24 research outputs found

    Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

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    Background Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.info:eu-repo/semantics/publishedVersio

    Telomerase promoter mutations in cancer: an emerging molecular biomarker?

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    João Vinagre, Vasco Pinto and Ricardo Celestino contributed equally to the manuscript.Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the “alternative mechanism of telomere lengthening” (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and non-neoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target

    DNA vaccination for prostate cancer: key concepts and considerations

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    While locally confined prostate cancer is associated with a low five year mortality rate, advanced or metastatic disease remains a major challenge for healthcare professionals to treat and is usually terminal. As such, there is a need for the development of new, efficacious therapies for prostate cancer. Immunotherapy represents a promising approach where the host’s immune system is harnessed to mount an anti-tumour effect, and the licensing of the first prostate cancer specific immunotherapy in 2010 has opened the door for other immunotherapies to gain regulatory approval. Among these strategies DNA vaccines are an attractive option in terms of their ability to elicit a highly specific, potent and wide-sweeping immune response. Several DNA vaccines have been tested for prostate cancer and while they have demonstrated a good safety profile they have faced problems with low efficacy and immunogenicity compared to other immunotherapeutic approaches. This review focuses on the positive aspects of DNA vaccines for prostate cancer that have been assessed in preclinical and clinical trials thus far and examines the key considerations that must be employed to improve the efficacy and immunogenicity of these vaccines

    Comunidade fitoplanctônica de um pesqueiro na cidade de São Paulo Phytoplankton community in a recreational fishing lake, Brazil

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    OBJETIVO: A avaliação da qualidade da água e da comunidade fitoplanctônica em ambientes destinados à recreação permite estabelecer formas de manejo desses sistemas, evitando possíveis problemas à saúde humana. Assim, realizou-se estudo com objetivo de analisar a variação sazonal do fitoplâncton de um sistema lacustre natural, e sua relação com a qualidade da água. MÉTODOS: O lago estudado faz parte de um pesqueiro localizado na zona sul da cidade de São Paulo. Foram realizadas quatro coletas no período de um ano, em três pontos de amostragem. As amostras foram analisadas quanto à composição florística e às variáveis físicas e químicas da água. RESULTADOS: A análise qualitativa do fitoplâncton revelou o total de 91 táxons distribuídos em oito classes: Chlorophyceae (52%), Cyanophyceae (16%), Euglenophyceae (12%), Zygnemaphyceae (10%), Bacillariophyceae (5%), Xantophyceae (3%), Dinophyceae (1%) e Chrysophyceae (1%). Alguns dos parâmetros físicos e químicos parecem ter influenciado o comportamento do fitoplâncton; a classe Chlorophyceae foi a mais favorecida pelas condições ambientais. Dentre as espécies de cianofíceas identificadas, destacaram-se Microcystis paniformis, Cylindrospermopsis raciborskii e espécies de Anabaena, que apresentaram maior importância do ponto de vista sanitário devido à produção de toxinas. CONCLUSÕES: Algumas variáveis físicas e químicas da água interferiram na estrutura da comunidade fitoplanctônica. A presença de Microcystis paniformis, Cylindrospermopsis raciborskii e espécies de Anabaena indicam o potencial tóxico e os possíveis problemas que podem ocorrer à saúde pública, caso esse ambiente não seja continuamente monitorado. Estudos adicionais são recomendados, com a finalidade de se evitar efeitos deletérios ao ambiente e à saúde da população.<br>OBJECTIVE: The assessment of water quality and phytoplankton community in recreational environments allows to setting management programs aiming at preventing potential harm to human health. The purpose of the present study was to describe phytoplankton seasonal changes in a freshwater system and their relation to water quality. METHODS: The recreational fishing lake is located in the southern area of the city of São Paulo, Brazil. Water samples were collected in three previously selected sites in the lake throughout a year and analyzed regarding floristic composition and physical and chemical parameters. RESULTS: The phytoplankton qualitative analysis revealed 91 taxa distributed among eight classes: Chlorophyceae, Cyanophyceae, Euglenophyceae, Zygnemaphyceae, Bacillariophyceae, Xantophyceae, Dinophyceae, and Chrysophyceae. Some physical and chemical parameters seemed to influence phytoplankton community behavior. Chlorophyceae development was favored by local conditions. Among the species of cyanobacteria identified, Microcystis paniformis, Cylindrospermopsis raciborskii, and Anabaena species were the most important due to their ability to produce toxins, posing a high risk to public health. CONCLUSIONS: Some physical and chemical parameters had an impact on the structure of phytoplankton community. The presence of Microcystis paniformis, Cylindrospermopsis raciborskii and Anabaena species indicates toxic potential and likelihood of public health problems unless there is constant monitoring. Further studies are recommended to prevent hazardous effects to the environment and public health
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