Recomendações para manipulação e sujeição de ratos e camundongos de laboratório

Cuando hablamos de experimentación con animales, generalmente se centra la atención en los protocolos de investigación, dejando de lado un tema fundamental que es el manejo de los sujetos experimentales. A fin de resaltar la importancia de esto último, nos hemos propuesto dar énfasis en las técnicas de manipulación y sujeción de ratas y ratones de laboratorio privilegiando el bienestar animal, la influencia en la investigación y la seguridad del personal.When we speak of experimentation with animals, we generally focus on research protocols, leaving aside the fundamental matter of handling experimental subjects. To underline the importance of this aspect, we have chosen to emphasize techniques for manipulation and subjection of laboratory rats and mice, prioritizing animal welfare, its influence on research and on the safety of personnel.Quando se fala de experimentação com animais, geralmente se centra a atenção nos protocolos de pesquisa e deixa-se de lado um tema fundamental que é o manejo dos sujeitos experimentais. A fim de ressaltar a importância deste último, propusemo-nos enfatizar as técnicas de manipulação e sujeição de ratos e camundongos de laboratório, o que privilegia o bem-estar animal, a influência na pesquisa e na segurança do pessoal.Fil: Mourelle, Ana Carolina. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Herrero, Emiliana. Hospital Italiano de Buenos Aires; ArgentinaFil: Ricca, Micaela. Universidad Católica de Chile; Chil

Recomendaciones para manipulación y sujeción de ratas y ratones de laboratorio

When we speak of experimentation with animals, we generally focus on research protocols, leaving aside the fundamental matter of handling experimental subjects. To underline the importance of this aspect, we have chosen to emphasize techniques for manipulation and subjection of laboratory rats and mice, prioritizing animal welfare, its influence on research and on the safety of personnel.Cuando hablamos de experimentación con animales, generalmente se centra la atención en los protocolos de investigación, dejando de lado un tema fundamental que es el manejo de los sujetos experimentales. A fin de resaltar la importancia de esto último, nos hemos propuesto dar énfasis en las técnicas de manipulación y sujeción de ratas y ratones de laboratorio privilegiando el bienestar animal, la influencia en la investigación y la seguridad del personal

MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia

Resistance to tyrosine kinase inhibitors (TKIs) remains a clinical challenge in Ph-positive variants of chronic myeloid leukemia. We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. We find that activated MEK1/2 assemble into a pentameric complex with BCR::ABL1, BCR and ABL1 to induce phosphorylation of BCR and BCR::ABL1 at Tyr360 and Tyr177, and ABL1, at Thr735 and Tyr412 residues thus provoking loss of BCR's tumor-suppression functions, enhanced oncogenic activity of BCR::ABL1, cytoplasmic retention of ABL1 and consequently drug resistance. Coherently, pharmacological blockade of MEK1/2 induces dissociation of the pentameric MEK1/2/BCR::ABL1/BCR/ABL1 complex and causes a concurrent BCRY360/Y177, BCR::ABL1Y360/Y177 and cytoplasmic ABL1Y412/T735 dephosphorylation thereby provoking the rescue of the BCR's anti-oncogenic activities, nuclear accumulation of ABL1 with tumor-suppressive functions and consequently, growth inhibition of the leukemic cells and an ATO sensitization via BCR-MYC and ABL1-p73 signaling axes activation. Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia

Functional interplay between NIK and c-Abl kinases limits response to Aurora inhibitors in multiple myeloma

Considering that Aurora kinase inhibitors are currently under clinical investigation in hematologic cancers, the identification of molecular events that limit the response to such agents is essential for enhancing clinical outcomes. Here, we discover a NF-κB-inducing kinase (NIK)-cAbl-STAT3 signaling-centered feedback loop that restrains the efficacy of Aurora inhibitors in multiple myeloma. Mechanistically, we demonstrate that Aurora inhibition promotes NIK protein stabilization via downregulation of its negative regulator TRAF2. Accumulated NIK converts c-Abl tyrosine kinase from a nuclear proapoptotic into a cytoplasmic antiapoptotic effector by inducing its phosphorylation at Thr735, Tyr245 and Tyr412 residues, and, by entering into a trimeric complex formation with c-Abl and STAT3, increases both the transcriptional activity of STAT3 and expression of the antiapoptotic STAT3 target genes PIM1 and PIM2. This consequently promotes cell survival and limits the response to Aurora inhibition. The functional disruption of any of the components of the trimer NIK-c-AblSTAT3 or the PIM survival kinases consistently enhances the responsiveness of myeloma cells to Aurora inhibitors. Importantly, concurrent inhibition of NIK or c-Abl disrupts Aurora inhibitor-induced feedback activation of STAT3 and sensitizes myeloma cells to Aurora inhibitors, implicating a combined inhibition of Aurora and NIK or c-Abl kinases as potential therapies for multiple myeloma. Accordingly, pharmacological inhibition of cAbl together with Aurora resulted in substantial cell death and tumor regression in vivo. The findings reveal an important functional interaction between NIK, Abl and Aurora kinases, and identify the NIK, c-Abl and PIM survival kinases as potential pharmacological targets for improving the efficacy of Aurora inhibitors in myeloma