengue vaccines by estimating the willingness to pay and its associated factors in endemic communities of the North Caribbean region of Colombia. METHODS: A population survey was administered from October to December 2015, including 1037 families in 11 municipalities in Colombia. One adult per family was interviewed on their perception and history of dengue. Participants received a description of four hypothetical scenarios of dengue vaccines, administered in a single dose or in 3 doses, with an effectiveness of 70% for 5 years or 95% for 30 years. The willingness to pay for each one of these vaccines was inquired vs. 5 hypothetical prices in Colombian pesos. RESULTS: Most participants recognized dengue as a serious disease in children (99.3%) and adults (98.6%). 33 (3.2%) of the total respondents reported having suffered dengue and 19 (57.6%) of them required hospitalization. The price of the vaccine was inversely related to the willingness to pay. In addition, single dose vaccines (compared to 3 doses) and one with a protection of 95% for 30 years (compared to an effectiveness of 70% for 5 years), were associated with greater willingness to pay. Greater willingness to pay was observed among the respondents who considered it likely to get the disease, either themselves (OR 1.56; CI 95% 1.08-2.26) or their children (OR 1.89; CI 95% 1.28-2.81), in the next 5 years. The participants who have been diagnosed with dengue also showed greater willingness to pay (OR 1.89; CI 95% 1.01-3.54) compared to those who did not have this history. CONCLUSION: Factors such as price, number of doses and effectiveness can independently influence the decision to purchase a vaccine against an endemic disease, such as dengue. Additionally, this study reveals that background and perceptions of the disease can affect individuals' interest in acquiring this type of preventive interventions.
Assuntos
Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/economia , Dengue/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Adulto , Região do Caribe/epidemiologia , Estudos de Coortes , Colômbia/epidemiologia , Dengue/diagnóstico , Dengue/economia , Dengue/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Participação do Paciente/economia , Participação do Paciente/psicologia , Fatores de Risco , Inquéritos e Questionários , Vacinação/economia , Vacinação/psicologiaRESUMO
El proceso de recolección de material biológico humano, necesita cada vez más la organización de la información para la gestión de las muestras y la integración de los datos relacionados con el participante o donante, provenientes de diferentes fuentes. Con el avance de la computación, esto permitirá identificar posibles interacciones sociodemográficas, genéticas, ambientales, entre otras con determinada enfermedad. Las estructuras de datos, los sistemas de codificación y los sistemas de metadatos, se han convertido en un desafío para la organización de los biobancos. La gestión, integración, seguridad, privacidad y análisis de los datos, son retos importantes para los investigadores y la informática. La normalización de los datos, la armonización e interoperabilidad de sistemas informáticos de biobancos permitirán el óptimo uso del material biológico, convirtiéndose en no solo un gran recurso para estudios epidemiológicos y clínicos a gran escala, sino también en bases para nuevas pruebas de diagnóstico e intervenciones terapéuticas personalizadas.
The collection, processing and storage of biological samples need a system for not only organizing and managing the patient samples but also integrating data records from different sources related to these patients. Along with computer advancement, these integration processes will allow to identify possible relationships between sociodemographic, genetic and environmental factors with specific diseases. Therefore, data structures, coding and metadata systems, have become essential elements for controlling biobanks. In fact, management, integration, security, privacy and data analysis are current challenges for scientists and computer administrators. The standardization of data, harmonization and interoperability of biobank computer systems will help to have an optimum use of biological material. As a result, these advances will turn into a great resource for large-scale epidemiological and clinical studies as well as the basis for new diagnostic tests and personalized therapies.