Chronic myeloid leukemia (CML) is a Ph-positive myeloproliferative neoplasm giving rise to BCR-ABL1 oncogene. Usually, the disease is diagnosed in the chronic phase (CML-CP) with uncontrolled clonal ...expansion and high white blood cell count. Without therapy intervention, CML progress to advanced phases (accelerated and blastic phases; CML-AP). The Tyrosine Kinase Inhibitors (TKI) are the first-line therapeutic approach for CML. TKI targets the BCR-ABL tyrosine kinase activity and restrain the disease. The knowledge about the mechanisms involved in disease progression and resistance to TKI, beyond BCR-ABL1, is limited. The relation among TKI treatment, disease progression and eicosanoids pattern in CML is unknown.
Lipid mediators were quantified in healthy individuals (Controls; n = 9) as well as in CML patients in CP (n = 10), CML-AP (n = 13) and CML patients in molecular remission post-TKI therapy (RM; n = 6) using Liquid Chromatography/Mass Spectrometry (LC/MS). Mass spectral data were acquired with negative electrospray ionization. ProteinWizard was used to convert files to be used in bioinformatic subsequent analysis. Mummichog software was used for metabolic pathway enrichment analysis. Heatmaps were generated with the R package gplots and hierarchical clustering was performed with the R package amap with Spearman distance method and ward linkage algorithm. Volcano and bubble plots were obtained with the package ggplot2.
We described the metabolomic profiles of CML in different phases and post-TKI therapy. The metabolic patterns were able to distinguish the CML patients in different phases and resistant to TKI. The metabolomic results suggested an association between reprogramming in lipid metabolism and CML progression and resistance to TKI therapy. CML patients showed to be a lower producer of some eicosanoids compared to controls. Interestingly, AP-CML produced less 12-HETE and EPA than CP-CML patients. CML patients in molecular remission produced more EPA in comparison with each other group.
Taken together, the results established the eicosanoid profile of CML patients who progress to advanced phases and fail to respond to TKI.
Decision makers must react in a prompt and appropriate manner in various emergency situations. The bases for decisions are often predictions produced with decision support systems (DSS). Actual ...radiation measurement data can be used to improve the reliability of the predictions. Data assimilation is an important link between model calculations and measurements and thus decreases the overall uncertainty of the DSS predictions. However, different aspects have to be taken into account for the optimal use of the data assimilation technique: different countries may have differing measurement strategies and systems as well as differing calculation models. The scenario and the amount and composition of radionuclides released may vary. In this paper we analyse the situation during and after an accident and draw up a list of recommendations that can help modellers to take into account the measurements that are best suited for data assimilation.
Se realizó un estudio con el objetivo de validar un método sensible y confiable para la detección de ivermectina en leche y determinar la presencia de residuos en muestras provenientes de predios ...lecheros de la provincia de Ñuble. La validación de la metodología analítica se realizó en muestras de leche libres de fármaco sobrecargadas con ivermectina (IVM) (0,5, 1,0, 5,0, 10,0, 25,0 ng/mL), las que fueron sometidas a extracción en fase sólida y analizadas por cromatografía líquida de alta eficiencia (HPLC). Para el estudio de residuos se recolectaron muestras de leche desde estanques de acumulación de 24 predios pertenecientes a medianos productores de la provincia de Ñuble, en cuatro períodos del año: verano: enero, otoño: abril, invierno: agosto y primavera: noviembre. El límite de cuantificación del método fue establecido en 0,043 ng/mL. La ausencia de interferencias y la adecuada simetría de los cromatogramas sugieren una buena especificidad del método, con porcentajes de recuperación que fluctúan entre el 73,5 y 79,5%, para la concentración mínima y máxima del fármaco. El método analítico presentó resultados de sensibilidad, precisión y exactitud satisfactorios que permiten su utilización en la detección de residuos de ivermectina en leche. De 96 muestras de leche obtenidas desde estanques de recolección de predios lecheros de la provincia de Ñuble, el 8,3% presentó concentraciones de ivermectina iguales o superiores al límite de cuantificación del método analítico utilizado. Estos resultados demuestran la presencia de residuos de ivermectina en leche y justifican la realización de estudios más amplios tendientes a detectar estos fármacos en la leche, debido a que su presencia es un atributo negativo de calidad.
Locations of gamma dose rate sensors have often been chosen by administrative or geometrical criteria. Nowadays computational capacity allows for a more realistic basis. We use simulations of ...potential radioactive plumes based on weather data of one year to investigate the threats to regions without own nuclear power plants and to find good numbers and locations of sensors to detect such plumes. We optimise sensor locations by minimising a cost function that can take into account numbers of undetected plumes, their dose to the region in general, or on the population. Besides we assess the effect of administrative constraints, be it that sensors have to cover administrative units, or that optimisation is done for sub-regions separately. Finally we evaluate the robustness of the approach if less or other plumes are used. The main findings are that sensors at boundaries are often best, but also typical paths of plumes may be important, and that administrative constraints may necessitate much more sensors. The small numbers of sensors actually deployed in these regions seem sufficient. However, the latter may be an artefact of the low number of plumes we considered. Altogether, combined with other considerations, this approach can contribute to better decisions about gamma dose rate sensor locations.
In recent years, it has become evident that astrocytes harbor functional receptors to many neurotransmitters, including substance P (SP), an undecapeptide belonging to the tachykinin family of ...neuropeptides. SP is an important stimulus for reactive astrocytes in CNS development, infection and injury, and provides a link for bi-directional interactions between glial cells and neurons. In brain tumors, malignant glial cells originating from astrocytes, via NK sub(1) receptors, are triggered by tachykinins, SP and neurokinin A (NKA), to release soluble mediators, in particular cytokines, and increase their proliferative rate. In this paper, we review the results obtained in in vitro and in vivo studies on the role of SP as an inducer of human glioma responses that may be relevant for tumor progression. In addition, the presence of SP and the expression of NK sub(1) receptors in glioma explants have been examined. We discuss the possible use of selective NK sub(1) receptor antagonists as a therapeutic approach to treat malignant gliomas.
PDF
