Cronología y tecnología en el Parque Nacional Perito Moreno (PNPM): ¿continuidad o reemplazos?

Fil: Aschero, Carlos A.. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Bellelli, Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Civalero de Biset, María Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.FIl: Goñi, Rafael A.. Instituto Nacional de Antropología; Argentina.FIl: Goñi, Rafael A.. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina.Fil: Guráieb, Ana Gabriela. Universidad de Buenos Aires. Facultad de Filosofía y Letras; Argentina.FIl: Molinari, Roberto L..Administración Nacional de Parque Nacionales; Argentina.Incluye mapa y gráficos.25 ref

Influence of miR-10b on proliferation and the invasive potential of osteosarcoma

O Osteossarcoma (OS) é o tumor ósseo pediátrico mais comum. O tratamento atual consiste em remoção cirúrgica e quimioterapia multimodal neo- e adjuvante. No entanto, um terço dos pacientes são acometidos por recorrência pós-cirúrgica e metástases distantes sendo que apenas 20% daqueles com metástase sobrevivem após 5 anos. Diversos miRNAs vêm sendo apontados como metastamiRs, dentre eles o miR-10b. Este microRNA encontra-se hiperexpresso em uma série de tumores e associado a pior prognóstico. Estudos prévios têm demostrado que o miR-10b atua nos processos invasivos principalmente pareando-se de forma incompleta com o RNA mensageiro do gene HOXD10 e assim inibindo a sua tradução. Este fator de transcrição, assim como todos os membros da família dos genes HOX, exerce sua função ativando e reprimindo genes vitais para os processos de crescimento e diferenciação celular (inclusive durante o desenvolvimento do tecido ósseo), sendo também descrito como desregulado em diversos tumores. Em vista disso, o presente trabalho teve como objetivo estudar a influência do miR-10b no OS e sua associação com o gene HOXD10 em relação aos processos de proliferação, invasão e migração celular. Para tanto, foi avaliada a expressão de ambos em amostras tumorais, bem como os efeitos da modulação da expressão de miR-10b na capacidade proliferativa e invasiva de linhagens celulares de OS. Nossos resultados mostraram uma associação inversa entre os níveis de expressão do miR-10b e o grau de malignidade. O aumento de miR-10b in vitro levou a supressão da capacidade clonogênica e à redução dos processos de adesão, migração e invasão, sugerindo um papel de supressor tumoral em OS. Não foi encontrada correlação entre a expressão gênica do miR-10b e a do HOXD10, e ainda o aumento deste microRNA não alterou a expressão proteica do fator de transcrição. Sendo assim, o mecanismo pelo qual miR-10b contribui para a agressividade do OS permanece indefinido, mas parece ser independente de HOXD10. Paralelamente, a expressão do gene KLF4 (recentemente descrito como alvo direto de miR-10b) e de genes sabidamente associados à invasão (MMP2 e ROCK1) e proliferação (TP53 e BCL2) tampouco foi afetada após transfecção. Por outro lado, apesar de não ter sido confirmado como alvo de miR-10b no nosso estudo, HOXD10 foi encontrado significativamente hiperexpresso nas amostras de OS. Assim, considerando a importância da desregulação de vias de desenvolvimento no surgimento de tumores pediátricos e a participação do HOXD10 no desenvolvimento ósseo, o seu papel como oncogene e seu potencial como alvo terapêutico neste tipo tumoral merecem estudos posteriores.Osteosarcoma (OS) is the most common pediatric bone tumor. The current treatment consists of surgical removal and neo- and adjuvant multimodal chemotherapy. Nonetheless, one-third of patients are affected by post-surgical recurrence and distant metastases, with only 20% of metastatic cases surviving after 5 years. Several miRNAs have been designated as metastamiRs, among them miR-10b. This microRNA is overexpressed in a series of tumors and associated with poor prognosis. Previous studies have shown that miR-10b acts on invasive processes mainly by pairing with the messenger RNA of the HOXD10 and thereby inhibiting its translation. This transcription factor, like all members of the HOX family, exerts its function by activating and/or repressing vital genes for cell growth and differentiation (even during the development of bone tissue) and is also described as deregulated in several tumors. In view of this, the aim of this work was to study the influence of miR-10b on OS and its association with the HOXD10 in relation to proliferation, invasion and cell migration. For this, the expression of both genes in tumor samples, as well as the effects of miR-10b expression modulation on the proliferative and invasive capacity of OS cell lines, were evaluated. Our results showed an inverse association between miR-10b expression levels and the degree of malignancy. The increase of miR-10b in vitro led to the suppression of clonogenic capacity and reduction of adhesion, migration and invasion, suggesting a role as a tumor suppressor in OS. No correlation was found between the gene expression of miR-10b and HOXD10, while the increase of the microRNA did not alter the protein levels of the transcription factor. Thus, the mechanism by which miR- 10b could contribute to OS aggressiveness remains undefined, though it appears to be independent of HOXD10. In parallel, the expression of KLF4 (recently described as a direct miR-10b target) and of genes known to be associated with invasion (MMP2 and ROCK1) and proliferation (TP53 and BCL2) was not affected after transfection. On the other hand, although HOXD10 was not confirmed as a miR-10b target in our study, this gene was found to be significantly overexpressed in the OS samples. Thus, considering the importance of the deregulation of developmental pathways on pediatric tumors and HOXD10 contribution on bone development, its role as an oncogene and its potential as a therapeutic target in this tumor type deserves further studies

MiRNA Dysregulation in Childhood Hematological Cancer

For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors

In vitro targeting of Polo-like kinase 1 in bladder carcinoma: Comparative effects of four potent inhibitors

Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and preclinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs. © 2013 Landes Bioscience

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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