Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia.

Current therapeutic approaches for chronic lymphocytic leukemia (CLL) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the phosphatidylinositol-3-phosphate/AKT (PI3K/AKT)-signaling pathway may be leveraged to trigger CLL cell death. Though counterintuitive, our data show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SH2-containing-inositol-5'-phosphatase-1 (SHIP1) induces acute cell death in CLL cells. Our mechanistic studies reveal that increased AKT activity upon inhibition of SHIP1 leads to increased mitochondrial respiration and causes excessive accumulation of reactive oxygen species (ROS), resulting in cell death in CLL with immunogenic features. Our results demonstrate that CLL cells critically depend on mechanisms to fine-tune PI3K/AKT activity, allowing sustained proliferation and survival but avoid ROS-induced cell death and suggest transient SHIP1-inhibition as an unexpectedly promising concept for CLL therapy

Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells

Exploración vocacional en adolescentes: evaluación de una intervención en clase

Analisa-se o impacto de uma intervenção psicológica na exploração e tomada de decisão vocacional em adolescentes portugueses. Em contexto curricular e de classe, desenvolveram-se actividades de exploração do meio e do Eu com 39 alunos e 43 alunas do 9o ano, entre 13 e 17 anos (M=14,4, DP=0,95). Em um design pré/pós-teste, aplicaram-se o Career Exploration Survey (CES) e o Career Decision Difficulties Questionnaire (CDDQ). Os resultados do teste do sinal evidenciaram ganhos significativos (p<0,01) nas dimensões de exploração e diminuição significativa da falta de informação profissional (p<0,01) e do total das dificuldades de decisão (p<0,05). Observou-se um padrão de correlações negativas (ró de Spearman) entre as duas medidas vocacionais, evidenciando uma relação entre a informação explorada na intervenção e a diminuição das dificuldades de decisão por falta de motivação. Em geral, os resultados suportam a importância do papel da exploração da carreira na diminuição das dificuldades de tomada de decisão.This study analyses the impact of a psychological intervention to promote vocational exploration and decisionmaking in Portuguese adolescents. Activities to foster exploration of self and environment were developed in a classroom program with 39 boys and 43 girls, all 9th grade students, between 13 and 17 years of age (M=14,4, SD=0.95). Following a pre/post-test design, the Career Exploration Survey (CES), and the Career Decision Difficulties Questionnaire (CDDQ) were administered. Results of sign-test showed significant increments (p<0.01) in all of the exploration dimensions, significant reduction of lack of occupational information (p<0.01) and of the total of career decision-making difficulties (p<0.05). Negative correlations (Spearman’s rho) between the two career measures was observed, evidencing a relationship between information explored during intervention and decreased difficulty with decision-making due to lack of motivation. In general, results support the importance of career exploration on diminishing decision-making difficulties.Evalúa-se el impacto de una intervención psicológica que fomenta la exploración y la decisión vocacional en adolescentes portugueses. Fueran efectuadas actividades de exploración del medio ambiente y del yo en contexto curricular de clase con 39 alumnos y 43 alumnas del curso 3º ESO, 13 hasta 17 años (M=14,4, DP=0,95). Utilizó-se un diseño pre/posteste, con aplicación del Career Exploration Survey (CES) y Career Decision Difficulties Questionnaire (CDDQ). Resultados del test del señal evidencian beneficios significativos (p<0,01) en las dimensiones de la exploración, reducción significativa de ausencia de información ocupacional (p<0,01) y total de dificultades de decisión (p<0,05). Ha sido observado un patrón de correlaciones negativas (ró de Spearman) entre las dos medidas vocacionales, mostrando relación entre la información explorada e la disminución de las dificultades de decisión por falta de motivación. En general, resultados sostienen la importancia de la exploración de carrera en la disminución de las dificultades de decisió

Polymorphisms within the Novel Type 2 Diabetes Risk Locus MTNR1B Determine β-Cell Function

BACKGROUND:Very recently, a novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS:We genotyped 1,578 non-diabetic subjects, metabolically characterized by oral glucose tolerance test, for five tagging single nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency > 0.05) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638). In a subgroup (N = 513), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and in a further subgroup (N = 301), glucose-stimulated insulin secretion was determined by intravenous glucose tolerance test. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the tagging SNPs was reliably associated with measures of adiposity. SNPs rs10830962, rs4753426, and rs10830963 were significantly associated with higher fasting plasma glucose concentrations (p < 0.0001) and reduced OGTT- and IVGTT-induced insulin release (p < or = 0.0007 and p < or = 0.01, respectively). By contrast, SNP rs3781638 displayed significant association with lower fasting plasma glucose levels and increased OGTT-induced insulin release (p<0.0001 and p < or = 0.0002, respectively). Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p < or = 0.0021). None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion. CONCLUSIONS/SIGNIFICANCE:In conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on beta-cell function might represent the prevailing pathomechanism how MTNR1B variants increase the type 2 diabetes risk

Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia

Current therapeutic approaches for chronic lymphocytic leukemia (CLL) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the phosphatidylinositol-3-phosphate/AKT (PI3K/AKT)-signaling pathway may be leveraged to trigger CLL cell death. Though counterintuitive, our data show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SH2-containing-inositol-5'-phosphatase-1 (SHIP1) induces acute cell death in CLL cells. Our mechanistic studies reveal that increased AKT activity upon inhibition of SHIP1 leads to increased mitochondrial respiration and causes excessive accumulation of reactive oxygen species (ROS), resulting in cell death in CLL with immunogenic features. Our results demonstrate that CLL cells critically depend on mechanisms to fine-tune PI3K/AKT activity, allowing sustained proliferation and survival but avoid ROS-induced cell death and suggest transient SHIP1-inhibition as an unexpectedly promising concept for CLL therapy

Slow processes in close-to-equilibrium conditions for radionuclides in water/solid systems of relevance to nuclear waste management – SKIN

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