PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia

The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy6151310513118CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação08/10034–

Chronic activation of γ2 AMPK induces obesity and reduces β cell function

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease23582183

A study about the acquisition and the audio's process of the chorus mixed, adults, poliphonics and not professional at Sao Paulo and others cities closes

Orientador: José Eduardo Ribeiro de PaivaDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de ArtesResumo: Este trabalho trata da tecnologia aplicada em produções de áudio em estúdios com corais mistos, polifônicos, amadores e adultos, tendo a cidade de São Paulo e cidades adjacentes como referências. Apresenta como objetivo central prover material de pesquisa capaz de auxiliar o regente coral em performances no estúdio, entendendo qual deve ser a capacitação deste para esta função dentro do ambiente controlado de gravação e, como objetivo secundário, apurar as etapas para a produção de um registro de áudio em estúdio. Trata-se de um trabalho direcionado a regentes que atuam à frente de coros mistos, polifônicos e adultos de natureza amadora (SATB) que pretendem submeter seu coro a uma performance de música gravada. Após uma reflexão introdutória, são apresentados o papel do coro e a função do regente, etapas do processo de gravação, bem como um levantamento acerca dos avanços tecnológicos no processo de captação e edição de áudio, analisando seus desdobramentos na relação entre regentes, coralistas e ouvintes. Na sequência, há o material compilado dos corais que, ao longo de sua carreira, registraram em áudio momentos da sua produção artística e a transcrição dos depoimentos recolhidos durante a execução deste projeto, findando com a análise do material coletadoAbstract: This work deals with the technology applied in audio productions in mixed coral, polyphonic, amateur and adult studios, with the city of São Paulo and adjacent cities as references. Its main objective is to provide research material capable of assisting the choir conductor in studio performances, understanding what should be his qualification for this function within the controlled recording environment and, as a secondary objective, to ascertain the steps for producing a record. Audio studio. It is a work directed to conductors who perform mixed, polyphonic and amateur adult (SATB) choirs who intend to subject their choir to a performance of recorded music. After an introductory reflection, we present the role of the choir and the function of the conductor, stages of the recording process, as well as a survey of the technological advances in the process of capturing and editing audio, analyzing their developments in the relationship between conductors, choralists and listeners. Following, there is the compiled material of the choirs that, throughout their career, recorded audio moments of their artistic production and the transcription of the statements collected during the execution of this project, ending with the analysis of the collected materialMestradoMúsica, Teoria, Criação e PráticaMestra em Músic

Oropouche virus infection and pathogenesis are restricted by MAVS, IRF-3, IRF-7, and type i interferon signaling pathways in nonmyeloid cells

Oropouche virus (OROV) is a member of the Orthobunyavirus genus in the Bunyaviridae family and a prominent cause of insect-transmitted viral disease in Central and South America. Despite its clinical relevance, little is known about OROV pathogenesis. To define the host defense pathways that control OROV infection and disease, we evaluated OROV pathogenesis and immune responses in primary cells and mice that were deficient in the RIG-I-like receptor signaling pathway (MDA5, RIG-I, or MAVS), downstream regulatory transcription factors (IRF-3 or IRF-7), beta interferon (IFN-β), or the receptor for type I IFN signaling (IFNAR). OROV replicated to higher levels in primary fibroblasts and dendritic cells lacking MAVS signaling, the transcription factors IRF-3 and IRF-7, or IFNAR than in wild-type (WT) cells. In mice, deletion of IFNAR, MAVS, or IRF-3 and IRF-7 resulted in uncontrolled OROV replication, hypercytokinemia, extensive liver damage, and death, whereas WT congenic animals failed to develop disease. Unexpectedly, mice with a selective deletion of IFNAR on myeloid cells (CD11c Cre+ Ifnar f/f or LysM Cre+ Ifnar f/f) did not sustain enhanced disease with OROV or a selective (flox/flox) deletion La Crosse virus, a closely related encephalitic orthobunyavirus. In bone marrow chimera studies, recipient irradiated Ifnar −/− mice reconstituted with WT hematopoietic cells sustained high levels of OROV replication and liver damage, whereas WT mice reconstituted with Ifnar −/− bone marrow were resistant to disease. Collectively, these results establish a dominant protective role for MAVS, IRF-3 and IRF-7, and IFNAR in restricting OROV infection and tissue injury and suggest that IFN signaling in nonmyeloid cells contributes to the host defense against orthobunyaviruses89947204737CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ246513/2012-

Anemia should not be the reason for consideration of heavy menstrual bleeding

sem informação69121526152

Variantes no gene da interleucina 8 e a resposta a broncodilatadores inalatórios na fibrose cística

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOInterleukin 8 protein promotes inflammatory responses, even in airways. The presence of interleukin 8 gene variants causes altered inflammatory responses and possibly varied responses to inhaled bronchodilators. Thus, this study analyzed the interleukin 8936639648FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO2011/129392011/18845-12015/12183-82015/12858-52013/19052-

Survival of elderly outpatients: effects of frailty, multimorbidity and disability

sem informaçãoO objetivo deste estudo foi analisar o impacto da fragilidade, da multimorbidade e da incapacidade funcional na sobrevida de idosos assistidos em ambulatório de geriatria e identificar os fatores clínicos de risco associados ao óbito. Estudo longitudinal,241137146sem informaçãosem informaçãosem informaçã

Estimating species diversity and distribution in the era of Big Data: to what extent can we trust public databases?

Massive digitalization of natural history collections is now leading to a steep accumulation of publicly available species distribution data. However, taxonomic errors and geographical uncertainty of species occurrence records are now acknowledged by the scientific community - putting into question to what extent such data can be used to unveil correct patterns of biodiversity and distribution. We explore this question through quantitative and qualitative analyses of uncleaned versus manually verified datasets of species distribution records across different spatial scales. The American tropics. As test case we used the plant tribe Cinchoneae (Rubiaceae). We compiled four datasets of species occurrences: one created manually and verified through classical taxonomic work, and the rest derived from GBIF under different cleaning and filling schemes. We used new bioinformatic tools to code species into grids, ecoregions, and biomes following WWF's classification. We analysed species richness and altitudinal ranges of the species. Altitudinal ranges for species and genera were correctly inferred even without manual data cleaning and filling. However, erroneous records affected spatial patterns of species richness. They led to an overestimation of species richness in certain areas outside the centres of diversity in the clade. The location of many of these areas comprised the geographical midpoint of countries and political subdivisions, assigned long after the specimens had been collected.Open databases and integrative bioinformatic tools allow a rapid approximation of large-scale patterns of biodiversity across space and altitudinal ranges. We found that geographic inaccuracy affects diversity patterns more than taxonomic uncertainties, often leading to false positives, i.e. overestimating species richness in relatively species poor regions. Public databases for species distribution are valuable and should be more explored, but under scrutiny and validation by taxonomic experts. We suggest that database managers implement easy ways of community feedback on data quality248973984Carlsberg Foundation; Faculty of Science, University of Copenhagen; European Research Council (ERC); Swedish Research Council; Wallenberg Foundatio

The role of grandparents of children with cancer in the hospital

Orientador: Ana Márcia Chiaradia Mendes-CastilloDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de EnfermagemResumo: Diante do aumento da expectativa de vida e dos relacionamentos intergeracionais, os avós exercem papel relevante na família. Em momentos de doença, eles são descritos como a retaguarda, estando sempre à disposição e ajudando em tudo que podem; porém, sua experiência é pouco considerada pelos profissionais de saúde. Os avós de crianças com câncer relatam sofrimento multiplicado e emudecido, impactando em sua saúde e qualidade de vida e também na possibilidade de desenvolverem seu papel da forma como gostariam. O objetivo deste estudo é compreender o papel dos avós das crianças com câncer quando estas estão hospitalizadas. Trata-se de um estudo qualitativo, em que foram entrevistados onze avós de crianças com câncer em tratamento oncológico no Centro Infantil Boldrini. Os participantes foram abordados por meio de entrevistas semiestruturadas e os dados foram analisados a partir do Modelo Híbrido de Análise Temática, tendo, por modelo teórico, o Modelo do Bom Pai. Foram encontrados seis temas para descrever a função dos avós neste contexto: Ser o alicerce da família; Transmitir amor para o meu filho e meu neto; Estar presente para o meu filho e meu neto; Oferecer suporte espiritual para o meu filho e meu neto; Lutar para conseguir manejar os próprios sentimentos; Equilibrar as demandas da hospitalização com os recursos disponíveis. A partir da compreensão do papel de avô quando o neto com câncer está hospitalizado, foram discutidas possíveis intervenções que tenham como propósito auxiliar esses familiares no enfrentamento da doença do neto e no desempenho de seu papelAbstract: In the face of increased life expectancy and intergenerational relationships, grandparents play an important role in the family. In times of illness, they are described as the rear, always being at their disposal and helping in all they can; however, their experience is seldom considered by health professionals. The grandparents of children with cancer report multiplied and muted suffering, impacting on their health and quality of life and also on the possibility of developing their role. The purpose of this study is to understand the role of grandparents of children with cancer when they are hospitalized. This is a qualitative study, in which eleven grandparents of children with cancer - diagnosed and / or oncological treatment were interviewed at Boldrini Children's Center. Participants were approached through semi-structured interviews and the data was analyzed through the Hybrid Thematic Analysis Model. The Good Parent Tool was used as a theoretical model. Six themes were found to describe the role of the grandparents in this context: Being the bedrock of the family; Conveying love to my son and my grandchild; Being there for my son and my grandchild; Offering spiritual support to my son and my grandchild; Fighting to manage my own feelings; Balancing the demands of hospitalization with available resources. From the understanding of the role of the grandparents when the grandchild with cancer is hospitalized, interventions were discussed that have the purpose to help these relatives in coping with the disease of the grandchild and in performing their roleMestradoCuidado e Inovação Tecnológica em Saúde e EnfermagemMestra em Ciências da Saúd

Comparisons between low-intensity resistance training with blood flow restriction and high-intensity resistance training on quadriceps muscle mass and strength in elderly

Comparisons between low-intensity resistance training with blood flow restriction and high-intensity resistance training on quadriceps muscle mass and strength in elderly. J Strength Cond Res 29(4): 1071-1076, 2015-High-intensity resistance training (HRT) has been recommended to offset age-related loss in muscle strength and mass. However, part of the elderly population is often unable to exercise at high intensities. Alternatively, lowintensity resistance training with blood flow restriction (LRTBFR) has emerged. The purpose of this study was to compare the effects of LRT-BFR and HRT on quadriceps muscle strength and mass in elderly. Twenty-three elderly individuals, 14 men and 9 women (age, 64.04 +/- 3.81 years; weight, 72.55 +/- 16.52 kg; height, 163 +/- 11 cm), undertook 12 weeks of training. Subjects were ranked according to their pretraining quadriceps cross-sectional area (CSA) values and then randomly allocated into one of the following groups: (a) control group, (b) HRT: 4 x 10 repetitions, 70-80% one repetition maximum (1RM), and (c) LRT-BFR: 4 sets (1 x 30 and 3 x 15 repetitions), 20-30% 1RM. The occlusion pressure was set at 50% of maximum tibial arterial pressure and sustained during the whole training session. Leg press 1RM and quadriceps CSA were evaluated at before and after training. A mixed-model analysis was performed, and the significance level was set at p <= 0.05. Both training regimes were effective in increasing pre-to post-training leg press 1RM (HRT:; similar to 54%, p < 0.001; LRT-BFR:; similar to 17%, p = 0.067) and quadriceps CSA (HRT: 7.9%, p < 0.001; LRT-BFR: 6.6%, p < 0.001); however, HRT seems to induce greater strength gains. In summary, LRT-BFR constitutes an important surrogate approach to HRT as an effective training method to induce gains in muscle strength and mass in elderly.2941071107