Transient disappearance of RAS mutant clones in plasma: A counterintuitive clinical use of EGFR inhibitors in RAS mutant metastatic colorectal cancer

Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more recently reported in some patients with primary RAS mutant cancers, supporting for the first time an unexpected negative selection of RAS mutations during the clonal evolution of mCRC. To date, the extent of conversion to RAS wild type disease at the time of progression has not been clarified yet. As a proof of concept, we prospectively enrolled mCRC patients progressing under anti-VEGF based treatments. Idylla™system was used to screen RAS mutations in plasma and the wild type status of RAS was further confirmed through IT-PGM (Ion Torrent Personal Genome Machine) sequencing. RAS was found mutant in 55% of cases, retaining the same plasma mutation as in the primary tumor at diagnosis, while it was found wild-type in 45%. Four patients testing negative for RAS mutations in plasma at the time of progression of disease (PD) were considered eligible for treatment with EGFR inhibitors and treated accordingly, achieving a clinical benefit. We here propose a hypothetical algorithm that accounts for the transient disappearance of RAS mutant clones over time, which might extend the continuum of care of mutant RAS colorectal cancer patients through the delivery of a further line of therapy

Circulating Tumor Cells Identify Patients with Super-High-Risk Non-Muscle-Invasive Bladder Cancer: Updated Outcome Analysis of a Prospective Single-Center Trial

Clinical behavior of non-muscle-invasive bladder cancer (NMIBC) is largely unpredictable, and even patients treated according to European Association of Urology recommendations have a heterogeneous prognosis. High-grade T1 (HGT1) bladder cancer is the highest-risk subtype of NMIBC, with an almost 40% rate of recurrence and 20% of progression at 5 years. Nomograms predicting risk of recurrence, progression, and cancer-specific survival (CSS) are not available specifically within HGT1 bladder cancer, and the identification of robust prognostic biomarkers to better guide therapeutic strategies in this subgroup of patients is of paramount importance. Strategies to identify putative biomarkers in liquid biopsies from blood and urine collected from patients with bladder cancer have been intensively studied in the last few years

PERCEPÇÃO DOS SERVIDORES TÉCNICO-ADMINISTRATIVOS DA UNIOESTE CAMPUS DE CASCAVEL EM RELAÇÃO A POLÍTICA DE AUXÍLIO FINANCEIRO PARA QUALIFICAÇÃO

Este artigo tem por objetivo analisar a percepção dos servidores da Unioeste Campus de Cascavel em relação a Política de Auxílio Financeiro para Qualificação e Capacitação. Trata-se de analisar junto aos servidores que buscaram a qualificação em cursos de pós-graduação lato sensu, se a política proporcionou motivação e mudanças na realização de seus trabalhos na instituição. O trabalho é caracterizado como um estudo de caso, onde utilizou-se como instrumento de coleta de dados para a realização da pesquisa, um questionário com 15 (quinze) perguntas, 14 fechadas e 1 aberta. Verifica-se que 79% dos entrevistados responderam que se sentiram motivados à fazer o curso de pós-graduação em virtude de terem recebido auxílio financeiro através da política, e 92% dos servidores entrevistados responderam que durante e após a conclusão do curso, se sentiram mais motivados para a realização das atividades no trabalho. Conclui-se que a política teve uma avaliação positiva quanto aos cumprimentos de seus objetivos, motivando os servidores da instituição na busca de qualificação e motivando-os nas suas atividades do dia-a-dia na instituição

Gerenciamento do Capital Intelectual em Instituições de Ensino Superior: Um Estudo de Caso

O capital intelectual se baseia no conhecimento que o ser humano adquire ao longo de sua vida, habilidades da empresa nos seus processos, valorização da marca entre outros. Este estudo tem como objetivo demonstrar indicadores para gerenciamento do capital intelectual de uma faculdade particular sem fins lucrativos. Inicialmente é feita uma abordagem teórica e em seguida apresentam-se os indicadores levantados para o gerenciamento do capital intelectual utilizando o modelo de Edvinsson e Malone separando os indicadores em cinco (5) focos - financeiro, clientes, processo, renovação e desenvolvimento e humano. A metodologia utilizada no estudo foi bibliográfica, exploratório e estudo de caso na faculdade Uni Z , através do modelo de Edvinsson e Malone utilizou-se o foco financeiro, clientes, processo, renovação e desenvolvimento e humano, estes dados foram coletados nos departamentos de contabilidade, recursos humanos, secretaria acadêmica e ainda, as demonstrações contábeis de 2003/2004. Finalizado com análise dos indicadores levantados na faculdade e considerações finais sobre o estudo capital intelectual

ANÁLISE LONGITUDINAL DO PERFIL SOCIOEDUCACIONAL DOS CANDIDATOS DO VESTIBULAR DE UMA UNIVERSIDADE PÚBLICA DO PARANÁ

O presente estudo teve por objetivo identificar o perfil do candidato ao processo seletivo de vestibular em relação a todos os campi ofertado pela instituição de ensino de estudo, para o alcance deste proposto foi realizada uma pesquisa de caráter quantitativo, exploratório e longitudinal, pesquisa bibliográfica e análise documental com base na população dos candidatos. Com base nos dados coletados, excluindo as exceções, pode-se observar que os inscritos independentemente do campus escolhido possuem um perfil comum, em maioria possuem: renda familiar de 1 a 10 salários mínimos, com até 20 anos, maior número do público é feminino, declaram-se brancos e que concluíram seus estudos em escola pública. Ao concluir que o público é semelhante independentemente do campus escolhido, infere-se que as estratégias para abordarem estes acadêmicos possam ser as mesmas, o que facilita o processo estratégico. Conhecendo-se o perfil do candidato, este serve como ferramenta para a tomada de decisão

Ribosomal stress activates eEF2K-eEF2 pathway causing translation elongation inhibition and recruitment of Terminal Oligopyrimidine (TOP) mRNAs on polysomes

The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes

Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53

Many chemotherapeutic drugs cause nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that ribosomal stress induced by Actinomycin D (Act D) is associated to the up-regulation of ribosomal protein L3 (rpL3) and its accumulation as ribosome-free form in lung and colon cancer cell lines devoid of p53. Free rpL3 regulates p21 expression at transcriptional and post-translational levels through a molecular mechanism involving extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2). Our data reveal that rpL3 participates to cell response acting as a critical regulator of apoptosis and cell migration. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of Act D suggesting that the loss of rpL3 makes chemotherapy drugs ineffective while rpL3 overexpression was associated to a strong increase of Act D-mediated inhibition of cell migration. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status revealing new specific targets involved in the molecular pathways activated by Act D in cancers lacking of p53. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancers

CPEB1 restrains proliferation of Glioblastoma cells through the regulation of p27(Kip1) mRNA translation

The cytoplasmic element binding protein 1 (CPEB1) regulates many important biological processes ranging from cell cycle control to learning and memory formation, by controlling mRNA translation efficiency via 3' untranslated regions (3'UTR). In the present study, we show that CPEB1 is significantly downregulated in human Glioblastoma Multiforme (GBM) tissues and that the restoration of its expression impairs glioma cell lines growth. We demonstrate that CPEB1 promotes the expression of the cell cycle inhibitor p27(Kip1) by specifically targeting its 3'UTR, and competes with miR-221/222 binding at an overlapping site in the 3'UTR, thus impairing miR-221/222 inhibitory activity. Upon binding to p27(Kip1) 3'UTR, CPEB1 promotes elongation of poly-A tail and the subsequent translation of p27(Kip1) mRNA. This leads to higher levels of p27(Kip1) in the cell, in turn significantly inhibiting cell proliferation, and confers to CPEB1 a potential value as a tumor suppressor in Glioblastoma

Impairing the production of ribosomal RNA activates mammalian target of rapamycin complex 1 signalling and downstream translation factors

Ribosome biogenesis is a key process for maintaining protein synthetic capacity in dividing or growing cells, and requires coordinated production of ribosomal proteins and ribosomal RNA (rRNA), including the processing of the latter. Signalling through mammalian target of rapamycin complex 1 (mTORC1) activates all these processes. Here, we show that, in human cells, impaired rRNA processing, caused by expressing an interfering mutant of BOP1 or by knocking down components of the PeBoW complex elicits activation of mTORC1 signalling. This leads to enhanced phosphorylation of its substrates S6K1 and 4E-BP1, and stimulation of proteins involved in translation initiation and elongation. In particular, we observe both inactivation and downregulation of the eukaryotic elongation factor 2 kinase, which normally inhibits translation elongation. The latter effect involves decreased expression of the eEF2K mRNA. The mRNAs for ribosomal proteins, whose translation is positively regulated by mTORC1 signalling, also remain associated with ribosomes. Therefore, our data demonstrate that disrupting rRNA production activates mTORC1 signalling to enhance the efficiency of the translational machinery, likely to help compensate for impaired ribosome production

Grammatical and funcional aspects of courtroom questioning

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Comunicação e ExpressãoEste estudo baseia-se na análise do depoimento de um réu sob julgamento criminalal em um tribunal britânico. A análise diz respeito ao padrão de pergunta-resposta utilizado pela defesa e acusação para convencer o júri de sua versão da estória. Neste caso, o interrogatório é conduzido pela defesa e a inquirição pela acusação. Com base em estudos lingüísticos, classificam-se as formas com função de pergunta, tanto no interrogatório, quanto na inquirição. Em seguida, analisa-se o modo como estas perguntas foram usadas pelos dois advogados e discutem-se algumas das estratégias empregadas pelos advogados, bem como o papel desempenhado pelas perguntas em tais estratégias. Os resultados demonstram que o interrogatório é desenvolvido de maneira cooperativa, já que advogado e réu contróem, conjuntamente, sua versão da estória em uma seqüência coerente. Visto que cabe à acusação provar a culpa, na inquirição analisada neste estudo, o promotor utiliza-se de perguntas para formular, progressivamente, uma acusação contra o réu. Os resultados sugerem que as estruturas das perguntas selecionadas pelos advogados são importantes no controle de informação durante o interrogatório nos julgamentos. No entanto, além de escolher cuidadosamente o tipo de pergunta, de modo a elicitar a resposta esperada, os advogados utilizam essas perguntas estrategicamente para influenciar o júri. Abstract : This study concentrates on the analysis of the evidence of a defendant in a criminal trial in the British legal system in terms of the pattern of question-answer employed by defense and prosecution counsels to convince the jury of their side of the story. Direct examination is conducted by the defense counsel and cross-examination is conducted by the prosecution. Based on linguistic studies, I classify the forms functioning as questions in both direct and cross-examination. Next, I analyse how these questions are used by each counsel, and I discuss some of the strategies used by the counsels and the role questions play in such strategies. Results show that direct examination is conducted in a supportive mode, in that counsel and defendant build together their version of the story in a coherent sequence. Because the burden of proof lies with the prosecution, in the cross-examination investigated in this study, the prosecution counsel uses questions so as to progressively build an accusation against the defendant. The study suggests that the forms of questions selected by counsels are important in the management of information in courtroom questioning. However, apart from carefully choosing the kind of question to ask, so as to elicit the response expected, counsels also use those questions in a strategic way for the benefit of the jury