Assembling defenses against therapy-resistant leukemic stem cells: Bcl6 joins the ranks

The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) relies on the cooperative activity of multiple signaling pathways and molecules, including TGFβ, AKT, and FOXO transcription factors (TFs). B cell lymphoma 6 (BCL6) is a transcriptional repressor whose translocation or mutation is associated with diffuse large BCL. New data now show that BCL6 is critical for the maintenance of leukemias driven by the BCR-ABL translocation (Philadelphia chromosome), suggesting that BCL6 is a novel, targetable member of the complex signaling pathways critical for leukemic stem cell survival

Efeitos da Suplementação de Vitamina D sobre Parâmetros Hemodinâmicos Centrais e Sistema Nervoso Autônomo em Indivíduos com Obesidade ou Sobrepeso

Resumo Fundamento Estudos prévios têm sido inconsistentes em demonstrar efeitos cardiovasculares benéficos da suplementação de vitamina D. Objetivo Avaliar efeitos da suplementação de vitamina D3 sobre parâmetros hemodinâmicos centrais e atividade autonômica em indivíduos obesos/sobrepeso e baixos níveis de vitamina D (0,05). Grupo VD apresentou aumento no índice do sistema nervoso (iSN) parassimpático (-0,64±0,94 vs. -0,16±1,10, p=0,028) e no intervalo R-R (866±138 vs. 924±161ms, p=0,026). Conclusão Nesta amostra, a suplementação diária de vitamina D durante oito semanas resultou em melhora dos níveis pressóricos, parâmetros hemodinâmicos centrais e do equilíbrio autonômico

Núcleo de estudos e defesa dos direitos da infância e juventude – NEDIJ área temática: Direitos humanos e justiça

The Center of Studies and Defense of Children and Youth Rights is an extension project of the State Universities of Paraná. It has been established by agreement between the Public Prosecution and the Government of Paraná State, through the State Secretaries of Science, Technology and Graduate School, of Justice and Labor and Social Action, the Institute of Social Action of Paraná and the State Council of Child and of Adolescent Rights of Paraná State. It integrates the “University without Borders” program, Subprogram Incubator of Social Rights. Its main objective is to protect the interests of children and adolescents, by inserting them into substitute family through the custody, guardianship and adoption, or by providing technical defense for adolescent offenders without financial conditions to have particular lawyer. Moreover, it has an advisory function about rights and obligations of children / adolescents and of their parents, besides the access to the Judiciary Power and to the judicial appropriate possible measures.O Núcleo de Estudos e Defesa de Direitos da Infância e da Juventude é um Projeto de extensão das Universidades Estaduais do Paraná. Instituído por convênio entre o Ministério Público e o Governo do Estado do Paraná, por intermédio das Secretarias de Estado da Ciência, Tecnologia e Ensino Superior, da Justiça e do Trabalho e Ação Social, o Instituto de Ação Social do Paraná e o Conselho Estadual dos Direitos da Criança e do Adolescente do Estado do Paraná, Integra o programa Universidade Sem Fronteiras, Subprograma Incubadora dos Direitos Sociais. Seu principal objetivo é proteger os interesses das crianças e dos adolescentes, através da inserção em família substituta, pela guarda, pela tutela ou pela adoção, ou proporcionando defesa técnica para adolescentes infratores, sem condições financeiras para constituir advogado. Ademais, possui uma função consultiva acerca dos direitos e dos deveres das crianças / adolescentes ou dos genitores, além do acesso ao Poder Judiciário e das possíveis medidas judiciais cabíveis

Frequency of fiber-rich food intake and associated factors in a Southern Brazilian population Freqüência do consumo de alimentos fontes de fibras e fatores associados em população do Sul do Brasil

The objective of this study was to verify the frequency of fiber-rich food intake and evaluate its association with socioeconomic, demographic and behavioral characteristics. A city representative sample was selected and 3,993 subjects (> 10 years) were interviewed. The study used the Block Screening Questionnaire. A majority of subjects - 65.6% (95%CI: 64.2-67.1) - presented an inadequate intake frequency. Adjusted analysis for the overall sample showed an increased risk of inadequate frequency among men, adolescents, people of lower socioeconomic levels, current smokers, those insufficiently active and those having fewer than four daily meals. Age group-stratified analysis showed that among adolescents, living alone was a risk factor; for adults, risk factors were sex (male), current smoker, insufficiently active and fewer than four daily meals and; among the elderly they were male and being a current smoker. A lower socioeconomic level was associated to the outcome in all groups. Although the inadequate frequency of intake is very common in this population, teenagers are at a higher risk, pointing to a need for public health actions targeting this particular age group.<br>Verificar a freqüência do consumo de alimentos fontes de fibras e avaliar sua associação com características sócio-econômicas, demográficas e comportamentais. Foi selecionada amostra representativa da cidade e 3.993 indivíduos (> 10 anos) foram entrevistados. Foi utilizado o instrumento Block Screening. A maioria da amostra, 65,6% (IC95%: 64,2-67,1), mostrou freqüência inadequada de consumo. A análise ajustada para amostra global mostrou risco aumentado de freqüência inadequada entre homens, adolescentes, de menor nível sócio-econômico, fumante atual, insuficientemente ativo e aqueles que faziam menos de 4 refeições/dia. A análise por faixa etária mostrou que entre adolescentes, morar sozinho foi um fator de risco; entre adultos, homens, fumantes, insuficientemente ativos e que realizavam menos de 4 refei��ões/dia; e, entre idosos, somente homens e fumantes. O menor nível sócio-econômico associou-se ao desfecho em todos os grupos. Ressalta-se que embora a população apresente alto porcentual do desfecho, chama atenção os adolescentes, sugerindo medidas prioritárias nesta faixa etária

Cross-Talk among Intracellular Signaling Pathways Mediates the Diphenyl Ditelluride Actions on the Hippocampal Cytoskeleton of Young Rats

In the present report, we showed that diphenyl ditelluride (PhTe) 2 induced in vitro hyperphosphorylation of glial fibrillary acidic protein (GFAP), vimentin and neurofilament (NF) subunits in hippocampus of 21 day-old rats. Hyperphosphorylation was dependent on L-voltage dependent Ca 2+ channels (L-VDCC), N-methyl-d-aspartate (NMDA) and metabotropic glutamate receptors, as demonstrated by the specific inhibitors verapamil, DL-AP5 and MCPG, respectively. Also, dantrolene, a ryanodine channel blocker, EGTA and Bapta-AM, extra and intracellular Ca2+ chelators respectively, totally prevented this effect. Activation of metabotropic glutamate receptors by (PhTe)2 upregulates phospholipase C (PLC), producing inositol 1, 4, 5-trisphosphate (IP3) and diacylglycerol (DAG). Therefore, high Ca2+ levels and DAG directly activate Ca 2+/calmodulin-dependent protein kinase (PKCaMII) and protein kinase C (PCK), resulting in the hyperphosphorylation of Ser-57 in the carboxyl-terminal tail domain of the low molecular weight NF subunit (NF-L). Also, the activation of Erk1/2, and p38MAPK resulted in hyperphosphorylation of KSP repeats of the medium molecular weight NF subunit (NF-M). It is noteworthy that PKCaMII and PKC inhibitors prevented (PhTe)2-induced Erk1/2MAPK and p38MAPK activation as well as hyperphosphorylation of KSP repeats on NF-M, suggesting that PKCaMII and PKC could be upstream of this activation. Taken together, our results highlight the role of Ca2+ as a mediator of the (PhTe) 2-elicited signaling targeting specific phosphorylation sites on IF proteins of neural cells of rat hippocampus. Interestingly, this action shows a significant cross-talk among signaling pathways elicited by (PhTe)2, connecting glutamate metabotropic cascade with activation of Ca2+ channels. The extensively phosphorylated amino- and carboxyl- terminal sites could explain, at least in part, the neural dysfunction associated with (PhTe)2 exposure</p

Current Concepts in Pediatric Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

The t(9;22)(q34;q11) or Philadelphia chromosome that creates a BCR-ABL1 fusion gene encoding for a chimeric BCR-ABL1 protein is present in 3-4% of pediatric acute lymphoblastic leukemia (Ph+ ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph+ ALL was associated with a very poor prognosis despite use of intensive chemotherapy and frequently hematopoietic stem cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph+ ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased survival for children with Ph+ ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph+ ALL expanded exponentially through careful mapping of pathways downstream of BCR-ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5 and EBF, the recognition of the complex clonal architecture of Ph+ ALL, and the delineation of genomic, epigenetic and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph+ ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph+ ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies holds great promise to decrease toxicity and improve survival in this high risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high risk leukemias