Functional characterization of the human mariner transposon Hsmar2

DNA transposons are mobile elements with the ability to mobilize and transport genetic information between different chromosomal loci. Unfortunately, most transposons copies are currently inactivated, little is known about mariner elements in humans despite their role in the evolution of the human genome, even though the Hsmar2 transposon is associated to hotspots for homologous recombination involved in human genetic disorders as Charcot-Marie-Tooth, Prader-Willi/Angelman, and Williams syndromes. This manuscript describes the functional characterization of the human HSMAR2 transposase generated from fossil sequences and shows that the native HSMAR2 is active in human cells, but also in bacteria, with an efficiency similar to other mariner elements. We observe that the sub-cellular localization of HSMAR2 is dependent on the host cell type, and is cytotoxic when overexpressed in HeLa cells. Finally, we also demonstrate that the binding of HSMAR2 to its own ITRs is specific, and that the excision reaction leaves non-canonical footprints both in bacteria and eukaryotic cells

Functional characterization of the human mariner transposon Hsmar2

DNA transposons are mobile elements with the ability to mobilize and transport genetic information between different chromosomal loci. Unfortunately, most transposons copies are currently inactivated, little is known about mariner elements in humans despite their role in the evolution of the human genome, even though the Hsmar2 transposon is associated to hotspots for homologous recombination involved in human genetic disorders as Charcot-Marie-Tooth, Prader-Willi/Angelman, and Williams syndromes. This manuscript describes the functional characterization of the human HSMAR2 transposase generated from fossil sequences and shows that the native HSMAR2 is active in human cells, but also in bacteria, with an efficiency similar to other mariner elements. We observe that the sub-cellular localization of HSMAR2 is dependent on the host cell type, and is cytotoxic when overexpressed in HeLa cells. Finally, we also demonstrate that the binding of HSMAR2 to its own ITRs is specific, and that the excision reaction leaves non-canonical footprints both in bacteria and eukaryotic cells

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax

The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis.The mammalian target of rapamycin (mTOR)is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR existsin two complexes, mTORC1 and mTORC2.Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modeling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment

Comentarios del Comité Español Interdisciplinario de Prevención Cardiovascular (CEIPC) a las Guías Europeas de Prevención Cardiovascular 2012

Resumen: Las guías europeas de prevención cardiovascular contemplan 2 sistemas de evaluación de la evidencia (SEC y GRADE) y recomiendan combinar las estrategias poblacional y de alto riesgo, interviniendo en todas las etapas de la vida, con la dieta como piedra angular de la prevención. La valoración del riesgo cardiovascular (RCV) incorpora los niveles de HDL y los factores psicosociales, una categoría de muy alto riesgo y el concepto edad-riesgo. Se recomienda el uso de métodos cognitivo-conductuales (entrevista motivadora, intervenciones psicológicas), aplicados por profesionales sanitarios, con la participación de familiares de los pacientes, para contrarrestar el estrés psicosocial y reducir el RCV mediante dietas saludables, entrenamiento físico, abandono del tabaco y cumplimiento terapéutico. También se requieren medidas de salud pública, como la prohibición de fumar en lugares públicos o eliminar los ácidos grasos trans de la cadena alimentaria. Otras novedades consisten en desestimar el tratamiento antiagregante en prevención primaria y la recomendación de mantener la presión arterial dentro del rango 130-139/80-85 mmHg en pacientes diabéticos o con RCV alto. Se destaca el bajo cumplimiento terapéutico observado, porque influye en el pronóstico de los pacientes y en los costes sanitarios. Para mejorar la prevención cardiovascular se precisa una verdadera alianza entre políticos, administraciones, asociaciones científicas y profesionales de la salud, fundaciones de salud, asociaciones de consumidores, pacientes y sus familias, que impulse la estrategia tanto poblacional como individual mediante el uso de toda la evidencia científica disponible, desde ensayos clínicos hasta estudios observacionales y modelos matemáticos para evaluar intervenciones a nivel poblacional, incluyendo análisis de coste-efectividad. Abstract: Based on the two main frameworks for evaluating scientific evidence (SEC and GRADE) European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions) led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions — such as smoking ban in public areas or the elimination of trans fatty acids from the food chain — are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure within the 130-139/80-85 mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses. Palabras clave: Prevención cardiovascular, Riesgo cardiovascular, Enfermedades cardiovasculares, Guías de práctica clínica, Keywords: Cardiovascular prevention, Cardiovascular risk, Cardiovascular diseases, Clinical practice guideline

Statement of the Spanish Interdisciplinary Cardiovascular Prevention Committee (CEIPC for its Spanish acronym) on the 2012 European Cardiovascular Prevention Guidelines

Based on the 2 main frameworks for evaluating scientific evidence (SEC and GRADE) European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions) led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions—such as smoking ban in public areas or the elimination of trans fatty acids from the food chain—are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure within the 130-139/80-85 mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses. Resumen: Las guías europeas de prevención cardiovascular contemplan 2 sistemas de evaluación de la evidencia (SEC y GRADE) y recomiendan combinar las estrategias poblacional y de alto riesgo, interviniendo en todas las etapas de la vida, con la dieta como piedra angular de la prevención. La valoración del riesgo cardiovascular (RCV) incorpora los niveles de HDL y los factores psicosociales, una categoría de muy alto riesgo y el concepto edad-riesgo. Se recomienda el uso de métodos cognitivo-conductuales (entrevista motivadora, intervenciones psicológicas), aplicados por profesionales sanitarios, con la participación de familiares de los pacientes, para contrarrestar el estrés psicosocial y reducir el RCV mediante dietas saludables, entrenamiento físico, abandono del tabaco y cumplimiento terapéutico. También se requieren medidas de salud pública, como la prohibición de fumar en lugares públicos o eliminar los ácidos grasos trans de la cadena alimentaria. Otras novedades consisten en desestimar el tratamiento antiagregante en prevención primaria y la recomendación de mantener la presión arterial dentro del rango 130-139/80-85 mmHg en pacientes diabéticos o con RCV alto. Se destaca el bajo cumplimiento terapéutico observado, porque influye en el pronóstico de los pacientes y en los costes sanitarios. Para mejorar la prevención cardiovascular se precisa una verdadera alianza entre políticos, administraciones, asociaciones científicas y profesionales de la salud, fundaciones de salud, asociaciones de consumidores, pacientes y sus familias, que impulse la estrategia tanto poblacional como individual mediante el uso de toda la evidencia científica disponible, desde ensayos clínicos hasta estudios observacionales y modelos matemáticos para evaluar intervenciones a nivel poblacional, incluyendo análisis de coste-efectividad. Keywords: Cardiovascular prevention, Cardiovascular risk, Cardiovascular diseases, Clinical practice guidelines, Palabras clave: Prevención cardiovascular, Riesgo cardiovascular, Enfermedades cardiovasculares, Guías de práctica clínic